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- Philos Trans R Soc Lond B Biol Sci
- v.365(1537); 2010 Jan 12
The therapeutic potential of stem cells
In recent years, there has been an explosion of interest in stem cells, not just within the scientific and medical communities but also among politicians, religious groups and ethicists. Here, we summarize the different types of stem cells that have been described: their origins in embryonic and adult tissues and their differentiation potential in vivo and in culture. We review some current clinical applications of stem cells, highlighting the problems encountered when going from proof-of-principle in the laboratory to widespread clinical practice. While some of the key genetic and epigenetic factors that determine stem cell properties have been identified, there is still much to be learned about how these factors interact. There is a growing realization of the importance of environmental factors in regulating stem cell behaviour and this is being explored by imaging stem cells in vivo and recreating artificial niches in vitro . New therapies, based on stem cell transplantation or endogenous stem cells, are emerging areas, as is drug discovery based on patient-specific pluripotent cells and cancer stem cells. What makes stem cell research so exciting is its tremendous potential to benefit human health and the opportunities for interdisciplinary research that it presents.
1. Introduction: what are stem cells?
The human body comprises over 200 different cell types that are organized into tissues and organs to provide all the functions required for viability and reproduction. Historically, biologists have been interested primarily in the events that occur prior to birth. The second half of the twentieth century was a golden era for developmental biology, since the key regulatory pathways that control specification and morphogenesis of tissues were defined at the molecular level ( Arias 2008 ). The origins of stem cell research lie in a desire to understand how tissues are maintained in adult life, rather than how different cell types arise in the embryo. An interest in adult tissues fell, historically, within the remit of pathologists and thus tended to be considered in the context of disease, particularly cancer.
It was appreciated long ago that within a given tissue there is cellular heterogeneity: in some tissues, such as the blood, skin and intestinal epithelium, the differentiated cells have a short lifespan and are unable to self-renew. This led to the concept that such tissues are maintained by stem cells, defined as cells with extensive renewal capacity and the ability to generate daughter cells that undergo further differentiation ( Lajtha 1979 ). Such cells generate only the differentiated lineages appropriate for the tissue in which they reside and are thus referred to as multipotent or unipotent ( figure 1 ).
Origin of stem cells. Cells are described as pluripotent if they can form all the cell types of the adult organism. If, in addition, they can form the extraembryonic tissues of the embryo, they are described as totipotent. Multipotent stem cells have the ability to form all the differentiated cell types of a given tissue. In some cases, a tissue contains only one differentiated lineage and the stem cells that maintain the lineage are described as unipotent . Postnatal spermatogonial stem cells, which are unipotent in vivo but pluripotent in culture, are not shown ( Jaenisch & Young 2008 ). CNS, central nervous system; ICM, inner cell mass.
In the early days of stem cell research, a distinction was generally made between three types of tissue: those, such as epidermis, with rapid turnover of differentiated cells; those, such as brain, in which there appeared to be no self-renewal; and those, such as liver, in which cells divided to give two daughter cells that were functionally equivalent ( Leblond 1964 ; Hall & Watt 1989 ). While it remains true that different adult tissues differ in terms of the proportion of proliferative cells and the nature of the differentiation compartment, in recent years it has become apparent that some tissues that appeared to lack self-renewal ability do indeed contain stem cells ( Zhao et al . 2008 ) and others contain a previously unrecognized cellular heterogeneity ( Zaret & Grompe 2008 ). That is not to say that all tissues are maintained by stem cells; for example, in the pancreas, there is evidence against the existence of a distinct stem cell compartment ( Dor et al . 2004 ).
One reason why it took so long for stem cells to become a well-established research field is that in the early years too much time and energy were expended in trying to define stem cells and in arguing about whether or not a particular cell was truly a stem cell ( Watt 1999 ). Additional putative characteristics of stem cells, such as rarity, capacity for asymmetric division or tendency to divide infrequently, were incorporated into the definition, so that if a cell did not exhibit these additional properties it tended to be excluded from the stem cell ‘list’. Some researchers still remain anxious about the definitions and try to hedge their bets by describing a cell as a stem/progenitor cell. However, this is not useful. The use of the term progenitor, or transit amplifying, cell should be reserved for a cell that has left the stem cell compartment but still retains the ability to undergo cell division and further differentiation ( Potten & Loeffler 2008 ).
Looking back at some of the early collections of reviews written as the proceedings of stem cell conferences, one regularly finds articles on the topic of cancer stem cells ( McCulloch et al . 1988 ). However, these cells have only recently received widespread attention ( Reya et al . 2001 ; Clarke et al . 2006 ; Dick 2008 ). The concept is very similar to the concept of normal tissue stem cells, namely that cells in tumours are heterogeneous, with only some, the cancer stem cells, or tumour initiating cells, being capable of tumour maintenance or regrowth following chemotherapy. The cancer stem cell concept is important because it suggests new approaches to anti-cancer therapies ( figure 2 ).
The cancer stem cell hypothesis. The upper tumour is shown as comprising a uniform population of cells, while the lower tumour contains both cancer stem cells and more differentiated cells. Successful or unsuccessful chemotherapy is interpreted according to the behaviour of cells within the tumour.
As in the case of tissue stem cells, it is important that cancer stem cell research is not sidetracked by arguments about definitions. It is quite likely that in some tumours all the cells are functionally equivalent, and there is no doubt that tumour cells, like normal stem cells, can behave differently under different assay conditions ( Quintana et al . 2008 ). The oncogene dogma ( Hahn & Weinberg 2002 ), that tumours arise through step-wise accumulation of oncogenic mutations, does not adequately account for cellular heterogeneity, and markers of stem cells in specific cancers have already been described ( Singh et al . 2004 ; Barabé et al . 2007 ; O'Brien et al . 2007 ). While the (rediscovered) cancer stem cell field is currently in its infancy, it is already evident that a cancer stem cell is not necessarily a normal stem cell that has acquired oncogenic mutations. Indeed, there is experimental evidence that cancer initiating cells can be genetically altered progenitor cells ( Clarke et al . 2006 ).
In addition to adult tissue stem cells, stem cells can be isolated from pre-implantation mouse and human embryos and maintained in culture as undifferentiated cells ( figure 1 ). Such embryonic stem (ES) cells have the ability to generate all the differentiated cells of the adult and are thus described as being pluripotent ( figure 1 ). Mouse ES cells are derived from the inner cell mass of the blastocyst, and following their discovery in 1981 ( Evans & Kaufman 1981 ; Martin 1981 ) have been used for gene targeting, revolutionizing the field of mouse genetics. In 1998, it was first reported that stem cells could be derived from human blastocysts ( Thomson et al . 1998 ), opening up great opportunities for stem cell-based therapies, but also provoking controversy because the cells are derived from ‘spare’ in vitro fertilization embryos that have the potential to produce a human being. It is interesting to note that, just as research on adult tissue stem cells is intimately linked to research on disease states, particularly cancer, the same is true for ES cells. Many years before the development of ES cells, the in vitro differentiation of cells derived from teratocarcinomas, known as embryonal carcinoma cells, provided an important model for studying lineage selection ( Andrews et al . 2005 ).
Blastocysts are not the only source of pluripotent ES cells ( figure 1 ). Pluripotent epiblast stem cells, known as epiSC, can be derived from the post-implantation epiblast of mouse embryos ( Brons et al . 2007 ; Tesar et al . 2007 ). Recent gene expression profiling studies suggest that human ES cells are more similar to epiSC than to mouse ES cells ( Tesar et al . 2007 ). Pluripotent stem cells can also be derived from primordial germ cells (EG cells), progenitors of adult gametes, which diverge from the somatic lineage at late embryonic to early foetal development ( Kerr et al . 2006 ).
Although in the past the tendency has been to describe ES cells as pluripotent and adult stem cells as having a more restricted range of differentiation options, adult cells can, in some circumstances, produce progeny that differentiate across the three primary germ layers (ectoderm, mesoderm and endoderm). Adult cells can be reprogrammed to a pluripotent state by transfer of the adult nucleus into the cytoplasm of an oocyte ( Gurdon et al . 1958 ; Gurdon & Melton 2008 ) or by fusion with a pluripotent cell ( Miller & Ruddle 1976 ). The most famous example of cloning by transfer of a somatic nucleus into an oocyte is the creation of Dolly the sheep ( Wilmut et al . 1997 ). While the process remains inefficient, it has found some unexpected applications, such as cloning endangered species and domestic pets.
A flurry of reports almost 10 years ago suggested that adult cells from many tissues could differentiate into other cell types if placed in a new tissue environment. Such studies are now largely discredited, although there are still some bona fide examples of transdifferentiation of adult cells, such as occurs when blood cells fuse with hepatocytes during repair of damaged liver ( Anderson et al . 2001 ; Jaenisch & Young 2008 ). In addition, it has been known for many years that adult urodele amphibians can regenerate limbs or the eye lens following injury; this involves dedifferentiation and subsequent transdifferentiation steps ( Brockes & Kumar 2005 ).
The early studies involving somatic nuclear transfer indicated that adult cells can be reprogrammed to pluripotency. However, the mechanistic and practical applications of inducing pluripotency in adult cells have only become apparent in the last 2 or 3 years, with the emergence of a new research area: induced pluripotent stem cells (iPS cells). The original report demonstrated that retrovirus-mediated transduction of mouse fibroblasts with four transcription factors (Oct-3/4, Sox2, KLF4 and c-Myc; figure 1 ) that are highly expressed in ES cells could induce the fibroblasts to become pluripotent ( Takahashi & Yamanaka 2006 ). Since then, rapid progress has been made: iPS cells can be generated from adult human cells ( Takahashi et al . 2007 ; Yu et al . 2007 ; Park et al . 2008 a ); cells from a range of tissues can be reprogrammed ( Aasen et al . 2008 ; Aoi et al . 2008 ); and iPS cells can be generated from patients with specific diseases ( Dimos et al . 2008 ; Park et al . 2008 b ). The number of transcription factors required to generate iPS cells has been reduced ( Kim et al . 2008 ); the efficiency of iPS cell generation increased ( Wernig et al . 2007 ); and techniques devised that obviate the need for retroviral vectors ( Okita et al . 2008 ; Stadtfeld et al . 2008 ). These latter developments are very important for future clinical applications, since the early mice generated from iPS cells developed tumours at high frequency ( Takahashi & Yamanaka 2006 ; Yamanaka 2007 ). Without a doubt, this is currently the most exciting and rapidly moving area of stem cell research.
2. Current clinical applications of stem cells
In all the publicity that surrounds embryonic and iPS cells, people tend to forget that stem cell-based therapies are already in clinical use and have been for decades. It is instructive to think about these treatments, because they provide important caveats about the journey from proof-of-principle in the laboratory to real patient benefit in the clinic. These caveats include efficacy, patient safety, government legislation and the costs and potential profits involved in patient treatment.
Haemopoietic stem cell transplantation is the oldest stem cell therapy and is the treatment that is most widely available ( Perry & Linch 1996 ; Austin et al . 2008 ). The stem cells come from bone marrow, peripheral blood or cord blood. For some applications, the patient's own cells are engrafted. However, allogeneic stem cell transplantation is now a common procedure for the treatment of bone marrow failure and haematological malignancies, such as leukaemia. Donor stem cells are used to reconstitute immune function in such patients following radiation and/or chemotherapy. In the UK, the regulatory framework put in place for bone marrow transplantation has now an extended remit, covering the use of other tissues and organs ( Austin et al . 2008 ).
Advances in immunology research greatly increased the utility of bone marrow transplantation, allowing allograft donors to be screened for the best match in order to prevent rejection and graft-versus-host disease ( Perry & Linch 1996 ). It is worth remembering that organ transplantation programmes have also depended on an understanding of immune rejection, and drugs are available to provide effective long-term immunosuppression for recipients of donor organs. Thus, while it is obviously desirable for new stem cell treatments to involve the patient's own cells, it is certainly not essential.
Two major advantages of haemopoietic stem cell therapy are that there is no need to expand the cells in culture or to reconstitute a multicellular tissue architecture prior to transplantation. These hurdles have been overcome to generate cultured epidermis to provide autologous grafts for patients with full-thickness wounds, such as third-degree burns. Proof-of-principle was established in the mid-1970s, with clinical and commercial applications following rapidly ( Green 2008 ). Using a similar approach, limbal stem cells have been used successfully to restore vision in patients suffering from chemical destruction of the cornea ( De Luca et al . 2006 ).
Ex vivo expansion of human epidermal and corneal stem cells frequently involves culture on a feeder layer of mouse fibroblastic cells in medium containing bovine serum. While it would obviously be preferable to avoid animal products, there has been no evidence over the past 30 years that exposure to them has had adverse effects on patients receiving the grafts. The ongoing challenges posed by epithelial stem cell treatments include improved functionality of the graft (e.g. through generation of epidermal hair follicles) and improved surfaces on which to culture the cells and apply them to the patients. The need to optimize stem cell delivery is leading to close interactions between the stem cell community and bioengineers. In a recent example, a patient's trachea was repaired by transplanting a new tissue constructed in culture from donor decellularized trachea seeded with the patient's own bone marrow cells that had been differentiated into cartilage cells ( Macchiarini et al . 2008 ).
Whereas haemopoietic stem cell therapies are widely available, treatments involving cultured epidermis and cornea are not. In countries where cultured epithelial grafts are available, the number of potential patients is relatively small and the treatment costly. Commercial organizations that sell cultured epidermis for grafting have found that it is not particularly profitable, while in countries with publicly funded healthcare the need to set up a dedicated laboratory to generate the grafts tends to make the financial cost–benefit ratio too high ( Green 2008 ).
Clinical studies over the last 10 years suggest that stem cell transplantation also has potential as a therapy for neurodegenerative diseases. Clinical trials have involved grafting brain tissue from aborted foetuses into patients with Parkinson's disease and Huntington's disease ( Dunnett et al . 2001 ; Wright & Barker 2007 ). While some successes have been noted, the outcomes have not been uniform and further clinical trials will involve more refined patient selection, in an attempt to predict who will benefit and who will not. Obviously, aside from the opposition in many quarters to using foetal material, there are practical challenges associated with availability and uniformity of the grafted cells and so therapies with pure populations of stem cells are an important, and achievable ( Conti et al . 2005 ; Lowell et al . 2006 ), goal.
No consideration of currently available stem cell therapies is complete without reference to gene therapy. Here, there have been some major achievements, including the successful treatment of children with X-linked severe combined immunodeficiency. However, the entire gene therapy field stalled when several of the children developed leukaemia as a result of integration of the therapeutic retroviral vector close to the LMO2 oncogene locus ( Gaspar & Thrasher 2005 ; Pike-Overzet et al . 2007 ). Clinical trials have since restarted, and in an interesting example of combined gene/stem cell therapy, a patient with an epidermal blistering disorder received an autologous graft of cultured epidermis in which the defective gene had been corrected ex vivo ( Mavilio et al . 2006 ).
These are just some examples of treatments involving stem cells that are already in the clinic. They show how the field of stem cell transplantation is interlinked with the fields of gene therapy and bioengineering, and how it has benefited from progress in other fields, such as immunology. Stem cells undoubtedly offer tremendous potential to treat many human diseases and to repair tissue damage resulting from injury or ageing. The danger, of course, lies in the potentially lethal cocktail of desperate patients, enthusiastic scientists, ambitious clinicians and commercial pressures ( Lau et al . 2008 ). Internationally agreed, and enforced, regulations are essential in order to protect patients from the dangers of stem cell tourism, whereby treatments that have not been approved in one country are freely available in another ( Hyun et al . 2008 ).
3. What are the big questions in the field?
Three questions in stem cell research are being hotly pursued at present. What are the core genetic and epigenetic regulators of stem cells? What are the extrinsic, environmental factors that influence stem cell renewal and differentiation? And how can the answers to the first two questions be harnessed for clinical benefit?
4. Core genetic and epigenetic regulators
Considerable progress has already been made in defining the transcriptional circuitry and epigenetic modifications associated with pluripotency ( Jaenisch & Young 2008 ). This research area is moving very rapidly as a result of tremendous advances in DNA sequencing technology, bioinformatics and computational biology. Chromatin immunoprecipitation combined with microarray hybridization or DNA sequencing ( Mathur et al . 2008 ) is being used to identify transcription factor-binding sites, and bioinformatics techniques have been developed to allow integration of data obtained by the different approaches. It is clear that pluripotency is also subject to complex epigenetic regulation, and high throughput genome-scale DNA methylation profiling has been developed for epigenetic profiling of ES cells and other cell types ( Meissner et al . 2008 ).
Oct4, Nanog and Sox2 are core transcription factors that maintain pluripotency of ES cells. These factors bind to their own promoters, forming an autoregulatory loop. They occupy overlapping sets of target genes, one set being actively expressed and the other, comprising genes that positively regulate lineage selection, being actively silenced ( Jaenisch & Young 2008 ; Mathur et al . 2008 ; Silva & Smith 2008 ). Nanog stabilizes pluripotency by limiting the frequency with which cells commit to differentiation ( Chambers et al . 2007 ; Torres & Watt 2008 ). The core pluripotency transcription factors also regulate, again positively and negatively, the microRNAs that are involved in controlling ES cell self-renewal and differentiation ( Marson et al . 2008 ).
As the basic mechanisms that maintain the pluripotent state of ES cells are delineated, there is considerable interest in understanding how pluripotency is re-established in adult stem cells. It appears that some cell types are more readily reprogrammed to iPS cells than others ( Aasen et al . 2008 ; Aoi et al . 2008 ), and it is interesting to speculate that this reflects differences in endogenous expression of the genes required for reprogramming or in responsiveness to overexpression of those genes ( Hochedlinger et al . 2005 ; Markoulaki et al . 2009 ). Another emerging area of investigation is the relationship between the epigenome of pluripotent stem cells and cancer cells ( Meissner et al . 2008 ).
Initial attempts at defining ‘stemness’ by comparing the transcriptional profiles of ES cells, neural and haemopoietic stem cells ( Ivanova et al . 2002 ; Ramalho-Santos et al . 2002 ) have paved the way for more refined comparisons. For example, by comparing the gene expression profiles of adult neural stem cells, ES-derived and iPS-derived neural stem cells and brain tumour stem cells, it should be possible both to validate the use of ES-derived stem cells for brain repair and to establish the cell of origin of brain tumour initiating cells. Furthermore, it is anticipated that new therapeutic targets will be identified from molecular profiling studies of different stem cell populations.
As gene expression profiling becomes more sophisticated, the question of ‘what is a stem cell?’ can be addressed in new ways. Several studies have used single cell expression microarrays to identify new stem cell markers ( Jensen & Watt 2006 ). Stem cells are well known to exhibit different proliferative and differentiation properties in culture, during tissue injury and in normal tissue homeostasis, raising the question of which elements of the stem cell phenotype are hard-wired versus a response to environmental conditions.
One of the growing trends in stem cell research is the contribution of mathematical modelling. This is illustrated in the concept of transcriptional noise: the hypothesis that intercellular variability is a manifestation of ‘noise’ in gene expression levels, rather than stable phenotypic variation ( Chang et al . 2008 ). Studies with clonal populations of haemopoietic progenitor cells have shown that slow fluctuations in protein levels can produce cellular heterogeneity that is sufficient to affect whether a given cell will differentiate along the myeloid or erythroid lineage ( Chang et al . 2008 ). Mathematical approaches are also used increasingly to model observed differences in cell behaviour in vivo . In studies of adult mouse interfollicular epidermis, it is observed that cells can divide to produce two undifferentiated cells, two differentiated cells or one of each ( figure 3 ); it turns out that this can be explained in terms of the stochastic behaviour of a single population of cells rather than by invoking the existence of discrete types of stem and progenitor cell ( Clayton et al . 2007 ).
The stem cell niche. Stem cells (S) are shown dividing symmetrically to produce two stem cells (1) or two differentiated cells (D) (2), or undergoing asymmetric division to produce one stem cell and one differentiated cell (3). Under some circumstances, a differentiated cell can re-enter the niche and become a stem cell (4). Different components of the stem cell niche are illustrated: extracellular matrix (ECM), cells in close proximity to stem cells (niche cells), secreted factors (such as growth factors) and physical factors (such as oxygen tension, stiffness and stretch).
5. Extrinsic regulators
There is strong evidence that the behaviour of stem cells is strongly affected by their local environment or niche ( figure 3 ). Some aspects of the stem cell environment that are known to influence self-renewal and stem cell fate are adhesion to extracellular matrix proteins, direct contact with neighbouring cells, exposure to secreted factors and physical factors, such as oxygen tension and sheer stress ( Watt & Hogan 2000 ; Morrison & Spradling 2008 ). It is important to identify the environmental signals that control stem cell expansion and differentiation in order to harness those signals to optimize delivery of stem cell therapies.
Considerable progress has been made in directing ES cells to differentiate along specific lineages in vitro ( Conti et al . 2005 ; Lowell et al . 2006 ; Izumi et al . 2007 ) and there are many in vitro and murine models of lineage selection by adult tissue stem cells (e.g. Watt & Collins 2008 ). It is clear that in many contexts the Erk and Akt pathways are key regulators of cell proliferation and survival, while pathways that were originally defined through their effects in embryonic development, such as Wnt, Notch and Shh, are reused in adult tissues to influence stem cell renewal and lineage selection. Furthermore, these core pathways are frequently deregulated in cancer ( Reya et al . 2001 ; Watt & Collins 2008 ). In investigating how differentiation is controlled, it is not only the signalling pathways themselves that need to be considered, but also the timing, level and duration of a particular signal, as these variables profoundly influence cellular responses ( Silva-Vargas et al . 2005 ). A further issue is the extent to which directed ES cell differentiation in vitro recapitulates the events that occur during normal embryogenesis and whether this affects the functionality of the differentiated cells ( Izumi et al . 2007 ).
For a more complete definition of the stem cell niche, researchers are taking two opposite and complementary approaches: recreating the niche in vitro at the single cell level and observing stem cells in vivo. In vivo tracking of cells is possible because of advances in high-resolution confocal microscopy and two-photon imaging, which have greatly increased the sensitivity of detecting cells and the depth of the tissue at which they can be observed. Studies of green fluorescent protein-labelled haemopoietic stem cells have shown that their relationship with the bone marrow niche, comprising blood vessels, osteoblasts and the inner bone surface, differs in normal, irradiated and c-Kit-receptor-deficient mice ( Lo Celso et al . 2009 ; Xie et al . 2009 ). In a different approach, in vivo bioluminescence imaging of luciferase-tagged muscle stem cells has been used to reveal their role in muscle repair in a way that is impossible when relying on retrospective analysis of fixed tissue ( Sacco et al . 2008 ).
The advantage of recreating the stem cell niche in vitro is that it is possible to precisely control individual aspects of the niche and measure responses at the single cell level. Artificial niches are constructed by plating cells on micropatterned surfaces or capturing them in three-dimensional hydrogel matrices. In this way, parameters such as cell spreading and substrate mechanics can be precisely controlled ( Watt et al . 1988 ; Théry et al . 2005 ; Chen 2008 ). Cells can be exposed to specific combinations of soluble factors or to tethered recombinant adhesive proteins. Cell behaviour can be monitored in real time by time-lapse microscopy, and activation of specific signalling pathways can be viewed using fluorescence resonance energy transfer probes and fluorescent reporters of transcriptional activity. It is also possible to recover cells from the in vitro environment, transplant them in vivo and monitor their subsequent behaviour. One of the exciting aspects of the reductionist approach to studying the niche is that it is highly interdisciplinary, bringing together stem cell researchers and bioengineers, and also offering opportunities for interactions with chemists, physicists and materials scientists.
6. Future clinical applications of stem cell research
Almost every day there are reports in the media of new stem cell therapies. There is no doubt that stem cells have the potential to treat many human afflictions, including ageing, cancer, diabetes, blindness and neurodegeneration. Nevertheless, it is essential to be realistic about the time and steps required to take new therapies into the clinic: it is exciting to be able to induce ES cells to differentiate into cardiomyocytes in a culture dish, but that is only one very small step towards effecting cardiac repair. The overriding concerns for any new treatment are the same: efficacy, safety and affordability.
In January 2009, the US Food and Drug Administration approved the first clinical trial involving human ES cells, just over 10 years after they were first isolated. In this trial, the safety of ES cell-derived oligodendrocytes in repair of spinal cord injury will be evaluated ( http://www.geron.com ). There are a large number of human ES cell lines now in existence and banking of clinical grade cells is underway, offering the opportunity for optimal immunological matching of donors and recipients. Nevertheless, one of the attractions of transplanting iPS cells is that the patient's own cells can be used, obviating the need for immunosuppression. Discovering how the pluripotent state can be efficiently and stably induced and maintained by treating cells with pharmacologically active compounds rather than by genetic manipulation is an important goal ( Silva et al . 2008 ).
An alternative strategy to stem cell transplantation is to stimulate a patient's endogenous stem cells to divide or differentiate, as happens naturally during skin wound healing. It has recently been shown that pancreatic exocrine cells in adult mice can be reprogrammed to become functional, insulin-producing beta cells by expression of transcription factors that regulate pancreatic development ( Zhou et al . 2008 ). The idea of repairing tissue through a process of cellular reprogramming in situ is an attractive paradigm to be explored further.
A range of biomaterials are already in clinical use for tissue repair, in particular to repair defects in cartilage and bone ( Kamitakahara et al . 2008 ). These can be considered as practical applications of our knowledge of the stem cell microenvironment. Advances in tissue engineering and materials science offer new opportunities to manipulate the stem niche and either facilitate expansion/differentiation of endogenous stem cells or deliver exogenous cells. Resorbable scaffolds can be exploited for controlled delivery and release of small molecules, growth factors and peptides. Conversely, scaffolds can be designed that are able to capture unwanted tissue debris that might impede repair. Hydrogels that can undergo controlled sol–gel transitions could be used to release stem cells once they have integrated within the target tissue.
Although most of the new clinical applications of stem cells have a long lead time, applications of stem cells in drug discovery are available immediately. Adult tissue stem cells, ES cells and iPS cells can all be used to screen for compounds that stimulate self-renewal or promote specific differentiation programmes. Finding drugs that selectively target cancer stem cells offers the potential to develop cancer treatments that are not only more effective, but also cause less collateral damage to the patient's normal tissues than drugs currently in use. In addition, patient-specific iPS cells provide a new tool to identify underlying disease mechanisms. Thus stem cell-based assays are already enhancing drug discovery efforts.
7. Conclusion
Amid all the hype surrounding stem cells, there are strong grounds for believing that over the next 50 years our understanding of stem cells will revolutionize medicine. One of the most exciting aspects of working in the stem cell field is that it is truly multidisciplinary and translational. It brings together biologists, clinicians and researchers across the physical sciences and mathematics, and it fosters partnerships between academics and the biotech and pharmaceutical industries. In contrast to the golden era of developmental biology, one of stem cell research's defining characteristics is the motivation to benefit human health.
Acknowledgements
We thank all members of our lab, past and present, for their energy, fearlessness and intellectual curiosity in the pursuit of stem cells. We are grateful to Cancer Research UK, the Wellcome Trust, MRC and European Union for financial support and to members of the Cambridge Stem Cell Initiative for sharing their ideas.
One contribution of 19 to a Theme Issue ‘ Personal perspectives in the life sciences for the Royal Society's 350th anniversary ’.
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Page 1 of 74
Retraction Note: Using a new HSPC senescence model in vitro to explore the mechanism of cellular memory in aging HSPCs
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A novel chondrocyte sheet fabrication using human-induced pluripotent stem cell-derived expandable limb-bud mesenchymal cells
Cell sheet fabrication for articular cartilage regenerative medicine necessitates a large number of chondrocytes of consistent quality as a cell source. Previously, we have developed human-induced pluripotent ...
Single cell and lineage tracing studies reveal the impact of CD34 + cells on myocardial fibrosis during heart failure
CD34 + cells have been used to treat the patients with heart failure, but the outcome is variable. It is of great significance to scrutinize the fate and the mechanism of CD34 + cell differentiation in vivo during ...
Dose-specific efficacy of adipose-derived mesenchymal stem cells in septic mice
Mesenchymal stem cells (MSCs) therapy for sepsis has been extensively studied in the past decade; however, the treatment regimen and mechanism of action of MSCs remain elusive. Here, we attempted to understand...
Flow-dependent shear stress affects the biological properties of pericyte-like cells isolated from human dental pulp
Human dental pulp stem cells represent a mesenchymal stem cell niche localized in the perivascular area of dental pulp and are characterized by low immunogenicity and immunomodulatory/anti-inflammatory propert...
Correction: Human endometrium-derived stem cell improves cardiac function after myocardial ischemic injury by enhancing angiogenesis and myocardial metabolism
The original article was published in Stem Cell Research & Therapy 2021 12 :344
Endothelial colony forming cell administration promotes neurovascular unit development in growth restricted and appropriately grown fetal lambs
Fetal growth restriction (FGR) is associated with deficits in the developing brain, including neurovascular unit (NVU) dysfunction. Endothelial colony forming cells (ECFC) can mediate improved vascular stabili...
Targeting ovarian cancer stem cells: a new way out
Ovarian cancer (OC) is the most lethal gynecological malignancy due to tumor heterogeneity, the lack of reliable early diagnosis methods and the high incidence of chemoresistant recurrent disease. Although the...
Overexpression of FoxM1 optimizes the therapeutic effect of bone marrow mesenchymal stem cells on acute respiratory distress syndrome
Injury of alveolar epithelial cells and capillary endothelial cells is crucial in the pathogenesis of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Mesenchymal stem cells (MSCs) are a promi...
Mechanisms and clinical application potential of mesenchymal stem cells-derived extracellular vesicles in periodontal regeneration
Periodontitis is a high prevalence oral disease which damages both the hard and soft tissue of the periodontium, resulting in tooth mobility and even loss. Existing clinical treatment methods cannot fully achi...
Hepatocyte growth factor-modified hair follicle stem cells ameliorate cerebral ischemia/reperfusion injury in rats
Hair follicle stem cells (HFSCs) are considered as a promising cell type in the stem cell transplantation treatment of neurological diseases because of their rich sources, easy access, and the same ectoderm so...
ABCB5 + mesenchymal stromal cells therapy protects from hypoxia by restoring Ca 2+ homeostasis in vitro and in vivo
Hypoxia in ischemic disease impairs Ca 2+ homeostasis and may promote angiogenesis. The therapeutic efficacy of mesenchymal stromal cells (MSCs) in peripheral arterial occlusive disease is well established, yet it...
Safety and efficacy outcomes after intranasal administration of neural stem cells in cerebral palsy: a randomized phase 1/2 controlled trial
Neural stem cells (NSCs) are believed to have the most therapeutic potential for neurological disorders because they can differentiate into various neurons and glial cells. This research evaluated the safety a...
Implantation and tracing of green fluorescent protein-expressing adipose-derived stem cells in peri-implant capsular fibrosis
Adipose-derived stem cells (ASCs) have been reported to reduce fibrosis in various tissues. In this study, we investigated the inhibitory role of ASCs on capsule formation by analyzing the histologic, cellular...
Shining the light on mesenchymal stem cell-derived exosomes in breast cancer
In women, breast cancer (BC) is the second most frequently diagnosed cancer and the leading cause of cancer death. Mesenchymal stem cells (MSCs) are a subgroup of heterogeneous non-hematopoietic fibroblast-lik...
Adipose-derived stem cell spheroid-laden microbial transglutaminase cross-linked gelatin hydrogel for treating diabetic periodontal wounds and craniofacial defects
Diabetes mellitus deteriorates the destruction and impairs the healing of periodontal wounds and craniofacial defects. This study is to evaluate the potential of self-assembled adipose-derived stem cell sphero...
Generation of multilineage liver organoids with luminal vasculature and bile ducts from human pluripotent stem cells via modulation of Notch signaling
The generation of liver organoids recapitulating parenchymal and non-parenchymal cell interplay is essential for the precise in vitro modeling of liver diseases. Although different types of multilineage liver ...
Acceptability of neural stem cell therapy for cerebral palsy: survey of the Australian cerebral palsy community
Neural stem cells (NSCs) have the potential to engraft and replace damaged brain tissue, repairing the damaged neonatal brain that causes cerebral palsy (CP). There are procedures that could increase engraftme...
Murine skin-derived multipotent papillary dermal fibroblast progenitors show germline potential in vitro
Many laboratories have described the in vitro isolation of multipotent cells with stem cell properties from the skin of various species termed skin-derived stem cells (SDSCs). However, the cellular origin of t...
CD24+CD44+CD54+EpCAM+ gastric cancer stem cells predict tumor progression and metastasis: clinical and experimental evidence
Gastric cancer (GC) is a leading cause of cancer-related deaths worldwide. Specific and thorough identification of cancer cell subsets with higher tumorigenicity and chemoresistance, such as cancer stem cells ...
Tumor stemness score to estimate epithelial-to-mesenchymal transition (EMT) and cancer stem cells (CSCs) characterization and to predict the prognosis and immunotherapy response in bladder urothelial carcinoma
A growing number of investigations have suggested a close link between cancer stem cells (CSCs), epithelial-to-mesenchymal transition (EMT), and the tumor microenvironment (TME). However, the relationships bet...
Combining single-cell transcriptomics and CellTagging to identify differentiation trajectories of human adipose-derived mesenchymal stem cells
Mesenchymal stromal cells (MSCs) have attracted great attention in the application of cell-based therapy because of their pluripotent differentiation and immunomodulatory ability. Due to the limited number of ...
Retraction Note: GDF11 enhances therapeutic functions of mesenchymal stem cells for angiogenesis
Transfer of mesenchymal stem cell mitochondria to cd4 + t cells contributes to repress th1 differentiation by downregulating t-bet expression.
Mesenchymal stem/stromal cells (MSCs) are multipotent cells with strong tissue repair and immunomodulatory properties. Due to their ability to repress pathogenic immune responses, and in particular T cell resp...
Hypoimmunogenic human pluripotent stem cells are valid cell sources for cell therapeutics with normal self-renewal and multilineage differentiation capacity
Hypoimmunogenic human pluripotent stem cells (hPSCs) are expected to serve as an unlimited cell source for generating universally compatible “off-the-shelf” cell grafts. However, whether the engineered hypoimm...
Synergistic therapeutic effects of intracerebral transplantation of human modified bone marrow-derived stromal cells (SB623) and voluntary exercise with running wheel in a rat model of ischemic stroke
Mesenchymal stromal cell (MSC) transplantation therapy is a promising therapy for stroke patients. In parallel, rehabilitation with physical exercise could ameliorate stroke-induced neurological impairment. In...
Retraction Note: Mesenchymal stem cell-derived exosome miR-542-3p suppresses inflammation and prevents cerebral infarction
Retraction note: effects of mir-672 on the angiogenesis of adipose-derived mesenchymal stem cells during bone regeneration, harnessing electromagnetic fields to assist bone tissue engineering.
Bone tissue engineering (BTE) emerged as one of the exceptional means for bone defects owing to it providing mechanical supports to guide bone tissue regeneration. Great advances have been made to facilitate t...
Laser-activated autologous adipose tissue-derived stromal vascular fraction restores spinal cord architecture and function in multiple sclerosis cat model
Multiple sclerosis (MS) is the most frequent non-traumatic neurological debilitating disease among young adults with no cure. Over recent decades, efforts to treat neurodegenerative diseases have shifted to re...
Mesenchymal stem cells limit vascular and epithelial damage and restore the impermeability of the urothelium in chronic radiation cystitis
Cellular therapy seems to be an innovative therapeutic alternative for which mesenchymal stem cells (MSCs) have been shown to be effective for interstitial and hemorrhagic cystitis. However, the action of MSCs...
Stability and biosafety of human epidermal stem cell for wound repair: preclinical evaluation
Cell therapy is a key technology to prevent sacrificing normal skin. Although some studies have shown the promise of human epidermal stem cells (EpiSCs), the efficacy, biosafety and quality control of EpiSC th...
Neural stem/progenitor cell therapy for Alzheimer disease in preclinical rodent models: a systematic review and meta-analysis
Alzheimer’s disease (AD) is a common progressive neurodegenerative disease characterized by memory impairments, and there is no effective therapy. Neural stem/progenitor cell (NSPC) has emerged as potential no...
Neuroblasts migration under control of reactive astrocyte-derived BDNF: a promising therapy in late neurogenesis after traumatic brain injury
Traumatic brain injury (TBI) is a disease with high mortality and morbidity, which leads to severe neurological dysfunction. Neurogenesis has provided therapeutic options for treating TBI. Brain derived neurot...
CDK8/19 inhibition plays an important role in pancreatic β-cell induction from human iPSCs
Transplantation of differentiated cells from human-induced pluripotent stem cells (hiPSCs) holds great promise for clinical treatments. Eliminating the risk factor of malignant cell transformation is essential...
Strategies of cell and cell-free therapies for periodontal regeneration: the state of the art
Periodontitis often causes irrevocable destruction of tooth-supporting tissues and eventually leads to tooth loss. Currently, stem cell-based tissue engineering has achieved a favorable result in regenerating ...
Efficient bone regeneration of BMP9-stimulated human periodontal ligament stem cells (hPDLSCs) in decellularized bone matrix (DBM) constructs to model maxillofacial intrabony defect repair
BMP9-stimulated DPSCs, SCAPs and PDLSCs are effective candidates for repairing maxillofacial bone defects in tissue engineering, while the most suitable seed cell source among these three hDMSCs and the optima...
KW-2449 and VPA exert therapeutic effects on human neurons and cerebral organoids derived from MECP2-null hESCs
Rett syndrome (RTT), mainly caused by mutations in methyl-CpG binding protein 2 (MECP2), is one of the most prevalent neurodevelopmental disorders in girls. However, the underlying mechanism of MECP2 remains l...
Effect of glucose depletion and fructose administration during chondrogenic commitment in human bone marrow-derived stem cells
Bone marrow mesenchymal stromal cells (BMSCs) are promising for therapeutic use in cartilage repair, because of their capacity to differentiate into chondrocytes. Often, in vitro differentiation protocols empl...
Image-based crosstalk analysis of cell–cell interactions during sprouting angiogenesis using blood-vessel-on-a-chip
Sprouting angiogenesis is an important mechanism for morphogenetic phenomena, including organ development, wound healing, and tissue regeneration. In regenerative medicine, therapeutic angiogenesis is a clinic...
Small molecule-mediated rapid maturation of human induced pluripotent stem cell-derived cardiomyocytes
Human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iPSC-CMs) do not display all hallmarks of mature primary cardiomyocytes, especially the ability to use fatty acids (FA) as an energy source, c...
Correction: Metformin promotes the survival of transplanted cardiosphere-derived cells thereby enhancing their therapeutic effect against myocardial infarction
The original article was published in Stem Cell Research & Therapy 2017 8 :17
Robust generation of human-chambered cardiac organoids from pluripotent stem cells for improved modelling of cardiovascular diseases
Tissue organoids generated from human pluripotent stem cells are valuable tools for disease modelling and to understand developmental processes. While recent progress in human cardiac organoids revealed the ab...
Co-treatment with grape seed extract and mesenchymal stem cells in vivo regenerated beta cells of islets of Langerhans in pancreas of type I-induced diabetic rats
Nowadays, diabetes mellitus is known as a silent killer because individual is not aware that he has the disease till the development of its complications. Many researchers have studied the use of stem cells in...
Mesenchymal stem cell-derived exosomes as a new therapeutic strategy in the brain tumors
Brain tumors are one of the most mortal cancers, leading to many deaths among kids and adults. Surgery, chemotherapy, and radiotherapy are available options for brain tumor treatment. However, these methods ar...
Correction: Facilitating islet transplantation using a three-step approach with mesenchymal stem cells, encapsulation, and pulsed focused ultrasound
The original article was published in Stem Cell Research & Therapy 2020 11 :405
3D printing of injury-preconditioned secretome/collagen/heparan sulfate scaffolds for neurological recovery after traumatic brain injury in rats
The effects of traumatic brain injury (TBI) can include physical disability and even death. The development of effective therapies to promote neurological recovery is still a challenging problem. 3D-printed bi...
Correction: The crosstalk between macrophages and bone marrow mesenchymal stem cells in bone healing
The original article was published in Stem Cell Research & Therapy 2022 13 :511
The role of miRNA and lncRNA in heterotopic ossification pathogenesis
Heterotopic ossification (HO) is the formation of bone in non-osseous tissues, such as skeletal muscles. The HO could have a genetic or a non-genetic (acquired) background, that is, it could be caused by muscu...
Correction: Expansion of mouse castration-resistant intermediate prostate stem cells in vitro
The original article was published in Stem Cell Research & Therapy 2022 13 :299
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- Published: 06 August 2022
Stem cell-based therapy for human diseases
- Duc M. Hoang ORCID: orcid.org/0000-0001-5444-561X 1 ,
- Phuong T. Pham 2 ,
- Trung Q. Bach 1 ,
- Anh T. L. Ngo 2 ,
- Quyen T. Nguyen 1 ,
- Trang T. K. Phan 1 ,
- Giang H. Nguyen 1 ,
- Phuong T. T. Le 1 ,
- Van T. Hoang 1 ,
- Nicholas R. Forsyth 3 ,
- Michael Heke 4 &
- Liem Thanh Nguyen 1
Signal Transduction and Targeted Therapy volume 7 , Article number: 272 ( 2022 ) Cite this article
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- Mesenchymal stem cells
- Stem-cell research
Recent advancements in stem cell technology open a new door for patients suffering from diseases and disorders that have yet to be treated. Stem cell-based therapy, including human pluripotent stem cells (hPSCs) and multipotent mesenchymal stem cells (MSCs), has recently emerged as a key player in regenerative medicine. hPSCs are defined as self-renewable cell types conferring the ability to differentiate into various cellular phenotypes of the human body, including three germ layers. MSCs are multipotent progenitor cells possessing self-renewal ability (limited in vitro) and differentiation potential into mesenchymal lineages, according to the International Society for Cell and Gene Therapy (ISCT). This review provides an update on recent clinical applications using either hPSCs or MSCs derived from bone marrow (BM), adipose tissue (AT), or the umbilical cord (UC) for the treatment of human diseases, including neurological disorders, pulmonary dysfunctions, metabolic/endocrine-related diseases, reproductive disorders, skin burns, and cardiovascular conditions. Moreover, we discuss our own clinical trial experiences on targeted therapies using MSCs in a clinical setting, and we propose and discuss the MSC tissue origin concept and how MSC origin may contribute to the role of MSCs in downstream applications, with the ultimate objective of facilitating translational research in regenerative medicine into clinical applications. The mechanisms discussed here support the proposed hypothesis that BM-MSCs are potentially good candidates for brain and spinal cord injury treatment, AT-MSCs are potentially good candidates for reproductive disorder treatment and skin regeneration, and UC-MSCs are potentially good candidates for pulmonary disease and acute respiratory distress syndrome treatment.
Introduction
The successful approval of cancer immunotherapies in the US and mesenchymal stem cell (MSC)-based therapies in Europe have turned the wheel of regenerative medicine to become prominent treatment modalities. 1 , 2 , 3 Cell-based therapy, especially stem cells, provides new hope for patients suffering from incurable diseases where treatment approaches focus on management of the disease not treat it. Stem cell-based therapy is an important branch of regenerative medicine with the ultimate goal of enhancing the body repair machinery via stimulation, modulation, and regulation of the endogenous stem cell population and/or replenishing the cell pool toward tissue homeostasis and regeneration. 4 Since the stem cell definition was introduced with their unique properties of self-renewal and differentiation, they have been subjected to numerous basic research and clinical studies and are defined as potential therapeutic agents. As the main agenda of regenerative medicine is related to tissue regeneration and cellular replacement and to achieve these targets, different types of stem cells have been used, including human pluripotent stem cells (hPSCs), multipotent stem cells and progenitor cells. 5 However, the emergence of private and unproven clinics that claim the effectiveness of stem cell therapy as “magic cells” has raised highly publicized concerns about the safety of stem cell therapy. The most notable case involved the injection of a cell population derived from fractionated lipoaspirate into the eyes of three patients diagnosed with macular degeneration, resulting in the loss of vision for these patients. 6 Thus, as regenerative medicine continues to progress and evolve and to clear the myth of the “magic” cells, this review provides a brief overview of stem cell-based therapy for the treatment of human diseases.
Stem cell therapy is a novel therapeutic approach that utilizes the unique properties of stem cells, including self-renewal and differentiation, to regenerate damaged cells and tissues in the human body or replace these cells with new, healthy and fully functional cells by delivering exogenous cells into a patient. 7 Stem cells for cell-based therapy can be of (1) autologous, also known as self-to-self therapy, an approach using the patient’s own cells, and (2) allogeneic sources, which use cells from a healthy donor for the treatment. 8 The term “stem cell” were first used by the eminent German biologist Ernst Haeckel to describe the properties of fertilized egg to give rise to all cells of the organism in 1868. 9 The history of stem cell therapy started in 1888, when the definition of stem cell was first coined by two German zoologists Theodor Heinrich Boveri and Valentin Haecker, 9 who set out to identify the distinct cell population in the embryo capable of differentiating to more specialized cells (Fig. 1a ). In 1902, studies carried out by the histologist Franz Ernst Christian Neumann, who was working on bone marrow research, and Alexander Alexandrowitsch Maximov demonstrated the presence of common progenitor cells that give rise to mature blood cells, a process also known as haematopoiesis. 10 From this study, Maximov proposed the concept of polyblasts, which later were named stem cells based on their proliferation and differentiation by Ernst Haeckel. 11 Maximov described a hematopoietic population presented in the bone marrow. In 1939, the first case report described the transplantation of human bone marrow for a patient diagnosed with aplastic anemia. Twenty years later, in 1958, the first stem cell transplantation was performed by the French oncologist George Mathe to treat six nuclear researchers who were accidentally exposed to radioactive substances using bone marrow transplantation. 12 Another study by George Mathe in 1963 shed light on the scientific community, as he successfully conducted bone marrow transplantation in a patient with leukemia. The first allogeneic hematopoietic stem cell transplantation (HSCT) was pioneered by Dr. E. Donnall Thomas in 1957. 13 In this initial study, all six patients died, and only two patients showed evidence of transient engraftment due to the unknown quantities and potential hazards of bone marrow transplantation at that time. In 1969, Dr. E. Donnall Thomas conducted the first bone marrow transplantation in the US, although the success of the allogeneic treatment remained exclusive. In 1972, the year marked the discovery of cyclosporine (the immune suppressive drug), 14 the first successes of allogeneic transplantation for aplastic anemia and acute myeloid leukemia were reported in a 16-year-old girl. 15 From the 1960s to the 1970s, series of works conducted by Friendenstein and coworkers on bone marrow aspirates demonstrated the relationship between osteogenic differentiation and a minor subpopulation of cells derived from bone marrow. 16 These cells were later proven to be distinguishable from the hematopoietic population and to be able to proliferate rapidly as adherent cells in tissue culture vessels. Another important breakthrough from Friendenstein’s team was the discovery that these cells could form the colony-forming unit when bone marrow was seeded as suspension culture following by differentiation into osteoblasts, adipocytes, and chondrocytes, suggesting that these cells confer the ability to proliferate and differentiate into different cell types. 17 In 1991, combined with the discovery of human embryonic stem cells (hESCs), which will be discussed in the next section, the term “mesenchymal stem cells”, previously known as stromal stem cells or “osteogenic” stem cells, was first coined in Caplan and widely used to date. 18 Starting with bone marrow transplantation 60 years ago, the journey of stem cell therapy has developed throughout the years to become a novel therapeutic agent of regenerative medicine to treat numerous incurable diseases, which will be reviewed and discussed in this review, including neurological disorders, pulmonary dysfunctions, metabolic/endocrine-related diseases, reproductive disorders, skin burns, and cardiovascular conditions).
Stem cell-based therapy: the history and cell source. a The timeline of major discoveries and advances in basic research and clinical applications of stem cell-based therapy. The term “stem cells” was first described in 1888, setting the first milestone in regenerative medicine. The hematopoietic progenitor cells were first discovered in 1902. In 1939, the first bone marrow transplantation was conducted in the treatment of aplasmic anemia. Since then, the translation of basic research to preclinical studies to clinical trials has driven the development of stem cell-based therapy by many discoveries and milestones. The isolations of “mesenchymal stem cells” in 1991 following by the discovery of human pluripotent stem cells have recently contributed to the progress of stem cell-based therapy in the treatment of human diseases. b Schematic of the different cell sources that can be used in stem cell-based therapy. (1) Human pluripotent stem cells, including embryonic stem cells (derived from inner cell mass of blastocyst) and induced pluripotent stem cells confer the ability to proliferate indefinitely in vitro and differentiate into numerous cell types of the human body, including three germ layers. (2) Mesenchymal stem cells are multipotent stem cells derived from mesoderm possessing self-renewal ability (limited in vitro) and differentiation potential into mesenchymal lineages. The differentiated/somatic cells can be reprogrammed back to the pluripotent stage using OSKM factors to generate induced pluripotent stem cells. It is important to note that stem cells show a relatively higher risk of tumor formation and lower risk of immune rejection (in the case of mesenchymal stem cells) when compared to that of somatic cells. The figure was created with BioRender.com
In this review, we described the different types of stem cell-based therapies (Fig. 1b ), including hPSCs and MSCs, and provided an overview of their definition, history, and outstanding clinical applications. In addition, we further created the first literature portfolio for the “targeted therapy” of MSCs based on their origin, delineating their different tissue origins and downstream applications with an in-depth discussion of their mechanism of action. Finally, we provide our perspective on why the tissue origin of MSCs could contribute greatly to their downstream applications as a proposed hypothesis that needs to be proven or disproven in the future to further enhance the safety and effectiveness of stem cell-based therapy.
Stem cell-based therapy: an overview of current clinical applications
Cardiovascular diseases.
The clinical applications of stem cell-based therapies for heart diseases have been recently discussed comprehensively in the reviews 19 , 20 and therefore will be elaborated in this study as the focus discussions related to hPSCs and MSCs in the following sections. In general, the safety profiles of stem cell-based therapies are supported by a large body of preclinical and clinical studies, especially adult stem cell therapy (such as MSC-based products). However, clinical trials have not yet yielded data supporting the efficacy of the treatment, as numerous studies have shown paradoxical results and no statistically significant differences in infarct size, cardiac function, or clinical outcomes, even in phase III trials. 21 The results of a meta-analysis showed that stem cells derived from different sources did not exhibit any therapeutic effects on the improvement of myocardial contractility, cardiovascular remodeling, or clinical outcomes. 22 The disappointing results obtained from the clinical trials thus far could be explained by the fact that the administered cells may exert their therapeutic effects via an immune modulation rather than regenerative function. Thus, well-designed, randomized and placebo-controlled phase III trials with appropriate cell-preparation methods, patient selection, follow-up schedules and suitable clinical measurements need to be conducted to determine the efficacy of the treatments. In addition, concerns related to optimum cell source and dose, delivery route and timing of administration, cell distribution post administration and the mechanism of action also need to be addressed. In the following section of this review, we present clinical trials related to MSC-based therapy in cardiovascular disease with the aim of discussing the contradictory results of these trials and analyzing the potential challenges underlying the current approaches.
Digestive system diseases
Gastrointestinal diseases are among the most diagnosed conditions in the developed world, altering the life of one-third of individuals in Western countries. The gastrointestinal tract is protected from adverse substances in the gut environment by a single layer of epithelial cells that are known to have great regenerative ability in response to injuries and normal cell turnover. 23 These epithelial cells have a rapid turnover rate of every 2–7 days under normal conditions and even more rapidly following tissue damage and inflammation. This rapid proliferation ability is possible owing to the presence of a specific stem cell population that is strictly compartmentalized in the intestinal crypts. 24 The gastrointestinal tract is highly vulnerable to damage, tissue inflammation and diseases once the degradation of the mucosal lining layer occurs. The exposure of intestinal stem cells to the surrounding environment of the gut might result in the direct destruction of the stem cell layer or disruption of intestinal functions and lead to overt clinical symptoms. 25 In addition, the accumulation of stem cell defects as well as the presence of chronic inflammation and stress also contributes to the reduction of intestinal stem cell quality.
In terms of digestive disorders, Crohn’s disease (CD) and ulcerative colitis are the two major forms of inflammatory bowel disease (IBD) and represent a significant burden on the healthcare system. The former is a chronic, uncontrolled inflammatory condition of the intestinal mucosa characterized by segmental transmural mucosal inflammation and granulomatous changes. 26 The latter is a chronic inflammatory bowel disease affecting the colon and rectum, characterized by mucosal inflammation initiating in the rectum and extending proximal to the colon in a continuous fashion. 27 Cellular therapy in the treatment of CD can be divided into haematopoietic stem cell-based therapy and MSC-based therapy. The indication and recommendation of using HSCs for the treatment of IBD were proposed in 1995 by an international committee with four important criteria: (1) refractory to immunosuppressive treatment; (2) persistence of the disease conditions indicated via endoscopy, colonoscopy or magnetic resonance enterography; (3) patients who underwent an imminent surgical procedure with a high risk of short bowel syndromes or refractory colonic disease; and (4) patients who refused to treat persistent perianal lesions using coloproctectomy with a definitive stroma implant. 28 In the standard operation procedure, patents’ HSCs were recruited using cyclophosphamide, which is associated with granulocyte colony-stimulating factor (G-CSF), at two different administered concentrations (4 g/m 2 and 2 g/m 2 ). Recently, it was reported that high doses of cyclophosphamide do not improve the number of recruited HSCs but increase the risk of cardiac and bladder toxicity. An interest in using HSCTs in CD originated from case reports that autologous HSCTs can induce sustained disease remission in some 29 , 30 but not all patients 31 , 32 , 33 with CD. The first phase I trial was conducted in Chicago and recruited 12 patients with active moderate to severe CD refractory to conventional therapies. Eleven of 12 patients demonstrated sustained remission after a median follow-up of 18.5 months, and one patient developed recurrence of active CD. 31 The ASTIC trial (the Autologous Stem Cell Transplantation International Crohn Disease) was the first randomized clinical trial with the largest cohort of patients undergoing HSCT for refractory CD in 2015. 34 The early report of the trial showed no statistically significant improvement in clinical outcomes of mobilization and autologous HSCT compared with mobilization followed by conventional therapy. In addition, the procedure was associated with significant toxicity, leading to the suggestion that HSCT for patients with refractory CD should not be widespread. Interestingly, by using conventional assessments for clinical trials for CD, a group reassessed the outcomes of patients enrolled in the ASTIC trial showing clinical and endoscopic benefits, although a high number of adverse events were also detected. 35 A recent systematic review evaluated 18 human studies including 360 patients diagnosed with CD and showed that eleven studies confirmed the improvement of Crohn’s disease activity index between HSCT groups compared to the control group. 36 Towards the cell sources, HSCs are the better sources as they afforded more stable outcomes when compared to that of MSC-based therapy. 37 Moreover, autologous stem cells were better than their allogeneic counterparts. 36 The safety of stem cell-based therapy in the treatment of CD has attracted our attention, as the risk of infection in patients with CD was relatively higher than that in those undergoing administration to treat cancer or other diseases. During the stem cell mobilization process, patient immunity is significantly compromised, leading to a high risk of infection, and requires carefully nursed and suitable antibiotic treatment to reduce the development of adverse events. Taken together, stem cell-based therapy for digestive disease reduced inflammation and improved the patient’s quality of life as well as bowel functions, although the high risk of adverse events needs to be carefully monitored to further improve patient safety and treatment outcomes.
Liver diseases
The liver is the largest vital organ in the human body and performs essential biological functions, including detoxification of the organism, metabolism, supporting digestion, vitamin storage, and other functions. 38 The disruption of liver homeostasis and function might lead to the development of pathological conditions such as liver failure, cirrhosis, cancer, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), and autoimmune liver disease (ALD). Orthotropic liver transplantation is the only effective treatment for severe liver diseases, but the number of available and suitable donor organs is very limited. Currently, stem cell-based therapies in the treatment of liver disease are associated with HSCs, MSCs, hPSCs, and liver progenitor cells.
Liver failure is a critical condition characterized by severe liver dysfunctions or decompensation caused by numerous factors with a relatively high mortality rate. Stem cell-based therapy is a novel alternative approach in the treatment of liver failure, as it is believed to participate in the enhancement of liver regeneration and recovery. The results of a meta-analysis including four randomized controlled trials and six nonrandomized controlled trials in the treatment of acute-on-chronic liver failure (ACLF) demonstrated that clinical outcomes of stem cell therapy were achieved in the short term, requiring multiple doses of stem cells to prolong the therapeutic effects. 39 , 40 Interestingly, although MSC-based therapies improved liver functions, including the model of end-stage liver disease score, albumin level, total bilirubin, and coagulation, beneficial effects on survival rate and aminotransferase level were not observed. 41 A randomized controlled trial illustrated the improvement of liver functions and reduction of severe infections in patients with hepatitis B virus-related ACLF receiving allogeneic bone marrow-derived MSCs (BM-MSCs) via peripheral infusion. 42 HSCs from peripheral blood after the G-CSF mobilization process were used in a phase I clinical trial and exhibited an improvement in serum bilirubin and albumin in patients with chronic liver failure without any specific adverse events related to the administration. 43 Taken together, an overview of stem cell-based therapy in the treatment of liver failure indicates the potential therapeutic effects on liver functions with a strong safety profile, although larger randomized controlled trials are still needed to assure the conclusions.
Liver cirrhosis is one of the major causes of morbidity and mortality worldwide and is characterized by diffuse nodular regeneration with dense fibrotic septa and subsequent parenchymal extinction leading to the collapse of liver vascular structure. 44 In fact, liver cirrhosis is considered the end-stage of liver disease that eventually leads to death unless liver transplantation is performed. Stem cell-based therapy, especially MSCs, currently emerges as a potential treatment with encouraging results for treating liver cirrhosis. In a clinical trial using umbilical cord-derived MSCs (UC-MSCs), 45 chronic hepatitis B patients with decompensated liver cirrhosis were divided into two groups: the MSC group ( n = 30) and the control group ( n = 15). 45 The results showed a significant reduction in ascites volume in the MSC group compared with the control. Liver function was also significantly improved in the MSC groups, as indicated by the increase in serum albumin concentration, reduction in total serum bilirubin levels, and decrease in the sodium model for end-stage liver disease score. 45 Similar results were also reported from a phase II trial using BM-MSCs in 25 patients with HCV-induced liver cirrhosis. 46 Consistent with these studies, three other clinical trials targeting liver cirrhosis caused by hepatitis B and alcoholic cirrhosis were conducted and confirmed that MSC administration enhanced and recovered liver functions. 47 , 48 , 49 With the large cohort study as the clinical trial conducted by Fang, the safety and potential therapeutic effects of MSC-based therapies could be further strengthened and confirmed the feasibility of the treatment in virus-related liver cirrhosis. 49 In terms of delivery route, a randomized controlled phase 2 trial suggested that systemic delivery of BM-MSCs does not show therapeutic effects on patients with liver cirrhosis. 50 MSCs are not the only cell source for liver cirrhosis. Recently, an open-label clinical trial conducted in 19 children with liver cirrhosis due to biliary atresia after the Kasai operation illustrated the safety and feasibility of the approach by showing the improvement of liver function after bone marrow mononuclear cell (BMNC) administration assessed by biochemical tests and pediatric end-stage liver disease (PELD) scores. 51 Another study using BMNCs in 32 decompensated liver cirrhosis patients illustrated the safety and effectiveness of BMNC administration in comparison with the control group. 52 Recently, a long-term analysis of patients receiving peripheral blood-derived stem cells indicated a significant improvement in the long-term survival rate when compared to the control group, and the risk of hepatocellular carcinoma formation did not increase. 53 CD133 + HSC infusion was performed in a multicentre, open, randomized controlled phase 2 trial in patients with liver cirrhosis; the results did not support the improvement of liver conditions, and cirrhosis persisted. 54 Notably, these results are in line with a previous randomized controlled study, which also reported that G-CSF and bone marrow-derived stem cells delivered via the hepatic artery did not introduce therapeutic potential as expected. 55 Thus, stem cell-based therapy for liver cirrhosis is still in its immature stage and requires larger trials with well-designed experiments to confirm the efficacy of the treatment.
Nonalcoholic fatty liver disease (NAFLD) is the most common medical condition caused by genetic and lifestyle factors and results in a severe liver condition and increased cardiovascular risk. 56 NAFLD is the hidden enemy, as most patients are asymptomatic for a long time, and their routine life is unaffected. Thus, the detection, identification, and management of NAFLD conditions are challenging tasks, as patients diagnosed with NAFLD often develop nonalcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma. 57 Although preclinical studies have shown that stem cell administration could enhance liver function in NAFLD models, a limited number of clinical trials were performed in human subjects. Recently, a multi-institutional clinical trial using freshly isolated autologous adipose tissue-derived regenerative cells was performed in Japan to treat seven NAFLD patients. 58 The results illustrated the improvement in the serum albumin level of six patients and prothrombin activity of five patients, and no treatment-related adverse events or severe adverse events were observed. This study illustrates the therapeutic potential of stem cell-based therapy in the treatment of NAFLD.
Autoimmune liver disease (ALD) is a severe liver condition affecting children and adults worldwide, with a female predominance. 59 The condition occurs in genetically predisposed patients when a stimulator, such as virus infection, leads to a T-cell-mediated autoimmune response directed against liver autoantigens. As a result, patients with ALD might develop liver cirrhosis, hepatocellular carcinoma, and, in severe cases, death. To date, HSCT and bone marrow transplantation are the two common stem cell-based therapies exhibiting therapeutic potential for ALD in clinical trials. An interesting report illustrated that haploidentical HSCTs could cure ALD in patients with sickle cells. 60 This report is particularly important, as it illustrates the potential therapeutic approach of using haploidentical HSCTs to treat patients with both sickle cells and ALD. Another case report described a 19-year-old man with a 4-year history of ALD who developed acute lymphoblastic leukemia and required allogeneic bone marrow transplantation from this wholesome brother. 61 The clinical data showed that immunosuppressive therapy for transplantation generated ALD remission in the patient. 62 However, the data also provided valid information related to the sustained remission and the normalization of ASGPR-specific suppressor-inducer T-cell activity following bone marrow transplantation, suggesting that these suppressor functions originated from donor T cells. 61 Thus, it was suggested that if standard immunosuppressive treatment fails, alternative cellular immunotherapy would be a viable option for patients with ALD. Primary biliary cholangitis (PBC), usually known as primary biliary cirrhosis, is a type of ALD characterized by a slow, progressive destruction of small bile ducts of the liver leading to the formation of cirrhosis and accumulation of bile and other toxins in the liver. A pilot, single-arm trial from China recruited seven patents with PBC who had a suboptimal response to ursodeoxycholic acid (UDCA) treatment. 63 These patients received UDCA treatment in combination with three rounds of allogeneic UC-MSCs at 4-week intervals with a dose of 0.5 × 10 6 cells/kg of patient body weight via the peripheral vein. No treatment-related adverse events or severe adverse events were observed throughout the course of the study. The clinical data indicated significant improvement in liver function, including reduction of serum ALP and gamma-glutamyltransferase (GGT) at 48 weeks post administration. The common symptoms of PBC, including fatigue, pruritus, and hypogastric ascites volume, were also reduced, supporting the feasibility of MSC-based therapy in the treatment of PBC, although major limitations of the study were nonrandomized, no control group and small sample size. Another study was conducted in China with ten PBC patients who underwent incompetent UDCA treatment for more than 1 year. These patients received a range of 3–5 allogeneic BM-MSCs/kg body weight by intravenous infusion. 64 Although these early studies have several limitations, such as small sample size, nonrandomization, and no control group, their preliminary data related to safety and efficacy herald the prospects and support the feasibility of stem cell-based therapy in the treatment of ALD.
In summary, the current number of trials for liver disease using stem cell-based therapy has provided fundamental data supporting the safety and potential therapeutic effects in various liver diseases. Unfortunately, due to the small number of trials, several obstacles need to be overcome to prove the effectiveness of the treatments, including (1) stem cell source and dose, (2) administration route, (3) time of intervention, and (4) clinical assessments during the follow-up period. Only by addressing these challenges we will be able to prove, facilitate and promote stem cell-based therapy as a mainstream treatment for liver diseases.
Arthritis is a general term describing cartilage conditions that cause pain and inflammation of the joints. Osteoarthritis (OA) is the most common form of arthritis caused by persistent degeneration and poor recovery of articular cartilage. 65 OA affects one or several diarthrodial joints, such as small joints at the hand and large joints at the knee and hips, leading to severe pain and subsequent reduction in the mobility of patients. There are two types of OA: (1) primary OA or idiopathic OA and secondary OA caused by causative factors such as trauma, surgery, and abnormal joint development at birth. 66 As conventional treatments for OA are not consistent in their effectiveness and might cause unbearable pain as well as long-term rehabilitation (in the case of joint replacement), there is a need for a more reliable, less painful, and curative therapy targeting the root of OA. 67 Thus, stem cell therapy has recently emerged as an alternative approach for OA and has drawn great attention in the regenerative field.
The administration of HSCs has been proven to reduce bone lesions, enhance bone regeneration and stimulate the vascularization process in degenerative cartilage. Attempts were made to evaluate the efficacy of peripheral blood stem cells in ten OA patients by three intraarticular injections. Post-administration analysis indicated a reduction in the WOMAC index with a significant reduction in all parameters. All patients completed 6-min walk tests with an increase of more than 54 meters. MRI analysis indicated an improvement in cartilage thickness, suggesting that cartilage degeneration was reduced post administration. To further enhance the therapeutic potential of HSCT, CD34 + stem cells were proposed to be used in combination with the rehabilitation algorithm, which included three stages: preoperative, hospitalization and outpatient periods. 68 Currently, a large wave of studies has been directed to MSC-based therapy for the treatment of OA due to their immunoregulatory functions and anti-inflammatory characteristics. MSCs have been used as the main cell source in several multiple and small-scale trials, proving their safety profile and potential effectiveness in alleviating pain, reducing cartilage degeneration, and enhancing the regeneration of cartilage structure and morphology in some cases. However, the best source of MSCs, whether from bone marrow, adipose tissue, or umbilical cord, for the management of OA is still a great question to be answered. A systematic review investigating over sixty-one of 3172 articles with approximately 2390 OA patients supported the positive effects of MSC-based therapy on OA patients, although the study also pointed out the fact that these therapeutic potentials were based on limited high-quality evidence and long-term follow-up. 69 Moreover, the study found no obvious evidence supporting the most effective source of MSCs for treating OA. Another systematic review covering 36 clinical trials, of which 14 studies were randomized trials, provides an interesting view in terms of the efficacy of autologous MSC-based therapy in the treatment of OA. 70 In terms of BM-MSCs, 14 clinical trials reported the clinical outcomes at the 1-year follow-up, in which 57% of trials reported clinical outcomes that were significantly better in comparison with the control group. However, strength analysis of the data set showed that outcomes from six trials were low, whereas the outcomes of the remaining eight trials were extremely low. Moreover, the positive evidence obtained from MRI analysis was low to very low strength of evidence after 1-year post administration. 70 Similar results were also found in the outcome analysis of autologous adipose tissue-derived MSCs (AT-MSCs). Thus, the review indicated low quality of evidence for the therapeutic potential of MSC therapy on clinical outcomes and MRI analysis. The low quality of clinical outcomes could be explained by the differences in interventions (including cell sources, cell doses, and administration routes), combination treatments (with hyaluronic acid, 71 peripheral blood plasma, 72 etc.), control treatments and clinical outcome measurements between randomized clinical trials. 73 In addition, the data of the systematic analysis could not prove the better source of MSCs for OA treatment. Taken together, although stem cell-based therapy has been shown to be safe and feasible in the management of OA, the authors support the notion that stem cell-based therapy could be considered an alternative treatment for OA when first-line treatments, such as education, exercise, and body weight management, have failed.
Cancer treatment
Stem cell therapy in the treatment of cancer is a sensitive term and needs to be used and discussed with caution. Clinicians and researchers should protect patients with cancer from expensive and potentially dangerous or ineffective stem cell-based therapy and patients without a cancer diagnosis from the risk of malignancy development. In general, unproven stem cell clinics employed three cell-based therapies for cancer management, including autologous HSCTs, stromal vascular fraction (SVF), and multipotent stem cells, such as MSCs. Allogeneic HSCTs confer the ability to generate donor lymphocytes that contribute to the suppression and regression of hematological malignancies and select solid tumors, a specific condition known as “graft-versus-tumor effects”. 74 However, stem cell clinics provide allogeneic cell-based therapy for the treatment of solid malignancies despite limited scientific evidence supporting the safety and efficacy of the treatment. High-quality evidence from the Cochrane library shows that marrow transplantation via autologous HSCTs in combination with high-dose chemotherapy does not improve the overall survival of women with metastatic breast cancer. In addition, a study including more than 41,000 breast cancer patients demonstrated no significant difference in survival benefits between patients who received HSCTs following high-dose chemotherapy and patients who underwent conventional treatment. 75 Thus, the use of autologous T-cell transplants as monotherapy and advertising stem cell-based therapies as if they are medically approved or preferred treatment of solid tumors is considered untrue statements and needs to be alerted to cancer patients. 76
Over the past decades, many preclinical studies have demonstrated the potential of MSC-based therapy in cancer treatment due to their unique properties. They confer the ability to migrate toward damaged sites via inherent tropism controlled by growth factors, chemokines, and cytokines. MSCs express specific C–X–C chemokine receptor type 4 (CXCR4) and other chemokine receptors (including CCR1, CCR2, CCR4, CCR7, etc.) that are essential to respond to the surrounding signals. 77 In addition, specific adherent proteins, including CD49d, CD44, CD54, CD102, and CD106, are also expressed on the MSC surface, allowing them to attach, rotate, migrate, and penetrate the blood vessel lumen to infiltrate the damaged tissue. 78 Similar to damaged tissues, tumors secrete a wide range of chemoattractant that also attract MSC migration via the CXCL12/CXCR4 axis. Previous studies also found that MSC migration toward the cancer site is tightly controlled by diffusible cytokines such as interleukin 8 (IL-8) and growth factors including transforming growth factor-beta 1 (TGF-β1), 79 platelet-derived growth factor (PDGF), 80 fibroblast growth factor 2 (FGF-2), 81 vascular endothelial growth factor (VEGF), 81 and extracellular matrix molecules such as matrix metalloproteinase-2 (MMP-2). 82 Once MSCs migrate successfully to cancerous tissue, accumulating evidence demonstrates the interaction between MSCs and cancer cells to exhibit their protumour and antitumour effects, which are the major concerns of MSC-based therapy. MSCs are well-known for their regenerative effects that regulate tissue repair and recovery. This unique ability is also attributed to the protumour functions of these cells. A previous study reported that breast cancer cells induce MSC secretion of chemokine (C–C motif) ligand 5 (CCL-5), which regulates the tumor invasion process. 83 , 84 Other studies also found that MSCs secrete a wide range of growth factors (VEGF, basic FGF, HGF, PDGF, etc.) that inhibits apoptosis of cancer cells. 85 Moreover, MSCs also respond to signals released from cancer cells, such as TGF-β, 86 to transform into cancer-associated fibroblasts, a specific cell type residing within the tumor microenvironment capable of promoting tumorigenesis. 87 Although MSCs have been proven to be involved in protumour activities, they also have potent tumor suppression abilities that have been used to develop cancer treatments. It has been suggested that MSCs exhibit their tumor inhibitory effects by inhibiting the Wnt and AKT signaling pathways, 88 reducing the angiogenesis process, 89 stimulating inflammatory cell infiltration, 90 and inducing tumor cell cycle arrest and apoptosis. 91 To date, the exact functions of MSCs in both protumour and antitumor activities are still a controversial issue across the stem cell field. Other approaches exploit gene editing and tissue engineering to convert MSCs into “a Trojan horse” that could exhibit antitumor functions. In addition, MSCs can also be modified to express specific anticancer miRNAs exhibiting tumor-suppressive behaviors. 92 However, genetically modified MSCs are still underdeveloped and require intensive investigation in the clinical setting.
To date, ~25 clinical trials have been registered on ClinicalTrials.gov aimed at using MSCs as a therapeutic treatment for cancer. 93 These trials are mostly phase 1 and 2 studies focusing on evaluating the safety and efficacy of the treatment. Studies exploiting MSC-based therapy have combined MSCs with an oncolytic virus approach. Oncolytic viruses are specific types of viruses that can be genetically engineered or naturally present, conferring the ability to selectively infect cancer cells and kill them without damaging the surrounding healthy cells. 94 A completed phase I/II study using BM-MSCs infected with the oncolytic adenovirus ICOVIR5 in the treatment of metastatic and refractory solid tumors in children and adult patients demonstrated the safety of the treatment and provided preliminary data supporting their therapeutic potential. 95 The same group also reported a complete disappearance of all signs of cancer in response to MSC-based therapy in one pediatric case three years post administration. 96 A reported study in 2019 claimed that adipose-derived MSCs infected with vaccinia virus have the potential to eradicate resistant tumor cells via the combination of potent virus amplification and senitization of the tumor cells to virus infection. 97 However, in a recently published review, a valid question was posed regarding the 2019 study that “do these reported data merit inclusion in the publication record when they were collected by such groups using a dubious therapeutic that was eventually confiscated by US Marshals?” 76
Taken together, cancer research and therapy have entered an innovative and fascinating era with advancements in traditional therapies such as chemotherapy, radiotherapy, and surgery on one hand and stem cell-based therapy on the other hand. Although stem cell-based therapy has been considered a novel and attractive therapeutic approach for cancer treatment, it has been hampered by contradictory results describing the protumour and antitumour effects in preclinical studies. Despite this contradictory reality, the use of stem cell-based therapy, especially MSCs, offers new hope to cancer patients by providing a new and more effective tool in personalized medicine. The authors support the use of MSC-based therapy as a Trojan horse to deliver specific anticancer functions toward cancer cells to suppress their proliferation, eradicate cancer cells, or limit the vascularization process of cancerous tissue to improve the clinical safety and efficacy of the treatment.
Human pluripotent stem cell-based therapy: a growing giant
The discovery of hPSCs, including human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), has revolutionized stem cell research and cell-based therapy. 98 hESCs were first isolated from blastocyst-stage embryos in 1998, 99 followed by breakthrough reprogramming research that converted somatic cells into hiPSCs using just four genetic factors. 100 , 101 Methods have been developed to maintain these cells long-term in vitro and initiate their differentiation into a wide variety of cell types, opening a new era in regenerative medicine, particularly cell therapy to replace lost or damaged tissues.
History of hPSCs
hPSCs are defined as self-renewable cell types that confer the ability to differentiate into various cellular phenotypes of the human body, including three germ layers. 102 Historically, the first pluripotent cell lines to be generated were embryonic carcinoma (EC) cell lines established from human germ cell tumors 103 and murine undifferentiated compartments. 104 Although EC cells are a powerful tool in vitro, these cells are not suitable for clinical applications due to their cancer-derived origin and aneuploidy genotype. 105 The first murine ESCs were established in 1981 based on the culture techniques obtained from EC research. 106 Murine ESCs are derived from the inner cell mass (ICM) of the pre-implantation blastocyst, a unique biological structure that contains outer trophoblast layers that give rise to the placenta and ICM. 107 In vivo ESCs only exist for a short period during the embryo’s development, and they can be isolated and maintained indefinitely in vitro in an undifferentiated state. The discovery of murine ESCs has dramatically changed the field of biomedical research and regenerative medicine over the last 40 years. Since then, enormous investigations have been made to isolate and culture ESCs from other species, including hESCs, in 1998. 99 The success of Thomson et al. in 1998 triggered the great controversy in media and ethical research boards across the globe, with particularly strong objections being raised to the use of human embryos for research purposes. 108 Several studies using hESCs have been conducted demonstrating their therapeutic potential in the clinical setting. However, the use of hESCs is limited due to (1) the ethical barrier related to the destruction of human embryos and (2) the potential risk of immunological rejection, as hESCs are isolated from pre-implantation blastocysts, which are not autologous in origin. To overcome these two great obstacles, several research groups have been trying to develop technology to generate hESCs, including nuclear transfer technology, the well-known strategy that creates Dolly sheep, although the generation of human nuclear transfer ESCs remains technically challenging. 109 Taking a different approach, in 2006, Yamanaka and Takahashi generated artificial PSCs from adult and embryonic mouse somatic cells using four transcription factors ( Oct-3/4 , Sox2 , Klf4 , and c-Myc , called OSKM) reduced from 24 factors. 100 Thereafter, in 2007, Takahashi and colleagues successfully generated the first hiPSCs exhibiting molecular and biological features similar to those of hESCs using the same OSKM factors. 101 Since then, hiPSCs have been widely studied to expand our knowledge of the pathogenesis of numerous diseases and aid in developing new cell-based therapies as well as personalized medicine.
Clinical applications of hPSCs
Since its beginning 24 years ago, hPSC research has evolved momentously toward applications in regenerative medicine, disease modeling, drug screening and discovery, and stem cell-based therapy. In clinical trial settings, the uses of hESCs are restricted by ethical concerns and tight regulation, and the limited preclinical data support their therapeutic potential. However, it is important to acknowledge several successful outcomes of hESC-based therapies in treating human diseases. In 2012, Steven Schwartz and his team reported the first clinical evidence of using hESC-derived retinal pigment epithelium (RPE) in the treatment of Stargardt’s macular dystrophy, the most common pediatric macular degeneration, and an individual with dry age-related macular degeneration. 110 , 111 With a differentiation efficiency of RPE greater than 99%, 5 × 10 4 RPEs were injected into the subretinal space of one eye in each patient. As the hESC source of RPE differentiation was exposed to mouse embryonic stem cells, it was considered a xenotransplantation product and required a lower dose of immunosuppression treatment. This study showed that hESCs improved the vision of patients by differentiating into functional RPE without any severe adverse events. The trial was then expanded into two open-label, phase I/II studies with the published results in 2015 supporting the primary findings. 112 In these trials, patients were divided into three groups receiving three different doses of hESC-derived RPE, including 10 × 10 4 , 15 × 10 4 and 50 × 10 4 RPE cells per eye. After 22 months of follow-up, 19 patients showed improvement in eyesight, seven patients exhibited no improvement, and one patient experienced a further loss of eyesight. The technical challenge of hESC-derived RPE engraftment was an unbalanced proliferation of RPE post administration, which was observed in 72% of treated patients. A similar approach was also conducted in two South Korean patients diagnosed with age-induced macular degeneration and two patients with Stargardt macular dystrophy. 113 The results supported the safety of hESC-derived RPE cells and illustrated an improvement in visual acuity in three patients. Recently, clinical-graded hESC-derived RPE cells were also developed by Chinese researchers under xeno-free culture conditions to treat patients with wet age-related degeneration. 114 As hESC development is still associated with ethical concerns and immunological complications related to allogeneic administration, hiPSC-derived RPE cells have emerged as a potential cell source for macular degeneration. Although RPE differentiation protocols have been developed and optimized to improve the efficacy of hiPSC-derived RPE cells, they are still insufficient, time-consuming and labor intensive. 115 , 116 For clinical application, an efficient differentiation of “primed” to “naïve” state hiPSCs toward the RPE was developed using feeder-free culture conditions utilizing the transient inhibition of the FGF/MAPK signaling pathway. 117 Overexpression of specific transcription factors in hiPSCs throughout the differentiation process is also an interesting approach to generate a large number of RPE cells for clinical use. In a recent study, overexpression of three eye-field transcription factors, including OTX2, PAX6, and MITF , stimulated RPE differentiation in hiPSCs and generated functional RPE cells suitable for transplantation. 118 To date, although reported data from phase I/II clinical trials have been produced enough to support the safety of hESC-derived RPE cells, the treatment is still in its immature stage. Thus, future studies should focus on the development of the cellular manufacturing process of RPE and the subretinal administration route to further improve the outcomes of RPE fabrication and engraftment into the patient’s retina (recommended review 119 ).
Numerous studies have demonstrated that hESC-derived cardiomyocytes exhibit cardiac transcription factors and display a cardiomyocyte phenotype and immature electrical phenotype. In addition, using hPSC-derived cardiomyocytes could provide a large number of cells required for true remuscularization and transplantation. Thus, these cells can be a promising novel therapeutic approach for the treatment of human cardiovascular diseases. In a case report, hESC-derived cardiomyocytes showed potential therapeutic effects in patients with severe heart failure without any subsequent complications. 120 This study was a phase I trial (ESCORT [Transplantation of Human Embryonic Stem Cell-derived Progenitors in Severe Heart Failure] trial) to evaluate the safety of cardiomyocyte progenitor cells derived from hESCs seeded in fibrin gel scaffolds for 10 patients with severe heart failure (NCT02057900). The encouraging results from this study demonstrated the feasibility of producing hESC-derived cardiomyocyte progenitor cells toward clinical-grade standards and combining them with a tissue-engineered scaffold to treat severe heart disease (the first patient of this trial has already reached the 7-year follow-up in October 2021). 121 Currently, the two ongoing clinical trials using hPSC-derived cardiomyocytes have drawn great attention, as their results would pave the way to lift the bar for approving therapies for commercial use. The first trial was conducted by a team led by cardiac surgeon Yoshiki Sawa at Osaka University using hiPSC-derived cardiomyocytes embedded in a cell sheet for engraftment (jRCT2052190081). The trials started first with three patients followed by ten patients to assess the safety of the approach. Once safety is met, the treatment can be sold commercially under Japan’s fast-track system for regenerative medicine. 122 Another trial used a collagen-based construct called BioVAT-HF to contain hiPSC-derived cardiomyocytes. The trial was divided into two parts to evaluate the cell dose: (Part A) recruiting 18 patients and (Part B) recruiting 35 patients to test a broad range of engineered human myocardium (EHM) doses. The expected results from this study will provide the “proof-of-concept” for the use of EHM in the stimulation of heart remuscularization in humans. To date, no adverse events or severe adverse events have been reported from these trials, supporting the safety of the procedure. However, as the number of treated patients was relatively small, limitations in drawing conclusions regarding efficacy are not yet possible. 21 , 123
One of the first clinical trials using hPSC-based therapy was conducted by Geron Corporation in 2010 using hESC-derived oligodendrocyte progenitor cells (OPC1) to treat spinal cord injury (SCI). The results confirmed the safety one year post administration in five participants, and magnetic resonance imaging demonstrated improvement of spinal cord deterioration in four participants. 124 Asterias Biotherapeutic (AST) continued the Geron study by conducting the SCiStar Phase I/IIa study to evaluate the therapeutic effects of AST-OPC1 (NCT02302157). The trial’s results published in clinicaltrials.gov demonstrated significant improvement in running speed, forelimb stride length, forelimb longitudinal deviations, and rear stride frequency. Interestingly, the recently published data of a phase 1, multicentre, nonrandomized, single-group assignment, interventional trial illustrated no evidence of neurological decline, enlarging masses, further spinal cord damage, or syrinx formation in patients 10 years post administration of the OPC1 product. 125 This data set provides solid evidence supporting the safety of OPC1 with an event-free period of up to 10 years, which strengthens the safety profile of the SCiStar trial.
Analysis of the global trends in clinical trials using hPSC-based therapy showed that 77.1% of studies were observational (no cells were administered into patient), and only 22.9% of studies used hPSC-derived cells as interventional treatment. 126 The number of studies using hiPSCs was relatively higher than that using hESCs, which was 74.8% compared to 25.2%, respectively. The majority of observational studies were performed in developed countries, including the USA (41.6%) and France (16.8%), whereas interventional studies were conducted in Asian countries, including China (36.7%), Japan (13.3%), and South Korea (10%). The trends in therapeutic studies were also clear in terms of targeted diseases. The three most studied diseases were ophthalmological conditions, circulatory disorders, and nervous systems. 127 However, it is surprising that the clinical applications of hPSCs have achieved little progress since the first hESCs were discovered worldwide. The relatively low number of clinical trials focusing on using iPSCs as therapeutic agents to administer into patients could be ascribed to the unstable genome of hiPSCs, 128 immunological rejection, 129 and the potential for tumor formation. 130
Mesenchymal stem/stromal cell-based therapy: is it time to consider their origin toward targeted therapy?
Approximately 55 years ago, fibroblast-like, plastic-adherent cells, later named mesenchymal stem cells (MSCs) by Arnold L. Caplan, 18 were discovered for the first time in mouse bone marrow (BM) and were later demonstrated to be able to form colony-like structures, proliferate, and differentiate into bone/reticular tissue, cartilage, and fat. 131 Protocols were subsequently established to directly culture this subpopulation of stromal cells from BM in vitro and to stimulate their differentiation into adipocytes, chondroblasts, and osteoblasts. 132 Since then, MSCs have been found in and derived from different human tissue sources, including adipose tissue (AT), the umbilical cord (UC), UC blood, the placenta, dental pulp, amniotic fluid, etc. 133 To standardize and define MSCs, the International Society for Cell and Gene Therapy (ISCT) set minimal identification criteria for MSCs derived from multiple tissue sources. 134 Among them, MSCs derived from AT, BM, and UC are the most commonly studied MSCs in human clinical trials, 135 and they constitute the three major tissue sources of MSCs that will be discussed in this review.
The discovery of MSCs opened an era during which preclinical studies and clinical trials have been performed to assess the safety and efficacy of MSCs in the treatment of various diseases. The major conclusion of these studies and trials is that MSC-based therapy is safe, although the outcomes have usually been either neutral or at best marginally positive in terms of the clinically relevant endpoints regardless of MSC tissue origin, route of infusion, dose, administration duration, and preconditioning. 136 It is important to note that a solid background of knowledge has been generated from all these studies that has fueled the recent translational research in MSC-based therapy. As MSCs have been intensively studied over the last 55 years and have become the subject of multiple reviews, systematic reviews, and meta-analyses, the objective of this paper is not to duplicate these publications. Rather, we will discuss the questions that both clinicians and researchers are currently exploring with regard to MSC-based therapy, diligently seeking answers to the following:
“With a solid body of data supporting their safety profiles derived from both preclinical and clinical studies, does the tissue origin of MSCs also play a role in their downstream clinical applications in the treatment of different human diseases?”
“Do MSCs derived from AT, BM, and UC exhibit similar efficacy in the treatment of neurological diseases, metabolic/endocrine-related disorders, reproductive dysfunction, skin burns, lung fibrosis, pulmonary disease, and cardiovascular conditions?”
To answer these questions, we will first focus on the most recently published clinical data regarding these targeted conditions, including neurological disorders, pulmonary dysfunctions, metabolic/endocrine-related diseases, reproductive disorders, skin burns, and heart-related diseases, to analyze the potential efficacy of MSCs derived from AT, BM, and UC. Based on the level of clinical improvement observed in each trial, we analyzed the potential efficacy of MSCs derived from each source to visualize the correlation between patient improvement and MSC sources. We will then address recent trends in the exclusive use of MSC-based products, focusing on the efficacy of treatment with MSCs from each of the abovementioned sources, and we will analyze the relationship between the respective efficacies of MSCs from these sources in relation to the targeted disease conditions. Finally, we propose a hypothesis and mechanism to achieve the currently still unmet objective of evaluating the use of MSCs from AT, BM, and UC in regenerative medicine.
An overview of MSC tissue origins and therapeutic potential
In general, MSCs are reported to be isolated from numerous tissue types, but all of these types can be organized into two major sources: adult 137 and perinatal sources 138 (Fig. 2 ). Adult sources of MSCs are defined as tissues that can be harvested or obtained from an individual, such as dental pulp, 139 BM, peripheral blood, 140 AT, 141 lungs, 142 hair, 143 or the heart. 144 Adult MSCs usually reside in specialized structures called stem cell niches, which provide the microenvironment, growth factors, cell-to-cell contacts and external signals necessary for maintaining stemness and differentiation ability. 145 BM was the first adult source of MSCs discovered by Friedenstein 131 and has become one of the most documented and largely used MSC sources to date, followed by AT. BM-MSCs are isolated and cultured in vitro from BM aspirates using a Ficoll gradient-centrifugation method 146 or a red blood cell lysate buffer to collect BM mononuclear cell populations, whereas AT-MSCs are obtained from stromal vascular fractions of enzymatically digested AT obtained through liposuction, 141 lipoplasty, or lipectomy procedures. 147 These tissue collection procedures are invasive and painful for the patient and are accompanied by a risk of infection, although BM aspiration and adipose liposuction are considered safe procedures for BM and AT biopsies. The number of MSCs that can be isolated from these adult tissues varies significantly in a tissue-dependent manner. The percentage of MSCs in BM mononuclear cells ranges from 0.001 to 0.01% following gradient centrifugation. 132 The number of MSCs in AT is at least 500 times higher than that in BM, with approximately 5,000 MSCs per 1 g of AT. Perinatal sources of MSCs consist of UC-derived components, such as UC, Wharton’s jelly, and UC blood, and placental structures, such as the placental membrane, amnion, chorion membrane, and amniotic fluid. 138 The collection of perinatal MSCs, such as UC-MSCs, is noninvasive, as the placenta, UC, UC blood, and amnion are considered waste products that are usually discarded after birth (with no ethical barriers). 148 Although MSCs represent only 10 −7 % the cells found in UC, their higher proliferation rate and rapid population doubling time allow these cells to rapidly replicate and increase in number during in vitro culture. 149 Under standardized xeno-free and serum-free culture platforms, AT-MSCs show a faster proliferation rate and a higher number of colony-forming units than BM-MSCs. 149 UC-MSCs have the fastest population doubling time compared to AT-MSCs and BM-MSCs in both conventional culture conditions and xeno- and serum-free environments. 149 MSCs extracted from AT, BM and UC exhibit all minimal criteria listed by the ISCT, including morphology (plastic adherence and spindle shape), MSC surface markers (95% positive for CD73, CD90 and CD105; less than 2% negative for CD11, CD13, CD19, CD34, CD45, and HLR-DR) and differentiation ability into chondrocytes, osteocytes, and adipocytes. 150
The two major sources of MSCs: adult and perinatal sources. The adult sources of MSCs are specific tissue in human body where MSCs could be isolated, including bone marrow, adipose tissue, dental pulp, peripheral blood, menstrual blood, muscle, etc. The perinatal sources of MSCs consist of umbilical cord-derived components, such as umbilical cord, Wharton’s jelly, umbilical cord blood, and placental structures, such as placental membrane, amnion, chorion membrane, amniotic fluid, etc. The figure was created with BioRender.com
In fact, although MSCs derived from either adult or perinatal sources exhibit similar morphology and the basic characteristics of MSCs, studies have demonstrated that these cells also differ from each other. Regarding immunophenotyping, AT-MSCs express high levels of CD49d and low levels of Stro-1. An analysis of the expression of CD49d and CD106 showed that the former is strongly expressed in AT-MSCs, in contrast to BM-MSCs, whereas CD106 is expressed in BM-MSCs but not in AT-MSCs. 151 Increased expression of CD133, which is associated with stem cell regeneration, differentiation, and metabolic functions, 152 was observed in BM-MSCs compared to MSCs from other sources. 153 A recent study showed that CD146 expression in UC-MSCs was higher than that in AT- and BM-MSCs, 153 supporting the observation that UC-MSCs have a stronger attachment and a higher proliferation rate than MSCs from other sources, as CD146 is a key cell adhesion protein in vascular and endothelial cell types. 154 In terms of differentiation ability, donor-matched BM-MSCs exhibit a higher ability to differentiate into chondrogenic and osteogenic cell types than AT-MSCs, whereas AT-MSCs show a stronger capacity toward the adipogenic lineage. 150 The findings from an in vitro differentiation study indicated that BM-MSCs are prone to osteogenic differentiation, whereas AT-MSCs possess stronger adipogenic differentiation ability, which can be explained by the fact that the epigenetic memory obtained from either BM or AT drives the favored MSC differentiation along an osteoblastic or adipocytic lineage. 155 Interestingly, although UC-MSCs have the ability to differentiate into adipocytes, osteocytes, or chondrocytes, their osteogenic differentiation ability has been proven to be stronger than that of BM-MSCs. 156 The most interesting characteristic of MSCs is their immunoregulatory functions, which are speculated to be related to either cell-to-cell contact or growth factor and cytokine secretion in response to environmental/microenvironmental stimuli. MSCs from different sources almost completely inhibit the proliferation of peripheral blood mononuclear cells (PBMCs) at PBMC:MSC ratios of 1:1 and 10:1. 149 At a higher ratio, BM-MSCs showed a significantly higher inhibitory effect than AT- or UC-MSCs. 153 Direct analysis of the immunosuppressive effects of BM- and UC-MSCs has revealed that these cells exert similar inhibitory effects in vitro with different mechanisms involved. 157 With these conflicting data, the mechanism of action related to the immune response of MSCs from different sources is still poorly understood, and long-term investigations both in preclinical studies and in clinical trial settings are needed to shed light on this complex immunomodulation function.
The great concern in MSC-based therapy is the fate of these cells post administration, especially through different delivery routes, including systemic administration via an intravenous (IV) route or tissue-specific administration, such as dorsal pancreatic administration. It is important to understand the distribution of these cells after injection to expand our understanding of the underlying mechanisms of action of treatments; in addition, this knowledge is required by authorized bodies (the Food and Drug Administration (FDA) in the United States or the regulation of advanced-therapy medicinal products in Europe, No. 1394/2007) prior to using these cells in clinical trials. The preclinical data using various labeling techniques provide important information demonstrating that MSCs do not have unwanted homing that could lead to the incorrect differentiation of the cells or inappropriate tumor formation. In a mouse model, human BM-MSCs and AT-MSCs delivered via an IV route are rapidly trapped in the lungs and then recirculate through the body after the first embolization process, with a small number of infused cells found mainly in the liver after the second embolization. 158 Using the technetium-99 m labeling method, intravenously infused human cells showed long-term persistence up to 13 months in the bone, BM compartment, spleen, muscle, and cartilage. 159 A similar result was reported in baboons, confirming the long-term homing of human MSCs in various tissues post administration. 160 Although the retainment of MSCs in the lungs might potentially reduce their systemic therapeutic effects, 161 it provides a strong advantage when these cells are used in the treatment of respiratory diseases. Local injection of MSCs also revealed their tissue-specific homing, as an injection of MSCs via the renal artery route resulted in the majority of the injected cells being found in the renal cortex. 162 Numerous studies have been conducted to track the migration of administered MSCs in human subjects. Henriksson and his team used MSCs labeled with iron sucrose in the treatment of intervertebral disc degeneration. 163 Their study showed that chondrocytes differentiated from infused MSCs could be detected at the injured intervertebral discs at 8 months but not at 28 months. A study conducted in a patient with hemophilia A using In-oxine-labeled MSCs showed that the majority of the cells were trapped in the lungs and liver 1 h post administration, followed by a reduction in the lungs and an increase in the number of cells in the liver after 6 days. 164 Interestingly, a small proportion of infused MSCs were found in the hemarthrosis site at the right ankle after 24 h, suggesting that MSCs are attracted and migrate to the injured site. The distribution of MSCs was also reported in the treatment of 21 patients diagnosed with type 2 diabetes using 18-FDG-tagged MSCs and visualized using positron emission tomography (PET). 165 The results illustrated that local delivery of MSCs via an intraarterial route is more effective than delivery via an IV route, as MSCs home to the pancreatic head (pancreaticoduodenal artery) or body (splenic artery). Therefore, although the available data related to the biodistribution of infused MSCs are still limited, the results obtained from both preclinical and clinical studies illustrate a comparable set of data supporting results on homing, migration to the injured site, and the major organs where infused MSCs are located. The following comprehensive and interesting reviews are highly recommended. 166 , 167 , 168
To date, 1426 registered clinical trials spanning different trial phases have used MSCs for therapeutic purposes, which is four times the number reported in 2013. 169 , 170 As supported by a large body of preclinical studies and advancements in conducting clinical trials, MSCs have been proven to be effective in the treatment of numerous diseases, including nervous system and brain disorders, pulmonary diseases, 171 cardiovascular conditions, 172 wound healing, etc. The outcomes of MSC-based therapy have been the subject of many intensive reviews and systematic analyses with the solid conclusion that these cells exhibit strong safety profiles and positive outcomes in most tested conditions. 173 , 174 , 175 In addition, the available data have revealed several potential mechanisms that could explain the beneficial effects of MSCs, including their homing efficiency, differentiation potential, production of trophic factors (including cytokines, chemokines, and growth factors), and immunomodulatory abilities. However, it is still not known which MSC types should be used for which diseases, as it seems to be that MSCs exhibit beneficial effects regardless of their sources. 169
Acquired brain and spinal cord injury treatment: BM-MSCs have emerged as key players
The theory that brain cells can never regenerate has been challenged by the discovery of newly formed neurons in the human adult hippocampus or the migration of stem cells in the brain in animal models. 176 These observations have triggered hope for regeneration in the context of neuronal diseases by using exogenous stem cell sources to replenish or boost the stem cell population in the brain. Moreover, the limited regenerative capacity of the brain and spinal cord is an obstacle for traditional treatments of neurodegenerative diseases, such as autism, cerebral palsy, stroke, and spinal cord injury (SCI). As current treatments cannot halt the progression of these diseases, studies throughout the world have sought to exploit cell-based therapies to treat neurodegenerative diseases on the basis of advances in the understanding and development of stem cell technology, including the use of MSCs. Successful stem cell therapy for treating brain disease requires therapeutic cells to reach the injured sites, where they can repair, replace, or at least prevent the deteriorative effects of neuronal damage. 177 Hence, the gold standard of cell-based therapy is to deliver the cells to the target site, stimulate the tissue repair machinery, and regulate immunological responses via either cell-to-cell contact or paracrine effects. 178 Among 315 registered clinical trials using stem cells for the treatment of brain diseases, MSCs and hematopoietic stem cells (HSCs; CD34+ cells isolated from either BM aspirate or UC blood) are the two main cell types investigated, whereas approximately 102 clinical trials used MSCs and 62 trials used HSCs for the treatment of brain disease (main search data from clinicaltrial.gov). MSCs are widely used in almost all clinical trials targeting different neuronal diseases, including multiple sclerosis, 179 stroke, 180 SCI, 181 cerebral palsy, 182 hypoxic-ischemic encephalopathy, 183 autism, 184 Parkinson’s disease, 185 Alzheimer’s disease 185 and ataxia. Among these trials in which MSCs were the major cells used, nearly two-thirds were for stroke, SCI, or multiple sclerosis. MSCs have been widely used in 29 registered clinical trials for stroke, with BM-MSCs being used in 16 of these trials. With 26 registered clinical trials, SCI is the second most common indication for using MSCs, with 16 of these trials using mainly expanded BM-MSCs. For multiple sclerosis, 15 trials employed BM-MSCs among a total of 23 trials conducted for the treatment of this disease. Hence, it is important to note that in neuronal diseases and disorders, BM-MSCs have emerged as the most commonly used therapeutic cells among other MSCs, such as AT-MSCs and UC-MSCs.
The outcomes of the use of BM-MSCs in the treatment of neuronal diseases have been widely reported in various clinical trial types. A review by Zheng et al. indicated that although the treatments appeared to be safe in patients diagnosed with stroke, there is a need for well-designed phase II multicentre studies to confirm the outcomes. 173 One of the earliest trials using autologous BM-MSCs was conducted by Bang et al. in five patients diagnosed with stroke in 2005. The results supported the safety and showed an improved Barthel index (BI) in MSC-treated patients. 186 In a 2-year follow-up clinical trial, 16 patients with stroke received BM-MSC infusions, and the results showed that the treatment was safe and improved clinical outcomes, such as motor impairment scale scores. 187 A study conducted in 12 patients with ischemic stroke showed that autologous BM-MSCs expanded in vitro using autologous serum improved the patient’s modified Rankin Scale (mRS), with a mean lesion volume reduced by 20% at 1 week post cell infusion. 188 In 2011, a modest increase in the Fugl Meyer and modified BI scores was observed after autologous administration of BM-MSCs in patients with chronic stroke. 189 More recently, a prospective, open-label, randomized controlled trial with blinded outcome evaluation was conducted, with 39 patients and 15 patients in the BM-MSC administration and control groups, respectively. The results of this study indicated that autologous BM-MSCs with autologous serum administration were safe, but the treatment led to no improvements at 3 months in modified Rankin Scale (mRS) scores, although leg motor improvement was observed. 180 Researchers explored whether the efficacy of BM-MSC administration was maintained over time in a 5-year follow-up clinical trial. Patients (85) were randomly assigned to either the MSC group or the control group, and follow-ups on safety and efficacy were performed for 5 years, with 52 patients being examined at the end of the study. The MSC group exhibited a significant improvement in terms of decreased mRS scores, whereas the number of patients with an mRS score increase of 0–3 was statistically significant. 187 Although autologous BM-MSCs did not improve the Basel index, mRS, or National Institutes of Health Stroke Scale (NIHSS) score 2 years post infusion, patients who received BM-MSC therapy showed improvement in their motor function score. 190 In addition, a prospective, open-label, randomized controlled trial by Lee et al. showed that autologous BM-MSCs primed with autologous “ischemic” serum significantly improved motor functions in the MSC-treated group. Neuroimaging analysis also illustrated a significant increase in interhemispheric connectivity and ipsilesional connectivity in the MSC group. 191 Recently, a single intravenous infection of allogeneic BM-MSCs has been proven to be safe and feasible in patients with chronic stroke with a significant improvement in BI score and NIHSS score. 192
In two systematic reviews using MSCs for the treatment of SCI, BM-MSCs ( n = 16) and UC-MSCs ( n = 5) were reported to be safe and well-tolerated. 193 , 194 The results indicated significant improvements in the stem cell administration groups compared with the control groups in terms of a composite of the American Spinal Injury Association (ASIA) impairment scale (AIS) grade, AIS grade A, and ASIA sensory scores and bladder function (Table 1 ). However, larger experimental groups with a randomized and multicentre design are needed for further confirmation of these findings. For multiple sclerosis, several early-phase (phase I/II) registered clinical studies have used BM-MSCs. A study compared the potential efficacy of BM-MSC and BM mononuclear cell (BMMNC) transplantation in 105 patients with spastic cerebral palsy. 195 The results showed that the GMFM (gross motor function measure) and the FMFM (fine motor function measure) scores of the BM-MSC transplant group were higher than those of the BMNNC transplant group at 3, 6, and 12 months of assessment. In terms of autism spectrum disorder, a review of 254 children after BMMNC transplantation found that over 90% of patients’ ISAA (Indian Scale for Assessment of Autism) and CARS (Childhood Autism Rating Scale) scores improved. Young patients and those in whom autism spectrum disorder was detected early generally showed better improvement. 196
One of the biggest limitations when using BM-MSCs is the bone marrow aspiration process, as it is an invasive procedure that can introduce a risk of complications, especially in pediatric and elderly patients. 197 Therefore, UC-MSCs have been suggested as an alternative to BM-MSCs and are being studied in clinical trials for the treatment of neurological diseases in approximately 1550 patients throughout the world; however, only three studies have been completed, with data published recently. 198 A recent study showed that UC-MSC administration improved both gross motor function and cognitive skills, assessed using the Activities of Daily Living (ADL), Comprehensive Function Assessment (CFA), and GMFM, in patients diagnosed with cerebral palsy. The improvements peaked 6 months post administration and lasted for 12 months after the first transplantation. 199 In a single-targeted phase I/II clinical trial using UC-MSCs for the treatment of autism, Riordan et al. reported decreases in Autism Treatment Evaluation Checklist (ATEC) and CARS scores for eight patients, but the paper has been retracted due to a violation of the journal’s guidelines. 200 In an open-label, phase I study, UC-MSCs were used as the main cells to treat 12 patients with autism spectrum disorder via IV infusions. It is important to note that five participants developed new class I anti-human leukocyte antigen in response to the specific lot of manufactured UC-MSCs, although these responses did not exhibit any immunological response or clinical manifestations. Only 50% of participants showed improvements in at least two autism-specific measurements. 201 Although not as widely used as BM-MSCs, these trials have demonstrated the efficacy of using UC-MSCs in the treatment of SCIs. In a pilot clinical study, Yang et al. showed that the use of UC-MSCs has the potential to improve disease status through an increase in total ASIA and SCI Functional Rating Scale of the International Association of Neurorestoratology (IANR-SCIFRS) scores, as well as an improvement in pinprick, light touch, motor and sphincter scores. 202 A study of 22 patients with SCIs showed a potential therapeutic effect in 13 patients post UC-MSC infusion. 203 AT-MSCs were also used to treat SCI, with a single case report indicating an improvement in neurological and motor functions in a domestic ferret patient. 204 However, a result obtained from another phase I trial using AT-MSCs showed mild improvements in neurological function in a small number of patients. 205 A phase II, randomized, double-blind, placebo-controlled, single-center, pilot clinical trial using AT-MSCs in the treatment of acute ischemic stroke published a data set that supports the safety of the therapy, although patients who received AT-MSCs showed a nonsignificant improvement after 24 months of follow-up. 206 In all of the above studies, the safety of using either AT-MSCs or UC-MSCs was evaluated, and no significant reactions were reported after infusion.
Therefore, based on the number of recovered patients post-transplantation and the number of recruited patients in large-scale trials using BM-MSCs, it seems that BM-MSCs are the prominent cells in regard to treating neurodegenerative disease with potentially good outcomes (Table 1 ). It is important to note that we do not negate the fact that AT- and UC-MSCs also show positive outcomes in the treatment of neuronal diseases, with numerous ongoing large-scale, multicentre, randomized, and placebo-control trials, 207 , 208 but we suggest alternative and thoughtful decisions regarding which sources of MSCs are best for the treatment of neuronal diseases and degenerative disorders.
Respiratory disease and lung fibrosis: clinical data support UC as a good source of MSCs
In the last decade, significant increases in respiratory disease incidence due to air pollution, smoking behavior, population aging, and recently, respiratory virus infections such as coronavirus disease 2019 (COVID-19) 209 have been observed, leading to substantial burdens on public health and healthcare systems worldwide. Respiratory inflammatory diseases, including bronchopulmonary dysplasia (BPD), chronic obstructive pulmonary disease (COPD), and acute respiratory distress syndrome (ARDS), have recently emerged as three prevalent pulmonary diseases in children and adults. These conditions are usually associated with inflammatory cell infiltration, a disruption of alveolar structural integrity, a reduction in alveolar fluid clearance ability, cytokine release and associated cytokine storms, airway remodeling, and the development of pulmonary fibrosis. Traditional treatments are focused on relieving symptoms and preventing disease progression using surfactants, artificial respiratory support, mechanical ventilation, and antibiotic/anti-inflammatory drugs, with limited effects on the damaged airway, alveolar fluid clearance, and other detrimental effects caused by the inflammatory response. MSCs are known for their immunomodulatory abilities, showing potential in injury reduction and aiding lung recovery after injury. According to ClinicalTrials.gov, from 2017 to date, there have been 159 studies testing the application of MSCs in the treatment of pulmonary diseases, including but not limited to BPD, COPD, and ARDS, suggesting a trend in the use of MSCs as an alternative approach for the treatment of respiratory diseases, especially MSCs from UC as an “off-the-shelf” and allogeneic source.
Extremely premature infants are born with arrested lung development at the canalicular-saccular phases prior to alveolarization and before pulmonary maturation occurs, which results in the development of BPD. 210 These infants require intensive care during the first three months of life using postnatal interventions, including positive pressure mechanical ventilation, external oxygen support, and surfactant infusions, and the newborns have recurrent infections that further compromise normal lung development. 211 To date, 13 clinical trials have been proposed to use UC-MSCs in the treatment of BPD, recruiting ~566 premature infants throughout the world, including Vietnam, Korea, the United States, Spain, Australia, and China. The majority of these trials use UC-derived stem cells for phases I and II, focusing on evaluating the safety and efficacy of stem cell-based therapy. 212 Human UC tissue and its derivative components are considered the most attractive cell sources for MSCs in the treatment of BPD due to the ease of obtaining them, being readily available, with no ethical concerns, low antigenicity, a high cell proliferation rate, and superior regenerative potential. Chang et al. used MSCs derived from UC blood in a phase I dose-escalation clinical trial to treat 9 preterm infants via intratracheal administration to prevent the development of BPD. 213 All 9 preterm infants survived, and only three developed BPD; these infants had significantly decreased BPD severity compared with the historically matched control group. A follow-up study of the same patients after 24 months indicated that only one infant had an E. cloacae infection after discharge at 4 months, with subsequent disseminated intravascular coagulation, which was later proven to be unrelated to the intervention. The remaining eight patients survived with normal pulmonary development and function, suggesting that the therapy was safe. MSCs from UC blood were also used for the treatment of 12 extremely low birthweight preterm patients using the same administration route, which further confirmed the safety of the therapy in the treatment of BPD, although ten of 12 infants still developed severe BPD at 36 weeks. 214 Our group also reported the safety and potential efficacy of using UC-MSCs in the treatment of four preterm infants, and the results supported the safety of UC-MSCs and demonstrated that patients could be weaned from oxygen supply and develop normal lung structure and function. 215 A phase II clinical trial of 66 infants born at 23–28 weeks with a birthweight of 500–1250 g who were recruited and randomized into an MSC-administration group and a control group was conducted. Although the results supported the safety of MSC administration in preterm infants, the efficacy of the treatment was not supported by statistical analysis, potentially due to the small sample size. Subgroup analysis showed that patients with severe BPD born at 23–24 weeks showed a significant improvement in BPD severity, but those born at 25–28 weeks did not. 216 Hence, it is important to conduct controlled phase II clinical trials with larger cohort sizes to further substantiate the efficacy of UC blood-derived MSCs in the treatment of infants with BPD.
With more than 65 million patients worldwide, COPD was the third-leading cause of death in 2020, according to World Health Organization records. COPD is classified as a chronic inflammatory and destructive pulmonary disease characterized by a progressive reduction in lung function. Averyanov et al. performed a randomized, placebo-controlled phase I/IIa study in 20 patients with mild to moderate idiopathic pulmonary fibrosis (IPF). Treatment group patients received two IV doses of allogeneic MSCs (2 × 10 8 cells) every 3 months, and the second group received a placebo. 217 Evaluation tests were performed at weeks 13, 26, 39, and 52. The 6-min walking test distance (6MWTD) results showed that patient fitness improved from week 13 onwards and was maintained until up to the 52nd week. Pulmonary function indicators improved markedly before and after treatment in the treated group but did not change significantly in the placebo group. The goal of MSC therapy in the treatment of COPD is to promote the regeneration of parenchymal cells and alveolar structure and the restoration of lung function. Based on the results of a phase I trial of a commercial BM-MSC product, Prochymal TM , which led to improvements in pulmonary function in treated patients, a multicentre, double-blind, placebo-controlled phase II trial was conducted in 62 patients diagnosed with COPD to determine the safety and potential efficacy of the product. Although the results supported the safety of BM-MSCs, their effectiveness in the treatment of COPD was not assured. No statistically significant differences in FEV 1 or FEV 1% , total lung capacity, or carbon monoxide diffusing capacity were detected after 2 years of follow-up between the two treatment groups. To date, there have been five clinical trials using BM-MSCs as the main stem cells for the treatment of COPD, but the overall clinical outcomes did not demonstrate the potential therapeutic effects of the treatment. 218 , 219 , 220 , 221 , 222 In clinical trial NCT001110252, the results showed that there was an overall reduction in the process of COPD pathological development 3 years after the administration of BM-MSCs, although the trial had a phase I design, with no control group, and evaluated only a small cohort (four patients). 219 To alleviate local inflammatory progression in COPD, Oliveira et al. studied the combination treatment of one-way endobronchial valve (EBV) and BM-MSC intubation. 223 Ten GOLD (Global Initiative for Obstructive Lung Disease) stage C or D patients were equally divided into 2 groups: one group received a dose of 10 8 cells before valve insertion, and the other group received a normal saline infusion. The follow-up time was 90 days. Inflammation was significantly improved as assessed by the CRP (C-reactive protein) index at 30 and 90 days after infusion. In addition, improvements in St. George’s Respiratory Questionnaire (SGRQ) scores indicated improved patient quality of life. Furthermore, an investigation into the homing ability of MSCs in vivo was performed on 9 GOLD patients, from stage A to stage D. Each patient received two 2 × 10 6 BM-MSC/kg IV infusions 1-week apart. 224 The marking of MSCs with indium-111 showed that MSCs were retained in the pulmonary vasculature longer in patients with mild COPD and that the levels of inflammatory mediators improved after 7 days of treatment. The results of the evaluation survey conducted after 1 year showed that the number of COPD exacerbations decreased to six times/year compared to 11 times/year before treatment. In addition, AT-MSCs present in the stromal vascular fraction were used to treat patients with COPD, and no adverse events were observed after 12 months of follow-up, but the clinical improvements post administration were not clear. 225 The results from a phase I clinical trial using AT-MSCs in eight patients with COPD also reported no significant change in pulmonary function test parameters. 226 A study evaluating the use of AT-MSCs as adjunctive therapy for COPD in 12 patients was performed. 227 AT was obtained using standard liposuction, MSCs were isolated, and 150–300 million cells were intravenously infused. The patients showed improvements in quality of life, with improved SGRQ scores after 3 and 6 months of treatment. Recently, UC-MSCs have emerged as potential allogeneic stem cell candidates for the treatment of COPD. 228 In a pilot clinical study, it was demonstrated that allogeneic administration of UC-MSCs in the treatment of COPD was safe and potentially effective. 229 In one study, 20 patients, including 9 at stage C and 11 at stage D per the GOLD classification, with histories of smoking were recruited and received cell-based therapy. The patients who received UC-MSC treatment showed significant reductions in Modified Medical Research Council scores, COPD assessment test scores, and the number of pulmonary exacerbations 6 months post administration. The results of the second trial using UC-MSCs showed that the mean FEV 1 /FVC ratios were increased along with improvements in SGRQ scores and 6MWTDs at three months post administration. 230 Although thorough assessments of the effectiveness of UC-MSCs are still in the early stages, the number of trials using UC-MSCs for the treatment of COPD is increasing steadily, with larger sample sizes and stronger designs (randomized or matched case–control studies), providing a data set strongly supporting the future applications of UC-MSCs. 231
The ongoing pandemic of the 21st century, the COVID-19 pandemic, emerged as a major pulmonary health problem worldwide, with a relatively high mortality rate. Numerous studies, reviews, and systematic analyses have been conducted to discuss and expand our knowledge of the virus and propose different mechanisms by which the virus could alter the immune system. 232 One of the most critical mechanisms is the generation of cytokine storms, which result from the initiation of hyperreactions of the adaptive immune response to viral infection. 233 These cytokine storms are formed by the establishment of waves of hypercytokinaemia generated from overreactive immune cells, which enhance their expression of TNF-α, IL-6, and IL-10, preventing T-lymphocyte recruitment and proliferation and culminating in T-lymphocyte apoptosis and T-cell exhaustion. In COVID-19, once a cytokine storm is formed, it spreads from an initial focal area through the body via circulation, which has been discussed in a comprehensive review by Jamilloux et al. 234 At the time of writing this review, there were 74 clinical trials using MSCs from UC (29 trials; including WJ-derived MSCs (WJ-MSCs) and placenta-derived MSCs (PL-MSCs)), AT (15 trials), and BM (11 trials) (comprehensive review 171 , 235 ). Hence, UC-MSCs have emerged as the most common MSCs for the treatment of COVID-19, with a total of 1047 patients participating in these trials. Among these trials, 15 completed trials using UC-MSCs (including WJ- and PL-MSCs) have been reported, with clinical data from approximately 600 recruited patients. 232 Eight of these 15 studies used allogenic UC-MSC transplantation to treat critically ill patients. 236 A list of case reports using UC-MSCs showed that the treatments were safe and well-tolerated in 14 patients with COVID-19, with the primary outcomes including increased percentages and numbers of T cells, 237 , 238 improved respiratory and renal functions, 239 reductions in inflammatory biomarker levels, 240 and positive outcomes in the PaO 2 /FiO 2 ratio. 240 In a pilot study conducted in ten patients with severe COVID-19, a single dose of UC-MSCs was safe and improved clinical outcomes, although the study did not investigate whether multiple doses of UC-MSCs could further improve the outcomes. 241 Two trials without a control group were conducted in 47 patients, and the results indicated that UC-MSCs were safe and feasible for the treatment of patients with COVID-19. 235 , 242 A single-center, open-label, individually randomized, standard treatment-controlled trial was performed in 41 patients (12 patients assigned to the UC-MSC group), and the results showed that significant improvements in C-reactive protein levels, IL-6 levels, oxygen indices, and lymphocyte numbers were found in the MSC groups. Chest computed tomography (CT) illustrated significant reductions in lung inflammatory responses as reflected by CT findings, the number of lobes involved, and pulmonary consolidation. 238 In a phase I trial conducted in 18 hospitalized patients with COVID-19, UC-MSCs were administered via an IV route in nine patients (five patients with moderate COVID-19 and 4 patients with severe COVID-19) at days 0, 3, and 6, with no treatment-related adverse events or severe adverse events. 243 Only one patient in the UC-MSC group required mechanical ventilation, compared to four patients in the control group. However, the clinical outcomes, such as COVID-19 symptoms, laboratory test results, CT findings of lung damage, and pulmonary function test parameters, were improved in both groups. Interestingly, a 1-year follow-up of the same sample revealed that the patients who received UC-MSC administration improved in terms of whole-lung lesion volume compared to the control group. 244 Moreover, chest CT at 12 months showed significant regeneration of lung tissue in the MSC-administered groups, whereas lung fibrosis was found in all patients in the control group. This finding is of interest because it indicates that a long time is needed to detect the regenerative functions of MSC-based therapy, as the biological process to enhance lung tissue regeneration occurs relatively slowly and requires multiple steps. The effects of UC-MSCs in the attenuation and prevention of the development of cytokine storms were illustrated in an interventional, prospective, three-parallel arm study with two control arms conducted in 30 patients in moderate and critical clinical conditions. 245 The results indicated a significant decrease in proinflammatory cytokines (IFNγ, IL-6, IL-17A, IL-2, and IL-12) and an increase in anti-inflammatory cytokines (IL-10, IL-13, and IL-1ra), suggesting that UC-MSCs might participate in the prevention of cytokine storm development. Lanzoni et al. performed a double-blind, randomized, controlled trial and found that UC-MSC infusions significantly decreased cytokine levels at day 6 and improved survival in patients with COVID-19 with ARDS. In this trial, 24 patients were randomized and assigned 1:1 to receive either MSCs or placebo. 246 MSC treatment was associated with a significant improvement in the survival rate without serious adverse events. To date, other trials conducted using UC-MSCs as the main MSCs provide a solid data set on their safety and efficacy in preventing the development of cytokine storms, reducing the inflammatory response, improving pulmonary function, reducing intensive care unit (ICU) stay duration, enhancing lung tissue regeneration, and reducing lung fibrosis progression. 240 , 247 , 248 , 249 In two large cohort studies (phase I with 210 patients and phase II with 100 patients), the volume of lung lesions and solid component injuries of patients’ lungs were reduced significantly after the administration of UC-MSCs, 250 and clinical symptoms and inflammatory levels were improved. 251 Of the 26 reported clinical trials for the treatment of COVID-19 with MSCs, 1 study used AT-MSCs as the main MSCs. 236 Thirteen COVID-19 adult patients under invasive mechanical ventilation who had received previous antiviral and/or anti-inflammatory treatments (including steroids, lopinavir/ritonavir, hydroxychloroquine, and/or tocilizumab, among others) were treated with allogeneic AT-MSCs. With a mean follow-up time of 16 days after infusion, 9/13 patients’ clinical symptoms improved, and 7/13 patients were intubated. A decrease in inflammatory cytokines and an increase in immunoregulatory cells were also observed in patients, especially in the group of patients with overall clinical improvement. Although there is a lack of clinical efficacy data supporting the use of AT-MSCs in the treatment of patients with COVID-19, AT-MSCs are still potential candidates for inhibiting COVID-19 due to their high secretory activity, strong immune-modulatory effects, and homing ability. 252 , 253 , 254
For ARDS, in a phase IIa trial, 60 patients with moderate to severe disease were randomized into 2 groups. A group of 40 patients received a single infusion of BM-MSCs at a dose of 1 × 10 6 cells/kg body weight, and another 20 patients received a placebo. 255 After 6 and 24 h of infusion, the decrease in plasma inflammatory cytokine levels in the MSC group was significantly greater than that in the placebo group. For severe pulmonary hypertension (PH) associated with BPD (BPD-PH), in a small trial, two preterm infants born at 26–27 weeks of age were intravenously administered heterologous BM-MSCs at a dose of 5 × 10 6 cells per kg of body weight; the treatment reduced oxygen requirements and supported respiration in the infants. 256 The administration of allogeneic AT-MSCs in the treatment of ARDS appeared to be safe and well-tolerated in 12 adult patients, but clinical outcomes were not observed. 257 The results of two patients who received BM-MSCs showed that both patients had improved respiratory function and hemodynamic function and a reduction in multiorgan failure. 258 Although the safety of BM-MSCs was confirmed in a multicentre, open-label, dose-escalation, phase I clinical trial (The Stem cells for ARDS treatment—START trial), 259 no significant improvements were found in a phase II trial, including in respiratory function and ARDS conditions. 260 The safety profile of UC-MSCs is also supported by the findings of a previous phase I clinical trial conducted in 9 patients, which showed that a single IV administration of UC-MSCs was safe and led to positive outcomes in terms of respiratory function and a reduction in the inflammatory response. 261 The findings of this study were also supported by those of the REALIST (Repair of Acute Respiratory Distress with Stromal Cell Administration) trial, which further confirmed the maximum tolerated dose of allogeneic UC-MSCs in patients with moderate to severe ARDS. 262
Although AT- and BM-MSCs have demonstrated therapeutic potential with similar mechanisms of action, UC-MSCs have emerged as potential candidates in the treatment of pulmonary diseases due to their ease of production as “off-the-shelf” products, rapid proliferation, noninvasive isolation methods, and supreme immunological regulation as well as anti-inflammatory effects. 263 However, it is important to note that there is a need to conduct phase III clinical trials with larger cohorts and trials with at least two sources of MSCs in the treatment of pulmonary conditions to further confirm this speculation. 264 Table 2 summarizes several clinical trials with published results discussed in this review.
Endocrine disorders, infertility/reproductive function recovery, and skin burns: should we consider AT-MSCs as the main MSCs based on their origin?
Endocrine disorders.
The human body maintains function and homeostatic regulation via a complex network of endocrine glands that synthesize and release a wide range of hormones. The endocrine system regulates body functions, including heartbeat, bone regeneration, sexual function, and metabolic activity. Endocrine system dysregulation plays a vital role in the development of diabetes, thyroid disease, growth disorder, sexual dysfunction, reproductive malfunction, and other metabolic disorders. The central dogma of regenerative medicine is the use of adult stem cells as a footprint for tissue regeneration and organ renewal. The functions of these stem cells are tightly regulated by microenvironmental stimuli from the nervous system (rapid response) and endocrine signals via hormones, growth factors, and cytokines. This harmonized and orchestrated system creates a symphony of signals that directly regulate tissue homeostasis and repair after injury. The disruption of these complex networks results in an imbalance of tissue homeostasis and regeneration that can lead to the development of endocrine disorders in humans, such as diabetes, sexual hormone deficiency, premature ovarian failure (POF), and Asherman syndrome.
In recent years, obesity and diabetes (type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM)) have been the two biggest challenges in endocrinology research, and the application of MSCs has emerged as a novel approach for therapeutic consideration. T1DM is characterized by the autoimmune destruction of pancreatic β-cells, whereas T2DM is defined as a combination of insulin resistance and pancreatic insulin-producing cell dysfunction. Regenerative medicine seeks to provide an exogenous cell source for replacing damaged or lost β-cells to achieve the goal of stabilizing patients’ blood glucose levels. To date, there are 28 clinical trials using MSCs in the treatment of T1DM ( http://www.clinicaltrials.gov , searched in October 2021), among which three trials were completed using autologous BM-MSCs (NCT01068951), allogeneic BM-MSCs (NCT00690066), and allogeneic AT-MSCs (NCT03920397). Interestingly, UC-MSCs were the most favored MSCs for the remaining trials. All published studies confirmed the safety of MSC therapy in the treatment of T1DM with no adverse events. The first study using autologous BM-MSCs showed that patients who were randomized into the MSC-administration group showed an increase in C-peptide levels in response to a mixed-meal tolerance test (MMTT) in comparison to the control group. 265 Unfortunately, there was no significant improvement in C-peptide levels, HbA1 C or insulin requirements. The use of autologous AT-MSCs in combination with vitamin D was safe and improved HbA1 C levels 6 months post administration. 266 WJ-MSCs were used as the main MSCs for the treatment of new-onset T1DM, which showed a significant improvement in both HbA1 C and C-peptide levels when compared to those of the control group at three and six months post administration. 267 , 268 The combination of allogeneic WJ-MSCs with autologous BM-derived mononuclear cells improved insulin secretion and reduced insulin requirements in patients with T1DM. 269 In terms of T2DM, 23 studies were registered on clinicaltrials.gov (searched in October 2021), with six completed studies (three studies used BM-MSCs and three studies used allogeneic UC-MSCs). Although the number of studies using MSCs for the treatment of T2DM is small, their findings support the safety of MSCs, with no severe adverse events observed during the course of these studies. 270 It was confirmed that MSC therapy potentially reduced fasting blood glucose and HbA1 C levels and increased C-peptide levels. However, these effects were short-term, and multiple doses were required to maintain the MSC effects. Interestingly, the autologous MSC approach in the treatment of patients with diabetes in general is hampered, as both BM-MSCs and AT-MSCs isolated from patients with diabetes showed reduced stemness and functional characteristics. 271 , 272 In addition, the durations of diabetes and obesity are strongly associated with autologous BM-MSC metabolic function, especially mitochondrial respiration, and the accumulation of mitochondrial DNA, which directly interfere with the functions of BM-MSCs and reduce the effectiveness of the therapy. 271 Therefore, the allogeneic approach using MSCs from healthy donors provides an alternative approach for stem cell therapy in the treatment of patients with diabetes.
Infertility and reproductive function recovery
Modern society is increasingly facing the problem of infertility, which is defined as the inability to become pregnant after more than 1 year of unprotected intercourse. 273 This problem has emerged as an important worldwide health issue and social burden. Assisted reproductive techniques and in vitro fertilization technology have recently become the most effective methods for the treatment of infertility in humans, but the use of these approaches is limited, as they cannot be applied in patients with no sperm or those who are unable to support implantation during pregnancy, they are associated with complications, they are time-consuming and expensive, and they are associated with ethical issues in certain territories. 274 Numerous conditions are related to infertility, including POF, nonobstructive azoospermia, endometrial dysfunction, and Asherman syndrome. Recent progress has been illustrated in preclinical studies for the potential applications of stem cell-based therapy for reproductive function recovery, especially recent studies in the field of MSCs, which provide new hope for patients with infertility and reproductive disorders. 275
POF is characterized by a loss of ovarian activity during middle age (before 40 years old) and affects 1–2% of women of reproductive age. 276 Patients diagnosed with POF exhibit oligo-/amenorrhea for at least 4 months, with increased levels of follicle-stimulating hormone (FSH) (>25 IU/L) on two occasions more than 1 month apart. 277 Diverse factors, such as genetic backgrounds, autoimmune disorders, environmental conditions, and iatrogenic and idiopathic situations, have been reported to be the cause of POF. 278 POF can be treated with limited effectiveness via psychosocial support, hormone replacement intervention, and fertility management. 279 MSCs from AT, BM, and UC have been used in the treatment of POF, with improvements in ovarian function in preclinical studies using chemotherapy-induced POF animal models. The early published POF study using BM-MSCs as the main cell source is a single case report in which a perimenopausal woman showed an improvement in follicular regeneration, and increased AMH levels resulted in a successful pregnancy followed by delivery of a healthy infant. 280 A report using autologous BM-MSCs in two women with POF illustrated an increase in baseline estrogen levels and the volume of the treated ovaries along with amelioration of menopausal symptoms. 281 The clinical procedures used in this early trial were invasive, as patients underwent two operations: (1) BM aspiration and (2) laparoscopy. A similar approach was used in two trials conducted in 10 women with POF (age range from 26–33 years old) and 30 patients (age from 18 to 40 years old). 282 A later study investigated two different routes of cell delivery, including laparoscopy and the ovarian artery, but the results have not been reported at this time. 282 Based on the positive outcomes of the mouse model, an autologous stem cell ovarian transplantation (ASCOT) trial was deployed using BM-derived stem cells with encouraging observations of improved ovarian function, as determined by elevated levels of AMH and AFC in 81.3% of participants, six pregnancies, and the successful delivery of three healthy babies. 283 A randomized trial (NCT03535480) was conducted in 20 patients with POF aged less than 39 years to further elaborate on the results of the ASCOT trial. 284 To date, there are no completed trials using AT-MSCs or UC-MSCs in the treatment of patients with POF, limiting the evaluation of these MSCs in the treatment of POF. The speculated reason is that POF is a rare disease, affecting 1% of women younger than 40 years, and with improvements in assisted productive technology, patients have several alternative options to enhance the recovery of reproductive function. 285
Wound healing and skin burns
Burns are the fourth most common injury worldwide, affecting ~11 million people, and are a major cause of death (180,000 patients annually). The severity of burns is defined based on the percentage of surface area burned, burn depth, burn location and patient age, and burns are usually classified into first-, second-, third-, and fourth-degree burns on the basis of their severity. 286 Postburn recovery depends on the severity of the burn and the effectiveness of treatment. Rapid healing may occur over weeks, while alternatively, healing can take months, with the ultimate result being scar formation and disability in patients with severe burns. Different from mechanical injury, burn injury is an invasive progression of damage to tissue at the burn site, including both mechanical damage to the skin surface and biological damage caused by natural apoptosis that prolongs excessive inflammation, oxidative stress, and impaired tissue perfusion. 287 To date, completely reversing the devastating damage of severe burns remains unachievable in medicine, and stem cell therapy provides an alternative option for patients with burn injury. The first case report of the use of BM-MSCs to treat a 45-year-old patient with burns on 40% of their body demonstrated the safety of the therapy and showed partial improvements in vascularization at the wound site and reduced coarse cicatrices. 288 , 289 Later, patients with second- and third-degree burns as well as deep burns were treated using either autologous BM-MSCs or allogeneic BM-MSCs by spraying the MSCs onto the burn sites or adding MSCs over a dermal matrix sheet to cover the wound. The results in these case reports revealed the potential efficacy of MSC-based therapy, which not only enhanced the speed of wound recovery but also reduced pain and improved blood supply without introducing infection. 288 , 290 , 291 In 2017, a study conducted in 60 patients with 10–25% of their total body surface areas burned treated with either autologous BM-MSCs or UC-MSCs showed that both MSC types improved the rate of healing and reduced the hospitalization period. 292 The drawback of BM-MSCs in the treatment of burns is the invasive harvesting method, which causes pain and possible complications in patients. Hence, treatment with allogeneic MSCs obtained from healthy donors is the method of choice, and AT- and UC-MSCs are two suitable candidates for this option. To date, a limited number of clinical trials have been conducted using MSC therapy. These trials have several limitations in trial design, such as a lack of a negative control group and blinding, small sample sizes, and the use of standardized measurement tools for burn injury and wound healing. Currently, AT-MSCs are being used in seven ongoing phase I and II trials in the treatment of burns. Hence, it is important to note that among the most widely studied MSCs, AT-MSCs have advantages over BM-MSCs when obtained from an allogeneic source, while their abilities in burn treatment remain to be determined. The main MSCs that should be used in the regeneration of burn tissue remain undefined (Table 3 ), and we observed the trend that AT-MSCs are more suitable candidates due to their biological nature, which contributes to the generation of keratinocytes and secretion profiles that strongly enhance the skin regeneration process. 293 , 294 , 295 , 296
MSC applications in cardiovascular disease: a promising but still controversial field
In the last two decades, great advancements have been achieved in the development of novel regenerative medicine and cardiovascular research, especially stem cell technology. 297 The discovery of human embryonic stem cells and human induced pluripotent stem cells (hiPSCs) opened a new door for basic research and therapeutic investigation of the use of these cells to treat different diseases. 298 However, the clinical path of hiPSCs and hiPSC-derived cardiomyocytes in the treatment of cardiovascular diseases is limited due to the potential for teratoma formation with hiPSCs and the immaturity of hiPSC-derived cardiomyocytes, which might pose a risk of cancer formation, 299 arrhythmia, and cardiac arrest to patients. 300 A recently emerged stem cell type is adult stem cells/progenitor cells, including MSCs, which can stimulate myocardial repair post administration due to their paracrine effects. Promising results of MSC-based therapy obtained from preclinical studies of cardiac diseases enhance the knowledge and strengthen the clinical research to investigate the safety and efficacy in a clinical trial setting. There are papers that discuss the importance of MSC therapy in the treatment of cardiovascular diseases, with the following references being highly recommended. 301 , 302 , 303 , 304 , 305 , 306 To date, 36 trials have evaluated the therapeutic potential of MSCs in different pathological conditions, with the most prevalent types being BM-MSCs (25 trials), followed by UC-MSCs (7 trials) and AT-MSCs (4 trials). 303 However, the reported results are contradictory and create controversy about the efficacy of the treatments.
One of the first trials using MSCs in the treatment of chronic heart failure was the Cardiopoietic Stem Cell Therapy in Heart Failure (C-CURE) trial, a multicentre, randomized clinical trial that recruited 47 patients. The trial findings supported the safety of BM-MSC therapy and provided a data set that demonstrated improvements in cardiovascular scores along with New York Heart Association functional class, quality of life, and general physical health. 307 Despite these encouraging results in the phase I trial, the treatment failed to achieve the primary outcomes in the phase II/III trial (CHART-1 trial), including no significant improvements in cardiac structure or function or patient quality of life. 308 A positive outcome was also found in a phase I/II, randomized pilot study called the POSEIDON trial, which was the first trial to demonstrate the superior effectiveness of the administration of allogeneic BM-MSCs compared to allogeneic MSCs from other sources. 309 , 310 Published results from the MSC-HF study, with 4 years of follow-up results, 311 , 312 and the TRIDENT study 313 illustrated the positive outcomes of BM-MSCs in the treatment of heart failure. However, a contradictory result from the recently published CONCERT-HF trial demonstrated that the administration of autologous BM-MSCs to patients diagnosed with chronic ischemic heart failure did not improve left ventricular function or reduce scar size at 12 months post administration, but the patient’s quality of life was improved. 314 This observation is similar to that of the TAC-HFT trial 315 but completely different from the reported results of the MSC-HF trial. A comprehensive investigation is still needed to determine the reasons behind these contradictory results. The largest clinical trial to date using BM-MSCs is the DREAM-HF study, which was a randomized, double-blind, placebo-controlled, phase III trial that was conducted at 55 sites across North America and recruited a total of 565 patients with ischemic and nonischaemic heart failure. 172 Although recent reports from the sponsor confirmed that the trial missed its primary endpoint (a reduction in recurrent heart failure-related hospitalization), other prespecified endpoints were met, such as a reduction in overall major adverse cardiac events (including death, myocardial infarction, and stroke). 306 Thus, a complete report from the DREAM-HF trial will provide pivotal data supporting the therapeutic potential of BM-MSCs in the treatment of heart failure and open a new path for the FDA to approve cell-based therapy for cardiovascular diseases.
The early trial using AT-derived cells was the PRECISE trial, which was a phase I, randomized, placebo-controlled, double-blind study that examined the safety and efficacy of adipose-derived regenerative cells (ADRCs) in the treatment of chronic ischemic cardiomyopathy. 316 ADRCs are a homogenous population of cells obtained from the vascular stromal fraction of AT, which contains a small proportion of AT-MSCs. 317 Although the study supported the safety of ADRC administration and illustrated a preserved functional capacity (peak VO 2 ) in the treated group and improvements in heart wall motion, neither poor left ventricle (LV) volume nor poor left ventricular ejection fraction (LVEF) was ameliorated. The follow-up trial of the PRECISE trial, called the ATHENA trial, was conducted in 31 patients, although the study was terminated prematurely because two cerebrovascular events occurred, which were not related to the cell product itself. 318 The results of the study illustrated increases in functional capacity, hospitalization rate, and MLHFQ scores, but the LV volume and LVEF were not significantly different between the two groups. Kastrup and colleagues conducted the first in vitro expanded AT-MSC trial in ten patients with ischemic heart disease and ischemic heart failure in 2017. The results confirmed that ready-to-use AT-MSCs were well-tolerated and potentially effective in the treatment of ischemic heart disease and heart failure. 319 Comparable results of AT-MSCs were also reported from the MyStromalCell Trial, which was a randomized placebo-controlled study. In this trial, 61 patients were randomized at a 2:1 ratio into two groups, with the results showing no significant difference in the primary endpoint, which was a change in the maximal bicycle exercise tolerance test (ETT) score from baseline to 6 months post administration. 320 A 3-year follow-up report from the MyStromalCell Trial confirmed that patients who received AT-MSC administration maintained their preserved exercise capacity and their cardiac symptoms improved, whereas the control group experienced a significant reduction in exercise performance and a worsened cardiovascular condition. 321
UC-MSCs are potential allogeneic cells for the treatment of cardiovascular disease, as they are “ready to use” and easy to isolate, they rapidly proliferate, and they secrete hepatocyte growth factors, 322 which are involved in cardioprotection and cardiovascular regeneration. 323 The pilot study using UC-MSCs in 30 patients with heart failure, called the RIMECARD trial, was the first reported trial for which the results supported the effectiveness of UC-MSCs, as seen in the improved ejection fraction, left ventricular function, functional status, and quality of life in patients administered UC-MSCs. 324 Encouraging results reported from a phase I/II HUC-HEART trial 325 showed improvements in LVEF and reductions in the size of the injured area of the myocardium. However, the opposite observations were also reported from a recently published phase I randomized trial using a combination of UC-MSCs and a collagen scaffold in patients with ischemic heart conditions, in which the size of fibrotic scar tissue was not significantly reduced. 326
Although MSCs from AT, BM, and UC have proven to be safe and feasible in the treatment of cardiovascular diseases, the correlation between the MSC types and their therapeutic potentials is still uncertain because different results have been reported from different clinical trials (Table 4 ). The mechanisms by which MSCs participate in recovery and enhance myocardial regeneration have been discussed comprehensively in a recently published review; 305 , 327 therefore, they will not be discussed in this review. In fact, the challenges of MSC-based therapy in cardiovascular diseases have been clearly described previously, 328 including (1) the lack of an in vitro evaluation of the transdifferentiation potential of MSCs to functional cardiac and endothelial cells, 329 (2) the uncontrollable differentiation of MSCs to undesirable cell types post administration, 330 and (3) the undistinguishable nature of MSCs derived from different sources with various levels of differentiation potential. 331 Therefore, the applications of MSC-based therapy in cardiovascular disease are still in their immature stage, with potential benefits to patients. Thus, there is a need to conduct large-scale, well-designed randomized clinical trials not only to confirm the therapeutic potential of MSCs from various sources but also to enhance our knowledge of cardiovascular regeneration post administration.
Proposed mechanism of BM-MSCs in the treatment of acquired brain and spinal injury
Bones are complex structures constituting a part of the vertebrate skeleton, and they play a vital role in the production of blood cells from HSCs. Similar to the functions of most vertebrate organs, bone function is tightly regulated by its constituents and by long-range signaling from AT and the adrenal glands, parathyroid glands, and nervous system. 332 The central nervous system (CNS) orchestrates the voluntary and involuntary input transmitted by a network of peripheral nerves, which act as the bridge between the nervous system and target organs. The CNS controls involuntary responses via the autonomic nervous system (ANS), consisting of the sympathetic nervous system and the parasympathetic nervous system, and voluntary responses via the somatic nervous system. The ANS penetrates deep into the BM cavity, reaching the regions of hematopoietic activity to deliver neurotransmitters that tightly regulate BM stem cell niches. 333 The BM microenvironment consists of various cell types that participate in the maintenance of HSC niches, which are composed of specialized cells, including BM-MSCs (Fig. 3a ). The release of a specific neurotransmitter, circadian norepinephrine, from the sympathetic nervous system at nerve terminals leads to a reduction in the circadian expression of C–X-C chemokine ligand 12 (CXCL12, which is also known as stromal cell-derived factor-1 (SDF-1)) by Nestin + /NG2 2+ BM-MSCs, resulting in the secretion of HSCs into the peripheral bloodstream. 334 , 335 In fact, BM-MSCs play a significant role in the regulation of HSC quiescence and are closely associated with arterioles and sympathetic nervous system nerve fibers. Nestin-expressing BM-MSCs have been shown to express high levels of SDF-1, stem cell factor (SCF), angiopoietin-1 (Ang-1), interleukin-7, vascular cell adhesion molecule 1 (VCAM-1), and osteopontin (OPN), which are directly involved in the regulation and maintenance of HSC quiescence. 336 The depletion of BM-MSCs in BM leads to the mobilization of HSCs into the peripheral bloodstream and spleen. The findings from a previous study demonstrated that reduced SDF-1 expression in norepinephrine-treated BM-MSCs resulted in the mobilization of CXCR4 + HSCs into circulation. 337 The ability of BM-MSCs to produce SDF-1 is tightly related to their neuronal protective functions. 338 SDF-1 is a member of a chemokine subfamily that orchestrates an enormous diversity of pathways and functions in the CNS, such as neuronal survival and proliferation. The chemokine has two receptors, CXCR4 and CXCR7, that are involved in the pathogenic development of neurodegenerative and neuroinflammatory diseases. 339 In the damaged brain, SDF-1 functions as a stem cell homing signal, and in acquired immune deficiency syndrome (AIDS), SDF-1 has been reported to be involved in the protection of damaged neurons by preventing apoptosis. In a traumatic brain injury model, SDF-1 was found to function as an inhibitor of the caspase-3 pathway by upregulating the Bcl-2/Bax ratio, which in turn protects neurons from apoptosis. 340 Moreover, the release of SDF-1 also facilitates cell recruitment, cell migration, and the homing of neuronal precursor cells in the adult CNS by activating the CXCR4 receptor. 341 , 342 Existing data support that SDF-1 acts as the guiding signal for the regeneration of axon growth in damaged neurons and enhances spinal nerve regeneration. 343 , 344 Hence, the ability of BM-MSCs to express SDF-1 in response to the neuronal environment provides a unique neuronal protective effect that could explain the potential therapeutic efficacy of BM-MSCs in the treatment of neurodegenerative diseases (Fig. 3b ).
The nature of the “stem niche” of bone marrow-derived mesenchymal stem cells (BM-MSCs) supports their therapeutic potential in neuron-related diseases. a Bone marrow is a complex stem cell niche regulated directly by the central nervous system to maintain bone marrow homeostasis and haematopoietic stem cell (HSC) functions. MSCs in bone marrow respond to the environmental changes through the release of norepinephrine (NE) from the sympathetic nerves that regulate the synthesis of SDF-1 and the migration of HSCs through the sinusoids. The secretion of stem cell factors (SCFs), VCAM-1 and angiotensin-1 from MSCs also plays a significant role in the maintenance of HSCs. b BM-MSCs have the ability to produce and release SDF-1, which directly contributes to neuroprotective functions at the damaged site through interaction with its receptors CXCR4/7, located on the neuronal membrane. c Neuronal protection and the functional remyelination induced by BM-MSCs are also modulated by the release of a wide range of growth factors, including VEGF, BDNF, and NGF, by the BM-MSCs. d BM-MSCs also have the ability to regulate neuronal immune responses by direct interaction or paracrine communication with microglia. Figure was created with BioRender.com
The migration of exogenous MSCs after systemic administration to the brain is limited by the physical blood–brain barrier (BBB), which is a selective barrier formed by CNS endothelial cells to restrict the passage of molecules and cells. The mechanism of molecular movement across the BBB is well established, but how stem cells can bypass the BBB and home to the brain remains unclear. Recent studies have reported that MSCs are able to migrate through endothelial cell sheets by paracellular or transcellular transport followed by migration to the injured or inflammatory site of the brain. 345 , 346 During certain injuries or ischemic events, such as brain injury, stroke, or cerebral palsy, the integrity and efficiency of BBB protection is compromised, which allows MSC migration across the BBB via paracellular transport through the transient formation of interendothelial gaps. 347 CD24 expression has been detected in human BM-MSCs, which are regulated by TGF-β3, 348 allowing them to interact with activated endothelial cells via P-selectin and initiate the tethering and rolling steps of MSCs. 349 Additionally, BM-MSCs express high levels of CXCR4 or CXCR7, 350 , 351 which bind to integrin receptors, such as VLA-4, to activate the integrin-binding process and allow the cells to anchor to endothelial cells, followed by the migration of MSCs through the endothelial cell layer and basement membrane in a process called transmigration. 352 This process is facilitated by the secretion of matrix metalloproteinases (MMPs), which degrade the endothelial basement membrane, allowing BM-MSCs to enter the brain environment. 353 , 354 BM-MSCs can also regulate the integrity of the BBB via the secretion of tissue inhibitor of matrix metalloproteinase-3 (TIMP3), which has been shown to ameliorate the effects of a compromised BBB in traumatic brain injury. 355 The secretion of TIMP3 from MSCs directly blocked vascular endothelial growth factor a (VEGF-a)-induced breakdown of endothelial cell adherent junctions, demonstrating the potential mechanism of BM-MSCs in the regulation of BBB integrity.
The therapeutic applications of BM-MSCs in neurodegenerative conditions have been significantly increased by the demonstration of BM-MSC involvement in axonal and functional remyelination processes. Remyelination is a spontaneous regenerative process occurring in the human CNS to protect oligodendrocytes, neurons, and myelin sheaths from neuronal degenerative diseases. 356 Remyelination is considered a neuroprotective process that limits axonal degeneration by demyelination and neuronal damage. The first mechanism of action of BM-MSCs related to remyelination is the activation of the JAK/STAT3 pathway to regulate dorsal root ganglia development. 357 It was reported that BM-MSCs secrete vascular endothelial growth factor-A (VEGF-A), 358 brain-derived neurotrophic factor (BDNF), interleukin-6, and leukemia inhibitor factor (LIF), which directly function in neurogenesis and neurite growth. 357 VEGF-A is a key regulator of hemangiogenesis during development and bone homeostasis. Postnatally, osteoblast- and MSC-derived VEGF plays a critical role in maintaining and regulating bone homeostasis by stimulating MSC differentiation into osteoblasts and suppressing their adipogenic differentiation. 359 , 360 , 361 To balance osteoblast and adipogenic differentiation, VEGF forms a functional link with the nuclear envelope protein laminin A, which in turn directly regulates the osteoblast and adipocyte transcription factors Runx2 and PPARγ, respectively. 361 , 362 In the brain, VEGF is a potent growth factor mediating angiogenesis, neural migration, and neuroprotection. VEGF-A, secreted from BM-MSCs under in vitro xeno- and serum-free culture conditions, is the most studied member of the VEGF family and is suggested to play a protective role against cognitive impairment, such as in the context of Alzheimer’s disease pathology or stroke. 363 , 364 , 365 Recently, it was reported that the neurotrophic and neuroprotective function of VEGF is mediated through VEGFR2/Flk-1 receptors, which are expressed in the neuroproliferative zones and extend to astroglia and endothelial cells. 366 In animal models of intracerebral hemorrhage and cerebral ischemia, the transfusion of Flk-1-positive BM-MSCs promotes behavioral recovery and anti-inflammatory and angiogenic effects. 367 , 368 Moreover, supplementation with VEGF-A in neuronal disorders enhances intraneural angiogenesis, improves nerve regeneration, and promotes neurotrophic capacities, which in turn increase myelin thickness via the activation of the prosurvival transcription factor nuclear factor-kappa B (NF-kB). This activation, together with the downregulation of Mdm2 and increased expression of the pro-apoptotic transcription factor p53, is considered to be the neuroprotective process associated with an increased VEGF-A level. 369 , 370 , 371 An analysis of microRNA (miRNA) in extracellular vesicles (EVs) secreted from BM-MSCs revealed that BM-MSCs release substantial amounts of miRNA133b, which suppresses the expression of connective tissue growth factor (CTGF) and protects hippocampal neurons from apoptosis and inflammatory injury 372 , 373 , 374 (Fig. 3c ).
In terms of immunoregulatory functions, the administration of human BM-MSCs into immunocompetent mice subjected to SCI or brain ischemia showed that BM-MSCs exhibited a short-term neuronal protective function against neurological damage (Fig. 3d ). Further investigation demonstrated the ability of BM-MSCs to directly communicate with host microglia/macrophages and convert them from phenotypic polarization into alternative activated microglia/macrophages (AAMs), which are key players in axonal extension and the reconstruction of neuronal networks. 375 Other studies have also illustrated that the administration of AAMs directly to the injured spinal cord induced axonal regrowth and functional improvement. 376 The mechanism by which BM-MSCs activate the conversion of microglia/macrophages occurs through two representative macrophage-related chemokine axes, CCL2/CCR2 and CCL-5/CCR5, both of which exhibit acute or chronic elevation following brain injury or SCI. 377 The CCL2/CCR2 axis contributed to the enhancement of inflammatory function, and BM-MSC-mediated induction of CCL2 did not alter the total granulocyte number (Fig. 3d ). Although the chemokine-mediated mechanism of BM-MSCs in the activation of AAMs and enhanced axonal regeneration at the damage sites is evident, the direct mechanism by which the communication between BM-MSCs and the target cells results in these phenomena remains unclear, and further investigation is needed.
BM-MSCs also confer the ability to regulate the inflammatory regulation of the immune cells present in the brain by (1) promoting the polarization of macrophages toward the M2 type, (2) suppressing T-lymphocyte activities, (3) stimulating the proliferation and differentiation of regulatory T cells (Tregs), and (4) inhibiting the activation of natural killer (NK) cells. BM-MSCs secrete glial cell line-derived neurotrophic factor (GDNF), a specific growth factor that contributes directly to the transition of the microglial destructive M1 phenotype into the regenerative M2 phenotype during the neuroinflammatory process. 378 A similar result was also found in AT- 379 and UC-MSCs 380 under neuroinflammation-associated conditions, suggesting that AT-, BM-, and UC-MSCs share the same mechanism in promoting macrophage polarization. In terms of T-lymphocyte suppression, compared to MSCs from AT and BM, UC-MSCs show the strongest potential to inhibit the proliferation of T-lymphocytes by promoting cell cycle arrest (G0/G1 phase) and apoptosis. 381 In addition, UC-MSCs have been proven to be more effective in promoting the proliferation of Tregs 382 and inhibiting NK activation. 383 Although MSCs are well-known for their inflammatory regulatory ability, the mechanism is not exclusive to BM-MSCs, especially in neurological disorders. 384
Proposed mechanism of UC-MSCs in the treatment of pulmonary diseases and lung fibrosis
In contrast to AT-MSCs and BM-MSCs, UC-MSCs have lower expression of major histocompatibility complex I (MHC I) and no expression of MHC II, which prevents the complications of immune rejection. 385 Moreover, as UC is considered a waste product after birth, with the option of noninvasive collection, UC-MSCs are easier to obtain and culture than AD- and BM-MSCs. 386 These advantages of UC-MSCs have contributed to their use in the treatment of pulmonary diseases, especially during the rampant COVID-19 pandemic, as “off-the-shelf” products. Numerous pulmonary diseases have been the subject of applications of UC-MSCs, including BPD, COPD, ARDS, and COVID-19-induced ARDS. In BPD, premature infants are born before the alveolarization process, resulting in arrested lung development and alveolar maturation. Upon administration via an IV route, the majority of exogenous UC-MSCs reach the immature lung and directly interact with immune cells to exert their immunomodulatory properties via cell-to-cell interaction mechanisms (Fig. 4a ). UC-MSCs interact with T cells via the PD-L1 ligand, which binds to the PD-1 inhibitory molecule on T cells, resulting in the suppression of CD3+ T-cell proliferation and effector T-cell responses. 387 In addition, UC-MSCs also express CD54 (ICAM-1), which plays a crucial role in the immunomodulatory functions of T cells. 388 Direct contact between UC-MSCs and macrophages via CD54 expression on UC-MSCs promotes the immune regulation of UC-MSCs via the regulation of phagocytosis by monocytes. 389 Moreover, the contact of UC-MSCs with macrophages during proinflammatory responses increases the secretion of TSG-6 by UC-MSCs, which in turn promotes the inhibitory regulation of CD3+ T cells, macrophages, and monocytes by MSCs. 390 Recently, upregulation of SDF-1 was described in neonatal lung injury, especially in layers of the respiratory epithelium. 391 SDF-1 has been shown to participate in the migration and initiation of the homing process of MSCs via the CXCR4 receptors on their surface. 392 It was reported that UC-MSCs express low levels of CXCR4, allowing them to induce SDF-1-associated migration processes via the Akt, ERK, and p38 signal transduction pathways. 393 Hence, in BPD, the upregulation of SDF-1 together with the homing ability of UC-MSCs strongly supports the therapeutic effects of UC-MSCs in the treatment of BPD. Furthermore, UC-MSCs have the ability to communicate with immune cells via cell-to-cell contact to reduce proinflammatory responses and the production of proinflammatory cytokines (such as TGF-β, INF-γ, macrophage MIF, and TNF-α). The modulation of the human innate immune system by UC-MSCs is mediated by cell–cell interactions via CD54-LFA-1 that switch macrophage polarization processes, promoting the proliferation of M2 macrophages, which in turn reduce inflammatory responses in the immature lung. 394 Moreover, UC-MSCs also have the ability to produce VEGF and hepatocyte growth factors (HGFs), promoting angiogenesis and enhancing lung maturation. 395
Adipose tissue-derived mesenchymal stem cells (AT-MSCs) and the nature of their tissue of origin support their use in therapeutic applications. a Adipose tissue is considered an endocrine organ, supporting and regulating various functions, including appetite regulation, immune regulation, sex hormone and glucocorticoid metabolism, energy production, the orchestration of reproduction, the control of vascularization, and blood flow, the regulation of coagulation, and angiogenesis and skin regeneration. b In terms of metabolic disorders, such as type 2 diabetes mellitus (T2DM), as adipose tissue is directly involved in the metabolism of glucose and lipids and the regulation of appetite, the detrimental effects of T2DM also alter the functions of AT-MSCs, which in turn, hampers their therapeutic effects. Hence, the use of autologous AT-MSCs is not recommended for the treatment of metabolic disorders, including T2DM, suggesting that allogeneic AT-MSCs from healthy donors could be a better alternative approach. c AT-MSCs are suitable for the treatment of reproductive disorders due to their unique ability to mobilize and home to the thecal layer of the injured ovary, enhance the regeneration and maturation of thecal cells, increase the structure and function of damaged ovaries via exosome-activated SMAD, decrease oxidative stress and autophagy, and increase the proliferation of granulosa cells via PI3K/AKT pathways. These functions are regulated specifically by growth hormones produced by AT-MSCs in response to the surrounding environment, including HGF, TGF-β, IGF-1, and EGF. d AT-MSCs are also good candidates for skin healing and regeneration as their growth factors strongly support neovascularization and angiogenesis by reducing PLL4, increase anti-apoptosis via the activation of PI3K/AKT pathways, regulate inflammation by downregulating NADPH oxidase isoform 1, and increase immunoregulation through the inhibition of NF-κB activation. The figure was created with BioRender.com
COPD is characterized by an increase in hyperinflammatory reactions in the lung, compromising lung function and increasing the development of lung fibrosis. The mechanism by which UC-MSCs contribute to the response to COPD is inflammatory regulation (Fig. 4b ). The administration of UC-MSCs prevented the infiltration of inflammatory cells in peribronchiolar, perivascular, and alveolar septa and switched macrophage polarization to M2. 396 A significant reduction in proinflammatory cytokines, including IL-1β, TNF-α, and IL-8, was also observed following UC-MSC administration. 224 MSCs, including UC-MSCs, have been reported to trigger the production of secretory leukocyte protease inhibitors in epithelial cells through the secretion of HGF and epidermal growth factor (EGF), which is believed to have beneficial effects on COPD. 397 , 398 In addition to their inflammatory regulation ability, UC-MSCs exhibit antimicrobial effects through the inhibition of bacterial growth and the alleviation of antibiotic resistance during Pseudomonas aeruginosa infection. 399 The combination of the regulation of the host immune response and the antimicrobial effects of UC-MSCs may be relevant for the prevention and treatment of COPD exacerbations, as inflammation and bacterial infections are important risk factors that significantly contribute to the morbidity and mortality of patients with COPD. In terms of regenerative functions, UC-MSCs were reported to be able to differentiate into type 2 alveolar epithelial cells in vitro and alleviate the development of pulmonary fibrosis via β-catenin-regulated cell apoptosis. 400 Furthermore, UC-MSCs enhanced alveolar epithelial cell migration and proliferation by increasing matrix metalloproteinase-2 levels and reduced their endogenous inhibitors, tissue inhibitors of matrix metalloproteinases, providing a potential mechanism underlying their anti-pulmonary-fibrosis effects. 401 , 402
In ARDS, especially that associated with COVID-19, the proinflammatory state is initiated by increases in plasma concentrations of proinflammatory cytokines, such as IL-1 beta, IL-7, IL-8, IL-9, IL-10, bFGF, granulocyte colony-stimulating factor (G-CSF), GM-CSF, IFN-γ, and TNF-α. The significant increases in the concentrations of these cytokines in patient plasma suggest the development of a cytokine storm, which is a leading cause of COVID-induced mortality. In addition to the immunomodulatory functions regulated via cell-to-cell interactions between UC-MSCs and immune cells, such as macrophages, monocytes, and T cells, UC-MSCs exert their functions via paracrine effects through the secretion of growth factors, cytokines, and exosomes (Fig. 4c ). The most relevant immunomodulatory function of UC-MSCs is considered to be their inhibition of effector T cells via the induction of T-cell apoptosis and cell cycle arrest by the production of indoleamine 2,3- dioxygenase (IDO), prostaglandin E2 (PGE-2), and TGF-β. Elevated levels of PGE-2 in patients with COVID-19 are reported to be a crucial factor in the initiation of inflammatory regulation by UC-MSCs post administration and prevent the development of cytokine storms by direct inhibition of T- and B lymphocytes. 403 UC-MSCs exert these inhibitory activities through a PGE-2-dependent mechanism. 404 It was reported that UC-MSCs confer the ability to secrete tolerogenic mediators, including TGF-β1, PGE-2, nitric oxide (NO), and TNF-α, which are directly involved in their immunoregulatory mechanism. The secretion of NO from UC-MSCs is reported to be associated with the desensitization of T cells via the IFN-inducible nitric oxide synthase (iNOS) pathways and to stimulate the migration of T cells in close proximity to MSCs that subsequently suppress T-cell sensitivities via NO. 405 Lung infection with viruses usually leads to impairments in alveolar fluid clearance and protein permeability. The administration of UC-MSCs enhances alveolar protection and restores fluid clearance in patients with COVID-19. UC-MSCs secrete growth factors associated with angiogenesis and the regeneration of pulmonary blood vessels and micronetworks, including angiotensin-1, VEGF, and HGF, which also reduce oxidative stress and prevent fibrosis formation in the lungs. These trophic factors have been identified as key players in the modulation of the microenvironment and promote pulmonary repair. Additionally, UC-MSCs are more effective than BM-MSCs in the restoration of impaired alveolar fluid clearance and the permeability of airways in vitro, supporting the use of UC-MSCs in the treatment of patients with pulmonary pneumonia. 406 In the context of pulmonary regeneration, UC-MSCs were shown to inhibit apoptosis and fibrosis in pulmonary tissue by activating the PI3K/AKT/mTOR pathways via the secretion of HGF, which also acts as an inhibitory stimulus that blocks alveolar epithelial-to-mesenchymal transition. 407 , 408 Moreover, UC-MSCs can reverse the process of fibrosis via enhanced expression of macrophage matrix-metallopeptidase-9 for collagen degradation and facilitate alveolar regeneration via Toll-like receptor-4 signaling pathways. 409 UC-MSCs were shown to communicate with CD4+ T cells through HGF induction not only to inhibit their differentiation into Th17 cells, reducing the secretion of IL-17 and IL-22 but also to switch their differentiation into regulatory T cells. 410 , 411 In addition, UC-MSCs conferred the ability to facilitate the number of M2 macrophages and reduce M1 cells via the control of the macrophage polarization process. 412
There are several potential mechanisms of UC-MSCs in the treatment of patients with pulmonary diseases and pneumonia, including the regulation of immune cell function, immunomodulation, the enhancement of alveolar fluid clearance and protein permeability, the modulation of endoplasmic reticulum stress, and the attenuation of pulmonary fibrosis. Hence, based on these discussions, UC-MSCs are recommended as suitable candidates for the treatment of pulmonary disease both in pediatric and adult patients.
Proposed mechanism of AT-MSCs in the treatment of endocrinological diseases, reproductive disorders, and skin burns
Human AT was first viewed as a passive reservoir for energy storage and later as a major site for sex hormone metabolism, the production of endocrine factors (such as adipsin and leptin), and a secretion source of bioactive peptides known as adipokines. 413 It is now clear that AT functions as a complex and highly active metabolic and endocrine organ, orchestrating numerous different biological features 414 (Fig. 5a ). In addition to adipocytes, AT contains hematopoietic-derived progenitor cells, connective tissue, nerve tissue, stromal cells, endothelial cells, MSCs, and pericytes. AT-MSCs and pericytes mobilize from their perivascular locations to aid in healing and tissue regeneration throughout the body. As AT is involved directly in energy storage and metabolism, AT-MSCs are also mediated and regulated by growth factors related to these pathways. In particular, interleukin-6 (IL-6), IL-33, and leptin regulate the maintenance of metabolic activities by increasing insulin sensitivity and preserving homeostasis related to AT. Nevertheless, in the development of obesity and diabetes, omental and subcutaneous AT maintains a low-grade state of inflammation, resulting in the impairment of glucose metabolism and potentially contributing to the development of insulin resistance. 415 In normal AT, direct regulation of Pre-B-cell leukemia homeobox (Pbx)-regulating protein-1 (PREP1) by leptin and thyroid growth factor-beta 1 (TGF-β1) in AT-MSCs and mature adipocytes is involved in the protective function and maintenance of AT homeostasis. However, under diabetic conditions, the balance between the expression of leptin and the secretion of TGF-β1 is compromised, resulting in the malfunction of AT-MSC metabolic activity and the proliferation, differentiation, and maturation of adipocytes. Therefore, the use of autologous AT-MSCs in the treatment of diabetic conditions is not a suitable option, as the functions of AT-MSCs are directly altered by diabetic conditions, which reduces their effectiveness in cell-based therapy (Fig. 5b ).
Umbilical cord-derived mesenchymal stem cells (UC-MSCs) are good candidates for the treatment of pulmonary diseases. a Lung immaturity and fibrosis are the major problems of patients with bronchopulmonary dysplasia and lead to increased levels of SDF-1, the development of fibrosis, the induction of the inflammatory response, and the impairment of alveolarization. UC-MSCs are attracted to the damaged lung via the chemoattractant SDF-1, which is constantly released from the immature lung via SDF-1 and CXCR4 communication. Moreover, UC-MSCs reduce the level of proinflammatory cytokines (TGF-β, INF-γ, macrophage MIF, and TNF-α) via a cell-to-cell contact mechanism. The ability of UC-MSCs to produce and secrete VEGF also involves in the regeneration of the immature lung through enhanced angiogenesis. b Upon an exacerbation of chronic obstructive pulmonary disease (COPD), UC-MSCs respond to the surrounding stimuli by reducing IL-8 and TNF-α levels, resulting in the inhibition of the inflammatory response but an increase in the secretion of growth factors participating in the protection of alveoli, fluid clearance and reduced oxidative stress and lung fibrosis, including HGF, TGF-β, IGF-1, and exosomes. c In a similar manner, UC-MSCs prevent the formation of cytokine storms in coronavirus disease 2019 (COVID-19) by inhibiting CD34+ T-cell differentiation into Th17 cells and enhancing the number of regulatory T cells. Moreover, UC-MSCs also have antibacterial activity by secreting LL-3717 and lipocalin. Figure was created with BioRender.com
Preclinical studies and clinical trials have revealed the therapeutic effects of MSCs, in general, and AT-MSCs, in particular, in the management of POF, with relatively high efficacy and enhanced regeneration of the ovaries. Understanding the molecular and cellular mechanisms underlying these effects is the first step in the development of suitable MSC-based therapies for POF. One of the mechanisms by which MSCs exert their therapeutic effects is their ability to migrate to sites of injury, a process known as “homing”. Studies have shown that MSCs from different sources have the ability to migrate to different compartments of the injured ovary. For example, BM-MSCs administered through IV routes migrated mostly to the ovarian hilum and medulla, 416 whereas a significant number of UC-MSCs were found in the medulla. 417 Interestingly, AT-MSCs were found to be engrafted in the theca layers of the ovary but not in the follicles, where they acted as supportive cells to promote follicular growth and the regeneration of thecal layers. 418 The structure and function of the thecal layer have a great impact on fertility, which has been reviewed elsewhere. 419 In brief, the thecal layer consists of two distinct parts, the theca interna, which contains endocrine cells, and the theca externa, which is an outer fibrous layer. The thecal layer contains not only endocrine-derived cells but also vascular- and immune-derived cells, whose functions are to maintain the structural integrity of the follicles, transport nutrients to the inner compartment of the ovary and produce key reproductive hormones such as androgens (testosterone and dihydrotestosterone) and growth factors (morphogenic proteins, e.g., BMPs and TGF-β). 420 As AT-MSCs originate from an endocrine organ, their ability to sense signals and migrate to the thecal layer is anticipated. Additionally, secretome analysis of AT-MSCs showed a wide range of growth factors, including HGF, TBG-β, VEGF, insulin-like growth factor-1 (IGF-1), and EGF, 421 that are directly involved in the restoration of the structure and function of damaged ovaries by stimulating cell proliferation and reducing the aging process of oocytes via the activation of the SIRT1/FOXO1 pathway, a key regulator of vascular endothelial homeostasis. 422 , 423 In POF pathology, autophagy and its correlated oxidative stress contribute to the development of POF throughout a patient’s life. Recently, AT-MSCs were shown to be able to improve the structure and function of mouse ovaries by reducing oxidative stress and inflammation, providing essential data supporting the mechanism of AT-MSCs in the treatment of POF. 424 Several studies have illustrated that AT-MSCs secrete biologically active EVs that regulate the proliferation of ovarian granulosa cells via the PI3K/AKT pathway, resulting in the enhancement of ovarian function. 425 Direct regulation of ovarian cell proliferation modulates the state of these cells, which in turn restores the ovarian reserve. 426 Other mechanisms supporting the effectiveness of MSCs have been carefully reviewed, confirming the therapeutic potential of MSCs derived from different sources 426 (Fig. 5c ).
In the last decade, the number of clinical trials using AT-MSCs in the treatment of chronic skin wounds and skin regeneration has exponentially increased, with data supporting the enhancement of the skin healing processes, the reduction of scar formation, and improvements in skin structure and quality. Several mechanisms are directly linked to the origin of AT-MSCs, including differentiation ability, neovascularization, anti-apoptosis, and immunological regulation. AT is a connective and supportive tissue positioned just beneath the skin layers. AT-MSCs have a strong ability to differentiate into adipocytes, endothelial cells, 427 epithelial cells 428 and muscle cells. 429 The adipogenic differentiation of AT-MSCs is one of the three mesoderm lineages that defines MSC features, and AT-MSCs are likely to be the best MSC type harboring this ability compared to BM- and UC-MSCs. Recent reports detailed that AT-MSCs accelerated diabetic wound tissue closure through the recruitment and differentiation of endothelial cell progenitor cells into endothelial cells mediated by the VEGF-PLCγ-ERK1/ERK2 pathway. 430 Upon injury, the skin must be healed as quickly as possible to prevent inflammation and excessive blood loss. The reparation process occurs through distinct overlapping phases and involves various cell types and processes, including endothelial cells, keratinocyte proliferation, stem cell differentiation, and the restoration of skin homeostasis. 431 Hence, the differentiation ability of AT-MSCs plays a critical role in their therapeutic effect on skin wound regeneration and healing processes. AT-MSCs accelerate wound healing via the production of exosomes that serve as paracrine factors. It was reported that AT-MSCs responded to skin wound injury stimuli by increasing their expression of the lncRNA H19 exosome, which upregulated SOX9 expression via miR-19b, resulting in the acceleration of human skin fibroblast proliferation, migration, and invasion. 432 In addition, the engraftment of AT-MSCs supported wound bed blood flow and epithelialization processes. 433 Anti-apoptosis plays a critical role in AT-MSC-based therapy, as without a microvascular supply network established within 4 days post injury, adipocytes undergo apoptosis and degenerate. Exogenous sources of AT-MSCs mediate anti-apoptosis via IGF-1 and exosome secretion by triggering the activation of PI3K signaling pathways. 434 Another mechanism supporting the therapeutic potential of AT-MSCs is their anti-inflammatory function, which results in the reduction of proinflammatory factors, such as tumor necrosis factor (TNF) and interferon-γ (IFN-γ), and increases the production of the anti-inflammatory factors IL-10 and IL-4. Exosomes from AT-MSCs in response to a wound environment were found to contain high levels of Nrf2, which downregulated wound NADPH oxidase isoform 1 (NOX1), NADPH oxidase isoform 4 (NOX4), IL-1β, IL-6, and TNF-α expression. The anti-inflammatory functions of AT-MSCs are also regulated by their immunomodulatory ability, partially through the inhibition of NF-κB activation in T cells via the PD-L1/PD-1 and Gal-9/TIM-3 pathways, providing a novel target for the acceleration of wound healing 435 (Fig. 5d ).
Therefore, as an endocrine organ in the human body, AT and its derivative stem cells, including AT-MSCs, have shown great potential in the treatment of reproductive disorders and skin diseases. Their potential is supported by mechanisms that are directly related to the nature of AT-MSCs in the maintenance of tissue homeostasis, angiogenesis, anti-apoptosis, and the regulation of inflammatory responses.
The current challenges for MSC-based therapies
Over the past decades, MSC-based research and therapy have made tremendous advancements due to their advantages, including immune evasion, diverse tissue sources for harvesting, ease of isolation, rapid expansion, and cryopreservation as “off-the-shelf” products. However, several important challenges have to be addressed to further enhance the safety profile and efficacy of MSC-based therapy. In our opinion, the most important challenge of MSC-based therapy is the fate of these cells post administration, especially the long-term survival of allogeneic cells in the treatment of certain diseases. Although reported data confirm that the majority of MSCs are trapped in the lung and rapidly removed from the circulation, caution has been raised related to the occurrence of embolism events post infusion, which was proven to be related to MSC-induced innate immune attack (called instant blood-mediated inflammatory reaction). 436 Another related challenge is the homing ability of infused cells, as successful homing at targeted tissue might result in long-term benefits to patients. Other concerns related to MSC-based therapy are the number of dead cells infused into the patients. An interesting study reported that dead MSCs alone still exerted the same immunomodulatory property as live MSCs by releasing phosphatidylserine. 437 This is an interesting observation, as there is always a certain number of dead cells present in the cell-based product, and concerns are always raised related to their effects on the patient’s health. Finally, the hypothesis presented in this review is also a great challenge of the field, which has been proposed for future studies to answer the question: “What is the impact of MSC sources on their downstream application?”. Tables 5 and 6 illustrate the comparative studies that were conducted in preclinical and clinical settings to address the MSC source challenge. Other challenges of MSC-based therapies have been discussed in several reviews and systematic studies, 135 , 185 , 438 , 439 which are highly recommended.
Limitations of the current hypothesis
The proposed hypothesis presented in this review was made based on (1) the calculated number of recovered patients from published clinical trials; (2) the empirical experience of the authors in the treatment of brain-related diseases, 440 pulmonary disorders, 215 and endocrinological conditions; 271 , 441 and (3) the proposed mechanisms by which each type of MSC exhibits its best potential for downstream applications. The authors understand that the approach that we used has a certain level of research bias, as a comprehensive meta-analysis is needed to first confirm the correlation between the origins of MSCs and their downstream clinical outcomes before a complete hypothesis can be made. However, to date, a limited number of clinical trials have been conducted to directly compare the efficacy of MSCs from different sources in treating the same disease, which in turn dampened our analysis to prove this hypothesis. In addition, MSC-based therapy is still in its early stages, as controversy and arguments are still present in the field, including (1) the name of MSCs (medicinal signaling cells vs. MSCs or mesenchymal stromal cells), 442 , 443 (2) the existence of “magic cells” (one cell type for the treatment of all diseases), 444 , 445 (3) the conflicting results from large-scale clinical trials, 135 and (4) the dangerous issues of unauthorized, unproven stem cell therapies and clinics. 446 , 447 Therefore, our hypothesis is proposed at this time to encourage active researchers and clinicians to either prove or disprove it so that future research can strengthen the uses of MSC-based therapies with solid mechanistic study results and clarify results for “one cell type for the treatment of all diseases”.
Another limitation is the knowledge coverage in the field of MSC-based regenerative medicine, as discussed in this study. First, the abovementioned diseases were narrowed to four major disease categories for which MSC-based therapy is widely applied, including neuronal, pulmonary, cardiovascular, and endocrinological conditions. In fact, other diseases also receive great benefits from MSC therapy, including liver cirrhosis, 448 bone regeneration, 360 plastic surgery, 449 autoimmune disease, 450 etc., which are not fully discussed in this review and included in our hypothesis. Recently, the secretome profile of MSCs and its potential application in clinical settings have emerged as a new player in the field, with a recently published comprehensive review including MSC-derived exosomes. 451 , 452 To date, the therapeutic potential of MSCs is believed to be strongly influenced by their secretomes, including growth factors, cytokines, chemokines, and exosomes. 453 However, this body of knowledge is also not fully included in our discussion, as this review focuses on the function and potency of MSCs as a whole with considerations derived from published clinical data. Therefore, the authors believe in and support the future applications of the secreted components derived from MSCs, including exosomes, in the treatment of human diseases. In fact, this potential approach could elevate the uses of MSCs to the next level, where the sources of MSCs could be neglected with advancements in the development of protocols that allow strict control of the secretome profiles of MSCs under specific conditions. 454 , 455 , 456 Finally, strategies that could potentially enhance the therapeutic outcomes of MSC-based therapy, such as the “priming” process, are not discussed in this review. The idea of “priming” MSCs is based on the nature of MSCs, which is similar to the immune cells, 457 that MSCs have proven to be able to “remember” the stimulus from the surrounding environment. 458 , 459 Thus, activating or priming MSCs using certain conditions, such as hypoxia, matrix mechanics, 3D environment, hormones, or inflammatory cytokines, could trigger the memory mechanism of the MSCs in vitro so that these cells are ready to function towards specific therapeutic activities without the need for in vivo activation. 3 , 460
From a cellular and molecular perspective and from our own experience in a clinical trial setting, AD-, BM- and UC-MSCs exhibit different functional activities and treatment effectiveness across a wide range of human diseases. In this paper, we have provided up-to-date data from the most recently published clinical trials conducted in neuronal diseases, endocrine and reproductive disorders, skin regeneration, pulmonary dysplasia, and cardiovascular diseases. The implications of the results and discussions presented in this review and in a very large body of comprehensive and excellent reviews as well as systematic analyses in the literature provide a different aspect and perspective on the use of MSCs from different sources in the treatment of human diseases. We strongly believe that the field of regenerative medicine and MSC-based therapy will benefit from active discussion, which in turn will significantly advance our knowledge of MSCs. Based on the proposed mechanisms presented in this review, we suggest several key mechanistic issues and questions that need to be addressed in the future:
The confirmation and demonstration of the mechanism of action prove that tissue origin plays a significant role in the downstream applications of the originated MSCs.
Is it required that MSCs derived from particular cell sources need to have certain functionalities that are unique to or superior in the original tissue sources?
As mechanisms may rely on the secretion of factors from MSCs, it is important to identify the specific stimuli from the wound environments to understand how MSCs from different sources can exhibit similar functions in the same disease and whether or not MSCs derived from a particular source have stronger effects than their counterparts derived from other tissue sources.
Should we create “universal” MSCs that could be functionally equal in the treatment of all diseases regardless of their origin by modeling their genetic materials?
Can new sources of MSCs from either perinatal or adult tissues better stimulate the innate mechanisms of specific cell types in our body, providing a better tool for MSC-based treatment?
A potential ‘priming’ protocol that allows priming, activating, and switching the potency of MSCs from one source to another with a more appropriate clinical phenotype to treat certain diseases. This idea is potentially relevant to our suggestion that each MSC type could be more beneficial in downstream applications, and the development of such a “priming” protocol would allow us to expand the bioavailability of specific MSC types.
From our clinical perspective, the underlying proposal in our review is to no longer use MSCs for applications while disregarding their sources but rather to match the MSC tissue source to the application, shifting from one cell type for the treatment of all diseases to cell source-specific disease treatments. Whether the application of MSCs from different sources still shows their effectiveness to a certain extent in the treatment of diseases or not, the transplantation of MSCs derived from different sources for each particular disease needs to be further investigated, and protocols need to be established via multicentre, randomized, placebo-controlled phase II and III clinical trials (Fig. 6 ).
The tissue sources of mesenchymal stem cells (MSCs) contribute greatly to their therapeutic potential, as all MSC types share safety profiles and overlapping efficacy. Although a large body of data and their review and systematic analysis indicated the shared safety and potential efficacy of MSCs derived from different tissue sources, targeted therapies considering MSC origin as an important factor are imperative to enhance the downstream therapeutic effects of MSCs. We suggest that bone marrow-derived MSCs (BM-MSCs) are good candidates for the treatment of brain and spinal cord injury, adipose tissue-derived MSCs (AT-MSCs) are suitable for the treatment of reproductive disorders and skin regeneration, and umbilical cord-derived MSCs (UC-MSCs) could be alternatives for the treatment of pulmonary diseases and acute respiratory distress syndrome (ARDS). Figure was created with BioRender.com
Data availability
All data generated or analyzed in this study are included in this published article.
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Acknowledgements
The authors would like to thank the Vingroup Scientific Research and Clinical Application Fund (grant number: PRO. 19.47) for supporting this work. All figures were created with Biorender.com. This work is supported by the Vingroup Scientific Research and Clinical Application Fund (Grant number: PRO.19.47).
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Duc M. Hoang, Trung Q. Bach, Quyen T. Nguyen, Trang T. K. Phan, Giang H. Nguyen, Phuong T. T. Le, Van T. Hoang & Liem Thanh Nguyen
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Hoang, D.M., Pham, P.T., Bach, T.Q. et al. Stem cell-based therapy for human diseases. Sig Transduct Target Ther 7 , 272 (2022). https://doi.org/10.1038/s41392-022-01134-4
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Stem cells: what they are and what they do.
Stem cells offer great promise for new medical treatments. Learn about stem cell types, current and possible uses, and the state of research and practice.
You've heard about stem cells in the news, and perhaps you've wondered if they might help you or a loved one with a serious disease. You may wonder what stem cells are, how they're being used to treat disease and injury, and why they're the subject of such vigorous debate.
Here are some answers to frequently asked questions about stem cells.
What are stem cells?
Stem cells: The body's master cells
Stem cells are the body's master cells. All other cells arise from stem cells, including blood cells, nerve cells and others.
Stem cells are the body's raw materials — cells from which all other cells with specialized functions are generated. Under the right conditions in the body or a laboratory, stem cells divide to form more cells called daughter cells.
These daughter cells become either new stem cells or specialized cells (differentiation) with a more specific function, such as blood cells, brain cells, heart muscle cells or bone cells. No other cell in the body has the natural ability to generate new cell types.
Why is there such an interest in stem cells?
Researchers hope stem cell studies can help to:
- Increase understanding of how diseases occur. By watching stem cells mature into cells in bones, heart muscle, nerves, and other organs and tissue, researchers may better understand how diseases and conditions develop.
Generate healthy cells to replace cells affected by disease (regenerative medicine). Stem cells can be guided into becoming specific cells that can be used in people to regenerate and repair tissues that have been damaged or affected by disease.
People who might benefit from stem cell therapies include those with spinal cord injuries, type 1 diabetes, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, heart disease, stroke, burns, cancer and osteoarthritis.
Stem cells may have the potential to be grown to become new tissue for use in transplant and regenerative medicine. Researchers continue to advance the knowledge on stem cells and their applications in transplant and regenerative medicine.
Test new drugs for safety and effectiveness. Before using investigational drugs in people, researchers can use some types of stem cells to test the drugs for safety and quality. This type of testing will most likely first have a direct impact on drug development for cardiac toxicity testing.
New areas of study include the effectiveness of using human stem cells that have been programmed into tissue-specific cells to test new drugs. For the testing of new drugs to be accurate, the cells must be programmed to acquire properties of the type of cells targeted by the drug. Techniques to program cells into specific cells are under study.
For instance, nerve cells could be generated to test a new drug for a nerve disease. Tests could show whether the new drug had any effect on the cells and whether the cells were harmed.
Where do stem cells come from?
There are several sources of stem cells:
Embryonic stem cells. These stem cells come from embryos that are 3 to 5 days old. At this stage, an embryo is called a blastocyst and has about 150 cells.
These are pluripotent (ploo-RIP-uh-tunt) stem cells, meaning they can divide into more stem cells or can become any type of cell in the body. This versatility allows embryonic stem cells to be used to regenerate or repair diseased tissue and organs.
Adult stem cells. These stem cells are found in small numbers in most adult tissues, such as bone marrow or fat. Compared with embryonic stem cells, adult stem cells have a more limited ability to give rise to various cells of the body.
Until recently, researchers thought adult stem cells could create only similar types of cells. For instance, researchers thought that stem cells residing in the bone marrow could give rise only to blood cells.
However, emerging evidence suggests that adult stem cells may be able to create various types of cells. For instance, bone marrow stem cells may be able to create bone or heart muscle cells.
This research has led to early-stage clinical trials to test usefulness and safety in people. For example, adult stem cells are currently being tested in people with neurological or heart disease.
Adult cells altered to have properties of embryonic stem cells. Scientists have successfully transformed regular adult cells into stem cells using genetic reprogramming. By altering the genes in the adult cells, researchers can reprogram the cells to act similarly to embryonic stem cells.
This new technique may allow use of reprogrammed cells instead of embryonic stem cells and prevent immune system rejection of the new stem cells. However, scientists don't yet know whether using altered adult cells will cause adverse effects in humans.
Researchers have been able to take regular connective tissue cells and reprogram them to become functional heart cells. In studies, animals with heart failure that were injected with new heart cells experienced improved heart function and survival time.
Perinatal stem cells. Researchers have discovered stem cells in amniotic fluid as well as umbilical cord blood. These stem cells have the ability to change into specialized cells.
Amniotic fluid fills the sac that surrounds and protects a developing fetus in the uterus. Researchers have identified stem cells in samples of amniotic fluid drawn from pregnant women for testing or treatment — a procedure called amniocentesis.
Why is there a controversy about using embryonic stem cells?
Embryonic stem cells are obtained from early-stage embryos — a group of cells that forms when eggs are fertilized with sperm at an in vitro fertilization clinic. Because human embryonic stem cells are extracted from human embryos, several questions and issues have been raised about the ethics of embryonic stem cell research.
The National Institutes of Health created guidelines for human stem cell research in 2009. The guidelines define embryonic stem cells and how they may be used in research, and include recommendations for the donation of embryonic stem cells. Also, the guidelines state that embryonic stem cells from embryos created by in vitro fertilization can be used only when the embryo is no longer needed.
Where do these embryos come from?
The embryos being used in embryonic stem cell research come from eggs that were fertilized at in vitro fertilization clinics but never implanted in women's uteruses. The stem cells are donated with informed consent from donors. The stem cells can live and grow in special solutions in test tubes or petri dishes in laboratories.
Why can't researchers use adult stem cells instead?
Although research into adult stem cells is promising, adult stem cells may not be as versatile and durable as are embryonic stem cells. Adult stem cells may not be able to be manipulated to produce all cell types, which limits how adult stem cells can be used to treat diseases.
Adult stem cells are also more likely to contain abnormalities due to environmental hazards, such as toxins, or from errors acquired by the cells during replication. However, researchers have found that adult stem cells are more adaptable than was first thought.
What are stem cell lines and why do researchers want to use them?
A stem cell line is a group of cells that all descend from a single original stem cell and are grown in a lab. Cells in a stem cell line keep growing but don't differentiate into specialized cells. Ideally, they remain free of genetic defects and continue to create more stem cells. Clusters of cells can be taken from a stem cell line and frozen for storage or shared with other researchers.
What is stem cell therapy (regenerative medicine) and how does it work?
Stem cell therapy, also known as regenerative medicine, promotes the repair response of diseased, dysfunctional or injured tissue using stem cells or their derivatives. It is the next chapter in organ transplantation and uses cells instead of donor organs, which are limited in supply.
Researchers grow stem cells in a lab. These stem cells are manipulated to specialize into specific types of cells, such as heart muscle cells, blood cells or nerve cells.
The specialized cells can then be implanted into a person. For example, if the person has heart disease, the cells could be injected into the heart muscle. The healthy transplanted heart muscle cells could then contribute to repairing the injured heart muscle.
Researchers have already shown that adult bone marrow cells guided to become heart-like cells can repair heart tissue in people, and more research is ongoing.
Have stem cells already been used to treat diseases?
Yes. Doctors have performed stem cell transplants, also known as bone marrow transplants. In stem cell transplants, stem cells replace cells damaged by chemotherapy or disease or serve as a way for the donor's immune system to fight some types of cancer and blood-related diseases, such as leukemia, lymphoma, neuroblastoma and multiple myeloma. These transplants use adult stem cells or umbilical cord blood.
Researchers are testing adult stem cells to treat other conditions, including a number of degenerative diseases such as heart failure.
What are the potential problems with using embryonic stem cells in humans?
For embryonic stem cells to be useful, researchers must be certain that the stem cells will differentiate into the specific cell types desired.
Researchers have discovered ways to direct stem cells to become specific types of cells, such as directing embryonic stem cells to become heart cells. Research is ongoing in this area.
Embryonic stem cells can also grow irregularly or specialize in different cell types spontaneously. Researchers are studying how to control the growth and differentiation of embryonic stem cells.
Embryonic stem cells might also trigger an immune response in which the recipient's body attacks the stem cells as foreign invaders, or the stem cells might simply fail to function as expected, with unknown consequences. Researchers continue to study how to avoid these possible complications.
What is therapeutic cloning, and what benefits might it offer?
Therapeutic cloning, also called somatic cell nuclear transfer, is a technique to create versatile stem cells independent of fertilized eggs. In this technique, the nucleus is removed from an unfertilized egg. This nucleus contains the genetic material. The nucleus is also removed from the cell of a donor.
This donor nucleus is then injected into the egg, replacing the nucleus that was removed, in a process called nuclear transfer. The egg is allowed to divide and soon forms a blastocyst. This process creates a line of stem cells that is genetically identical to the donor's cells — in essence, a clone.
Some researchers believe that stem cells derived from therapeutic cloning may offer benefits over those from fertilized eggs because cloned cells are less likely to be rejected once transplanted back into the donor and may allow researchers to see exactly how a disease develops.
Has therapeutic cloning in people been successful?
No. Researchers haven't been able to successfully perform therapeutic cloning with humans despite success in a number of other species.
However, in recent studies, researchers have created human pluripotent stem cells by modifying the therapeutic cloning process. Researchers continue to study the potential of therapeutic cloning in people.
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- Cloning fact sheet. National Human Genome Research Institute. https://www.genome.gov/about-genomics/fact-sheets/Cloning-Fact-Sheet. Accessed Feb. 7, 2022.
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Stem cell therapy: from idea to clinical practice.
1. Introduction
2. from idea to preclinical study, 3. from preclinical study to clinical trial, 3.1. stem cell source determination, 3.1.1. mesenchymal stem cells (mscs), 3.1.2. hematopoietic stem cells (hscs), 3.1.3. embryonic stem cells (escs), 3.1.4. induced pluripotent stem cells (ipscs), 3.2. cell dose specification, 3.3. route of administration, 3.4. manipulation of cell transplantation for safety and efficiency improvement of administration, 4. from clinical trial to clinical practice, 5. challenges and future directions, 6. conclusions, author contributions, conflicts of interest.
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Share and Cite
Mousaei Ghasroldasht, M.; Seok, J.; Park, H.-S.; Liakath Ali, F.B.; Al-Hendy, A. Stem Cell Therapy: From Idea to Clinical Practice. Int. J. Mol. Sci. 2022 , 23 , 2850. https://doi.org/10.3390/ijms23052850
Mousaei Ghasroldasht M, Seok J, Park H-S, Liakath Ali FB, Al-Hendy A. Stem Cell Therapy: From Idea to Clinical Practice. International Journal of Molecular Sciences . 2022; 23(5):2850. https://doi.org/10.3390/ijms23052850
Mousaei Ghasroldasht, Mohammad, Jin Seok, Hang-Soo Park, Farzana Begum Liakath Ali, and Ayman Al-Hendy. 2022. "Stem Cell Therapy: From Idea to Clinical Practice" International Journal of Molecular Sciences 23, no. 5: 2850. https://doi.org/10.3390/ijms23052850
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A global companion looked into IJSCRT, it distributes amazing open access examining articles with an exceptional attention on essential, translational and clinical exploration into undeveloped cell therapeutics and regenerative helps, including creature models and clinical trials. The journal additionally gives audits, perspectives, editorials and reports. Journal covers all parts of science including fundamental, clinical and translational research on heredity, organic chemistry, and physiology of different sorts of stem cells including embryonic, grown-up and actuated immature microorganisms. IJSCRT likewise distributes survey articles, specialized reports and treatise on moral issues.
Journal Information
Title: International Journal of Stem Cell Research & Therapy
ISSN: 2469-570X
Editor-in-chief: Faris Farassati
NLM title abbreviation: Int J Stem Cell Res Ther
ISO abbreviation: Int J Stem Cell Res Ther
Other titles: IJSCRT
Category: Stem cell research
DOI: 10.23937/2469-570X
Peer review: Double blind
Review speed: 3 weeks
Fast-track review: 10 days
Publication format (s): Electronic and print
Publication policy: Open Access; COPE guide
Publication type(s): Periodicals
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Country of publication: USA
Language: English
Contact email: [email protected]
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Stem Cell Therapy
Stem cell therapy is a promising strategy for regeneration of damaged organs, tissues or functions through the transplantation of stem cells.
From: Regenerated Organs , 2021
Related terms:
- Spontaneous Remission
- Mesenchymal Stem Cell
- Transplantation
- Regeneration
- Bone Marrow
- Cell Therapy
- Graft Versus Host Reaction
Stem Cells, Kidney Regeneration, and Gene and Cell Therapy in Nephrology
Alan S.L. Yu MB, BChir , in Brenner and Rector's The Kidney , 2020
Cell therapy involves the direct administration of cells into the body for healing purposes. The units of therapy in this approach are single cells. For regenerative medicine, the ultimate objective of cell therapy is to establish a long-term graft with the capacity to perform organ functions. A practical example is bone marrow transplantation, in which HSC are the units of therapy, engraft in the bone marrow, and repopulate the entire blood lineage. 105
Intravenous administration describes the direct injection of dissociated cells into the bloodstream using a syringe. It is the simplest delivery route for cell therapies and is used for HSC therapy in the clinic. Kidney cells, however, are different from blood cells and do not typically circulate throughout the body. The kidney is furthermore a densely-packed organ with no obvious route for stem cells to traverse from the bloodstream into the nephrons. Whether kidney stem cells have the ability to engraft and regenerate the kidney after intravenous administration therefore needs to be tested in preclinical animal models. In these experiments, the kidneys are typically subjected to acute injury. This damages the glomerular filtration barrier, which can enhance penetration of cells into the kidney and subsequent engraftment.
In one example, human iPS cell-derived cells expressing a variety of NPC and adult kidney cell markers were injected into the mouse tail vein 24 hours after administration of the nephrotoxic drug cisplatin. 106 Extensive engraftment was reported in proximal tubules, which coincided with a 55% reduction in urea levels in treated mice, compared with control animals administered with saline or undifferentiated iPS cells. 106 These experiments suggest a possible benefit of iPS-derived kidney cells on kidney injury. However, the isolated cells were not shown to demonstrate the ability to form kidney organoids with segmented nephrons. It is therefore unclear whether the implanted cells contained bona fide NPC or whether new nephrons were actually formed.
Intravenous administration has also been applied to adult kidney cell populations. Human glomerular epithelial transitional cells (see earlier), administered intravenously into a mouse model of chemically-induced podocytopathy, were found in glomeruli, and were associated with a decrease in proteinuria. 107 These cells also contributed to tubules after acute injury. 80 As these cells cannot form new nephrons, this approach seeks to repair and replace, rather than to completely regenerate.
MSC can be readily obtained, for instance from a patient's adipose tissue. Intravenous administration of MSC in experimental models can have a beneficial effect on ischemia-reperfusion injury. 99,102,108 This benefit can be obtained even in the absence of MSC engraftment, likely via a paracrine effect. However, MSC administered to injured kidneys do not contribute tangibly to new nephron formation and can differentiate ectopically into undesirable fat cells or fibroblasts within glomeruli. 108,109 Collectively, these findings suggest that intravenous administration of cell therapeutics may provide some benefit in cases where the glomerular filtration barrier has been compromised but may also have unwanted side effects.
Stem Cell Transplantation
Keren Osman , Raymond L. Comenzo , in Encyclopedia of Cancer (Second Edition) , 2002
V Conclusions
Stem cell transplantation has been established as a useful therapy for hematologic malignancies and some solid tumors. Some patients, however, still die in allogeneic SCT because T lymphocytes cause fatal GVHD and many are not cured in autologous SCT because disease recurs post-SCT. Disease may recur because the tumor was not completely eliminated or because the stem cell component was contaminated with tumor cells that home to sites of prior disease. For these reasons, manipulated or engineered stem cell grafts continue to attract interest. Approaches to graft engineering include methods of T-cell depletion designed to minimize GVHD without compromising the potential for graft-versus-disease effect, as well as purging with monoclonal antibodies or selection of CD34 + stem cells in order to eliminate contaminating tumor cells. However, to date, no form of engineered graft has shown itself to be superior to unmanipulated components with respect to survival in phase III trials in autologous SCT or allogeneic HLA identical SCT. In allogeneic-related HLA haploidentical SCT, it is generally agreed that T-cell depletion is required to reduce the risk of acute GVHD. With the apparent superiority of mobilized allogeneic peripheral blood stem cells over bone marrow in a recent large trial, and the promise of minimally myeloablative allogeneic SCT using PBSC, continued success with unmanipulated components is likely to continue. Nevertheless, should the CR rates for autologous SCT in NHL, HD, and MM increase due to advances in treatment, such as the use of new agents or of post-SCT tumor vaccines, the role of tumor cell contamination of stem cell components in disease recurrence post-SCT will likely increase as well.
The applications of cytotherapies will evolve and expand over the coming decades. Hematopoietic stem cell transplants may provide methods for inducing lifelong tolerance to xenografts or allow novel treatment of autoimmune diseases, whereas the discovery and use of nonhematopoietic stem cells may help minimize the toxicities of cancer therapy or cure non-malignant disorders. For example, the infusion of fetal islet cell progenitors may provide a treatment for severe diabetes. The future of stem cell transplantation and cytotherapies in general will require advances in our understanding of stem cell biology and transplantation immunology and will continue to depend on patients courageous enough to participate in well-designed clinical trials.
Stem Cells and Cellular Therapy
Andrew P. Schachat MD , in Ryan's Retina , 2018
Discerning the Legitimacy of A Human Stem Cell Treatment
When approached by a patient inquiring about the legitimacy of a specific human stem cell-based treatment, it can be a challenge to investigate the treatment and address the many concerns that naturally accompany such a treatment. Table 37.2 provides a list of the basic questions that should be initially answered to help evaluate the legitimacy of a human stem cell-based treatment, although this list should only be used as a starting point for further investigation. For additional information, the International Society for Stem Cell Research (ISSCR) provides several useful resources online, including the “Patient Handbook on Stem Cell Therapies,” “Stem Cell Treatments: What to Ask,” and “Guidelines for Stem Cell Research and Clinical Translation” ( http://www.isscr.org/ ).
Cardiac Regeneration and Stem Cells as Therapy for Heart Disease
A.J. Favreau-Lessard , D.B. Sawyer , in Encyclopedia of Cardiovascular Research and Medicine , 2018
Overview of Recent Stem Cell Clinical Trials for Heart Disease
Stem cell therapy for heart disease has yet to reach regulatory approval, and is still in development. The first clinical trial to use stem cell therapy for heart failure was reported in 2002 ( Vrtovec et al., 2013 ). Preclinical models and the current stem cell therapies used in the clinic for other noncardiac-related diseases have set the groundwork for stem cell therapy as a method to regenerate the damaged heart. As described earlier, there are many factors that need to be determined in order to find the most successful approach in this therapeutic area. The combination of the type of stem cells, source of the stem cells (allogeneic vs. autologous), mode of delivery, and the clinical problem which needs to be treated all need to be weighed carefully. In Table 2 a few of the ongoing and recently completed clinical trials are listed, and in Table 3 select clinical trials are organized to demonstrate the variety of clinical conditions being treated with stem cell therapy as well as the different stem cell therapy approaches in delivery, cell type, and source of cells.
Table 2 . Background on select clinical trials utilizing stem cell therapy to treat heart disease
Table 3 . Clinical trial parameters by stem cell type to treat heart disease
Skin Development and Maintenance
Jean L. Bolognia MD , in Dermatology , 2018
Stem Cell-Based Therapy for Genetic Skin Disease
Stem cells have been utilized in several strategies for gene therapy of heritable skin diseases ( Fig. 2.7 ). Treatment via delivery of gene-corrected stem cells has the advantage of continuous protein synthesis in the skin, but it may carry a risk of oncogenesis, especially with retroviral vectors. In a pilot study, laminin-β3-deficient skin from a man with junctional EB was corrected by transplantation of stem cell-enriched epidermal grafts transduced ex vivo with a retroviral vector encoding normal LAMB3 cDNA. The treatment resulted in expression of functional laminin 332 and an absence of blistering in the corrected epidermis, both sustained over several years of follow-up. Clinical trials are also ongoing to investigate the value of bone marrow-derived stem cell transplantation as a systemic treatment for the extremely severe recessive dystrophic form of EB (RDEB). In an initial report 29 , bone marrow transplantation after total or partial myeloablation resulted in substantial proportions of donor cells in the skin, increased collagen VII deposition at the dermal–epidermal junction, and variably decreased blistering in children with RDEB. Other investigators are studying alternative sources of stem cells for the treatment of EB, including allogeneic mesenchymal stromal/stem cells and autologous iPS cells derived from revertant keratinocytes 30 .
Stem Cell Therapy Facility Design
J. Liu , ... L. Song , in Reference Module in Biomedical Sciences , 2016
Stem cell transplantation has potential in many different areas of health and medical research. Advanced facilities for stem cell therapy , as well as effective and reasonable guidelines and strategies for stem cell transplant in different regions are of great importance for the realization and enhancement of stem cell transplant procedure. Our aim is to design the facilities for stem cell therapy from the respective of a developing country, e.g. China. The main idea of the stem cell facility design is described in this paper, with regards to the international standards, medical and health regulations of Chinese government and current conditions.
Thalassemia and sickle cell disease
Irene AG Roberts , Josu de la Fuente , in Hematopoietic Stem Cell Transplantation in Clinical Practice , 2009
SCT remains the only cure for sickle cell disease and thalassemia. Cure appears to be life-long and associated with minimal long-term risks. When deciding whether or not to proceed with SCT, families and physicians must weigh up the risks of the procedure, including TRM and graft failure, against the expected survival and quality of life with medical treatment. For thalassemia the outcome of SCT is best in patients under 16 years old who comply well with chelation treatment and who have no evidence of liver dysfunction. They can expect long-term survival of 95% and thalassemia-free survival of 90%. Patients with poor-risk features have a reduced chance of cure (56–82%) and higher TRM (up to 20%), but still have a long-term survival advantage over conventional medical management.
Sickle cell disease is more heterogeneous and the patients predicted to benefit most from SCT are those with CNS disease or recurrent acute chest syndrome despite hydroxyurea. Long-term disease-free survival after SCT for sickle cell disease in childhood is 82–86%. Since this is almost identical to recent US data on survival of homozygous sickle cell disease with medical treatment, SCT is likely to remain a valuable option even with advances in pharmacologic disease modifiers.
Stem cell transplantation – future prospects
A John Barrett , in Hematopoietic Stem Cell Transplantation in Clinical Practice , 2009
Stem cell transplantation as it is practiced today has little chance of surviving long into the 21st century. However, far from signaling the death of SCT, new developments in basic immunology and stem cell science and treatment, together with the beginnings of translational research to make sophisticated cell therapy a reality, should continue to move the field forward. These developments should ultimately render obsolete current preoccupations with GvHD, rejection, infection, disease relapse, and donor selection. There is every reason to expect SCT of the future to be performed more cheaply than at present, mainly on an outpatient basis, with few complications and with a low level of treatment failure. So daunting are the challenges medicine still faces with malignant disease and degenerative diseases in an increasingly older aged population that it is unlikely SCT will be replaced by small molecule ‘magic bullets’ (of which imatinib still remains the best example). Rather, it is more likely that diseases will continue to be treated as they are today, with a combination of integrated treatment approaches in which SCT will remain playing a key role.
Essential biology of stem cell transplantation
Allogeneic sct for bone marrow failure disorders.
SCT is an effective treatment for severe aplastic anemia, whether or not the disease is immune mediated. The curative effect of SCT in SAA relies on the restoration of missing stem cell function, while the preparative regimen making way for the establishment of donor immune function arrests the autoimmune process causing marrow failure. 36
SCT has also been used to treat victims of non-therapeutic irradiation causing bone marrow failure. In practice, this strategy has limited use because irradiated victims may have received supralethal doses of irradiation to non-hematopoietic tissue, have associated burns or blast injury or they may remain contaminated with radioactive materials that continue to damage the transplanted marrow. 37
Childhood leukemias
Kristin Baird , Alan S Wayne , in Hematopoietic Stem Cell Transplantation in Clinical Practice , 2009
Role of transplant
SCT is considered the only curative treatment for childhood MDS and JMML. Given the low response rates to non-transplant therapies, and because failure rates after SCT appear lower when transplant is performed soon after diagnosis, strong consideration should be given to early transplantation, especially when a matched sibling donor is available. DFS is significantly increased from less than 10% with immunosuppressive or cytoreductive therapy up to 50–64% with transplant. Results of the largest published SCT series for children with MDS and JMML are summarized in Table 6.14 . 191–197 Disease subtype, age greater than 4 years, and female gender are recognized poor prognostic indicators. For patients with JMML, those who develop GvHD have a lower incidence of relapse. 178, 198
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