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Cell therapy for neurological disorders: The elusive goal
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.185418
The positive outcomes of the transplantation of fetal neural tissue in adult rat models of a variety of neurological disorders, particularly Parkinson's disease, in the 1970s, and its translation to humans in the 1980s, raised great hopes for patients suffering from these incurable disorders. This resulted in a frantic research globally to find more suitable, reliable, and ethically acceptable alternatives. The discovery of adult stem cells, embryonic stem cells, and more recently, the induced pluripotent cells further raised our expectations. The useful functional recovery in animal models using these cell transplantation techniques coupled with the desperate needs of such patients prompted many surgeons to “jump from the rat-to-man” without scientifically establishing a proof of their utility. Each new development claimed to overcome the limitations, shortcomings, safety, and other technical problems associated with the earlier technique, yet newer difficulties prevented evidence-based acceptance of their clinical use. However, thousands of patients across the globe have received these therapies without a scientifically acceptable proof of their reliability. The present review is an attempt to summarize the current status of cell therapy for neurological disorders. Keywords: Mesenchymal stem cells; neural stem cells; neurological disorders; regenerative medicine
Due to the limited capacity of the central nervous tissue to regenerate, patients with brain damage have to suffer from lifelong disability. Till the early 1970s, all attempts at neural tissue transplantation proved to be a failure. The use of fetal neural tissue for cellular therapy provided the first unequivocal evidence that such grafts “take up,” grow, and develop at least a limited two-way connection with the host brain, and to a variable extent, restore functional deficits in rodents. The clinical use of this procedure soon highlighted its limitations and led to the search for more reliable and acceptable stem cells capable of transformation into any specific cell-types, including neurons and glia. Depending upon the culture conditions, these cells could be made to secrete the desired neurotransmitters, in vivo. Around the same time, stem cells capable of such transformations were isolated from adult bone marrow and many other tissues such as the umbilical cord blood, placenta, and amniotic fluid. Thus, the ethical concerns raised against the use of fetal or embryonic tissue were overcome. However, even the use of these transformed adult stem cells revealed new difficulties and limited success. Just about a decade ago, a revolutionary method was described to reprogram adult human cells using genetic engineering techniques. Thus, today, there are a host of sources from which the transplantable cells may be procured—fetal tissue, embryo-derived cells, mesenchymal cells from diverse sources, and induced pluripotent cells (iPSCs). Each one of these sources has been shown to have a therapeutic potential, at least in animal models of diverse neurological disorders—traumatic, ischemic, and degenerative. There are tantalizing, though mostly anecdotal, evidence of their usefulness in the treatment of human patients. In addition, these cells have been demonstrated to possess anti-inflammatory and immunoregulatory functions. At the same time, there is a risk of them undergoing neoplastic transformation, ageing, rejection, and host-disease transfer. Thus, all stem cells, though similar, are not identical, morphologically, genetically, functionally, and in their survival capacity, in vivo. Therefore, it is not surprising that till today, there are no large scale, randomized, double-blind successful studies to guide their general clinical application. The present review is an attempt to summarize the existing vast information for the benefit of clinicians, especially neurosurgeons.
Omnis cellulae cellula ( all cells come from other cells) Francois Vincent Raspail, 1825 EB Wilson introduced the term “stem cells” in his description of the development of the Ascaris worm.[1] He went on to describe the special characteristics of these cells to undergo asymmetrical divisions, so that each time they divide, they give rise to both a cell similar to themselves and a cell with a different fate (it was a theoretical postulate). The search for stem cells began after the bombing of civilian populations in Hiroshima and Nagasaki. “In 1956, three laboratories demonstrated that injected bone marrow cell regenerated the blood forming system (in whole body X-radiated mouse).”[2] The first experimental demonstration that stem cells exist dates back to the early 1960s, when the hematopoietic system was shown to harbor single cells with a potential to renew circulating blood.[3] These were further characterized by Irving Weissman et al.[4],[5] In 1981, Gail Martin,[6] in the US, and Martin Evans,[7] in the UK, published articles reporting that the embryonic stem cells (ESCs) of the inner cell mass of the preimplanted embryo could be grown in tissue culture in vitro under conditions that allowed them to proliferate without differentiating. Cell lines of pluripotent ESCs derived from mouse embryo could then be indefinitely maintained in culture. In 1998, Thomson et al., reported that they were able to derive embryonic stem cell lines from human embryo.[8] It was further demonstrated that these cells could generate neurons, astrocytes, and oligodendrocytes in culture as well as in vivo.[9],[10],[11] Park et al.,[12 and Perrier et al.,[13] established in vitro and in vivo differentiation of human ESCs into dopamine neurons.
Contrary to earlier belief, Gage et al.,[14] and McKay [15] demonstrated that neural stem cells persist throughout life at several other sites, in addition to the subventricular zone and hippocampus. Lie et al.,[16] and Young and Black [17] presented exhaustive reviews of the adult stem cells that have been cited extensively.
In November 2007, two research groups headed by Thomson et al.,[18] at the University of Wisconsin, and Shinya Yamanaka [19] and his postdoctoral student Kazutoshu Takahashi, at Kyoto University, Japan, described protocols to reprogram somatic adult human cells (from the skin) to a pluripotent state using genetic engineering techniques.[20] These cells, termed as induced pluripotent stem cells (iPSCs), were identical to human ESCs in morphology, proliferation, surface antigens, gene expression, epigenetic status of pluripotent cell-specific genes, and telomerase activity. Furthermore, these iPSCs could be differentiated into cell types of all the three germ layers.
Notwithstanding the failed attempts at neural transplant using adult tissue over a century ago,[21] it was the pioneering work of Das and Altman,[22] Bjorklund et al.,[23],[24],[25],[26] and Lund and Hauschka,[27] using fetal neural tissue for transplantation, that heralded an explosion of investigations globally regarding cellular therapy for neurological disorders. These studies, including ours from the late 1980s and early 1990s,[28],[29] unequivocally established that such grafts “take,” grow, and form at least a limited two-way connection with the host brain, produce appropriate neurotransmitters, and to a variable extent, restore functional deficits, resulting from disease or damage to the host brain. The results in rodent experiments were so spectacular, and the need to provide cure to the victims of these incurable disorders so desperate, that neurosurgeons jumped from “rat to man” without waiting for detailed studies in higher mammals.[30],[31],[32] In 1992, based on the reports in the literature as well as our experimental studies, we concluded, “While the studies carried out so far have laid a firm foundation for possible future therapeutic application, most critical investigators, including some of the pioneers, have unequivocally expressed their reservation regarding uncritical use of this procedure for treatment of human disease in the present state of our knowledge.”[33],[34],[35],[36] In 1994, in our review titled, “Clinical use of neural transplants: The unresolved problems,” we discussed the pitfalls and limitations of the existing techniques of cell-transplantation therapy. These included problems related to harvesting the donor tissue, the size of the transplant, its location, the paucity of neuronal connectivity, immunological considerations, and long-term changes in the transplant.[37] Following transplants of fetal ventral mesencephalic tissue, especially in hundreds of patients with Parkinson's disease, there were conflicting reports from very good to very little improvement, with some reporting distressing complications.[38],[39],[40],[41],[42],[43] Both Freed et al.,[41] and Olanow et al.,[42] in two large, randomized studies, could not demonstrate any significant differences between patients who were transplanted with fetal ventral mesencephalon (FVM) when compared to controls. They were the first to report graft-induced dyskinesia in transplant recipients, which persisted following the withdrawal of levodopa.[44],[45],[46] Detailed reviews on the subject were elegantly presented in subsequent years.[43],[47] Another multicentric collaborative study, TRANSNEURO also failed to provide an unequivocal answer. Meanwhile, Kordower et al.,[48] Kordower et al.,[49] and Li et al.,[50] reported Lewy body-like pathology in long-term fetal mesencephalic dopamine neuron transplants. These results, along with the psychosocial and ethical problems associated with obtaining fetal tissue for transplantation, dampened the enthusiasm for this type of therapy.
Cell therapy for transplantation received another boost with the discovery of ESCs from human blastocysts.[8],[51] These totipotent cells demonstrated the potential to differentiate into any type of adult cells, including those of the neuronal series. This was considered to be a breakthrough discovery by Fred Bloom, the editor of Science, in 1999, “A revolution in the making” by Tandon in 2001,[52] and as one of the greatest achievements of modern biotechnology by Douarin.[53] Soon it was shown that these cells can be directed into neural precursors that can generate neurons, oligodendroglia, and glia, both in culture and in vivo.[9],[10] In addition, it was possible to differentiate these cells into dopamine neurons.[12],[13],[47],[54],[55] In 2009, a US Biotech Company, Geron Corporation, received permission from the US Food and Drug Administration for the first human trial of embryonic-stem-cell-derived cell differentiated to the oligodendrocyte phenotype for implantation in spinal cord injury.[56] This permission was granted, notwithstanding a warning by Friedmann, a genetic scientist, who pointed out that “Discussions of the therapeutic applications of hESCs are characterized by the kind of exaggeration and elevated expectations that were characteristic of the gene transfer field.”[57] Geron Corporation gave up this trial within two years.[58] In addition to the risk of neoplasia and the ethical concerns related to the source of these blastocysts (despite the fact that blastocysts were from discards of the in vitro fertility clinics), prevented any sizeable clinical trials.
Demonstration by Lorenz et al., in 1951[59] that bone marrow injection could modify the effects of acute radiation injury in mice and guinea pigs led to the search for the cellular element responsible for it. The pioneering work of Weissman et al., among others, led to the identification and characterization of the mouse hematopoietic stem cells.[4],[60],[61],[62],[63],[64] Within a few years, mesenchymal stem cells (MSCs) became the most well-characterized adult stem cell population.[47] Soon a series of laboratories established that bone-marrow-derived stem cells could develop into liver cells, muscle cells, osteoblasts, and even neural cells. Around the same time, researchers established the possibility of generating neural progenitor cells from mesenchymal cells derived from the skin, adipose tissue, umbilical cord blood, etc., in addition to those derived from the bone-marrow.[65],[66],[67],[68],[69],[70],[71],[72],[73] However, Weissman boldly admitted that “We and others have attempted to reproduce the demonstration of production of cortical neurons from marrow or hematopoietic stem cell precursors and have failed.”[64] There are no unique markers for MSCs.[74],[75],[76] As a universally accepted criteria for defining an MSC was lacking, the Mesenchymal and Tissue Stem Cell Committee of the International Society for Cellular Therapy (ISCT) agreed on a set of standards to define human MSCs.[77] However, Park et al.,[78] Uccelli et al.,[74] Alvarez et al.,[79] and Atoui and Chiu [80] described some specific markers such as CD73, CD105, CD44, and CD90 to differentiate these cells from hematopoietic cells derived from bone marrow. There is growing evidence that MSCs from different sources are not entirely the same.[80],[81],[82] It is postulated that these differences may be responsible for diverse therapeutic potentials, as was reported earlier that the choice of serum used in the culture may influencethe in vitro expansion of human MSCs, cell proliferation, differentiation, gene expression, and transcriptome stability.[75],[83],[84],[85],[86],[87],[88],[89] More detailed comparative characteristics of MSCs derived from human bone marrow, adipose tissue, and umbilical cord blood are provided in other reviews.[88],[89],[90] MSCs have many advantages such as easy accessibility; no ethical issues; ability to cross blood–brain barrier (BBB); their path of tropism that leads not only to further attraction of other MSC migration to the site but also to activate signaling pathways in MSCs to promote paracrine secretion of cytokines and growth factors. This results in increased vasculogenesis and neuroprotection; having immune suppressive capability when the cell is placed in an area of inflammation; no tumor formation; no immunological rejection; and, the ability to be transplanted across the allogenic barrier.[76],[91],[92],[93],[94],[95] Harvesting autologous bone marrow cells from individual patients still poses problems in very young and very old subjects because it is a painful procedure,[80] cells are difficult to grow,[79],[82] and there is lack of long-term survival of the cells after transplantation. In a study by Park et al.,[78] the number of surviving human bone marrow derived mesenchymal stem cells (hMSCs) in the substantia nigra, 6 weeks after the last hMSCs administration, was approximately 1.7% of the total injected MSCs.[81], 91, [96],[97],[98] On the other hand, Hodgkinson et al.,[83] reported that, despite the advantages, stem cell therapy using MSCs is limited by their low survival, engraftment, and homing to damaged area, as well as differentiation into fully functional tissues.[81],[83] MSCs are present in adult bone marrow and represent <0.01% of all nucleated marrow cells.[78] In addition, bone marrow-derived MSCs barely differentiate into neurons or a glial lineage following transplantation, which makes their therapeutic potential questionable.[99],[100] Liu Y et al.,[92] pointed out that the ultimate clinical result will depend not only on the regenerative potential of the donor stem cells but also on the environment of the host recipient site as well as the pathology. The crosstalk between the implanted donor bone marrow MSCs and the recipient immune cells may play a key role in determining the success of bone-marrow-MSCs-mediated tissue regeneration. There are a number of reports, both using animal models and humans, claiming clinical improvement in a variety of neurological disorders like stroke,[96],[101],[102],[103] Parkinson's disease (PD),[78],[104] spinal cord injury (SCI),[99],[105],[106] multiple sclerosis (MS),[107] Alzheimer disease (AD),[74] amyotrophic lateral sclerosis (ALS),[108] and Huntington disease (HD).[91] Kern et al.,[89] reported that MSC-mediated therapy shows promise for cellular therapy, as was evident from the large number of preclinical trials. They also reported that several clinical trials using MSCs as a delivery method for treatment of a number of brain pathologies, including brain ischemia, ALS, MS, AD are ongoing, despite the possible side effects. However, among the clinical trials studied, there is no evidence that MSCs can survive for prolonged periods of time. The real issue is to unravel the mechanism for the observed improvement. There is enough evidence that the beneficial effect is primarily due to the trophic effect and not due to the replacement of damaged or lost brain tissue.[78],[91],[100] In addition, bone marrow MSCs are credited with their anti-inflammatory and immunomodulatory role.[78],[92],[93],[94],[109] However, there is no evidence to indicate that the transplanted MSCs, even if transdifferentiated into neurons, ever get integrated into the host nervous system or remodel the neuronal circuitry.
A significant advancement in the field of stem cell biology occurred when Takahashi and Yamanaka developed a simple and repeatable method to dedifferentiate mouse somatic cells (fibroblasts initially) to embryonic-like cells termed induced pluripotent stem cells (iPSCs). These iPSCs could give rise to almost every cell of the mouse body. The following year they reported that their method and similar methods were shown to work for other species, including humans.[19],[20] This not only resulted in a Nobel Prize but was followed by frantic research activity globally to refine and modify the technique as well as to explore the basic biology of the iPSCs and even test their therapeutic potential, at least in animal models. Originally, four transcription factors (Oct ¾, Sox-2, Klf-4, and c-Myc) were used for inducing pluripotency; later, others achieved similar results with only three transcription factors.[110] Yu et al.,[18] described the derivation of human iPSCs with the use of nonintegrating episomal vectors thus avoiding the risk of mutations. It was claimed that human iPSCs were similar to human embryonic stem cells (hESCs) in terms of morphology, proliferation, surface antigens, gene expression, epigenetic status of pluripotent cell-specific genes, and telomerase activity.[18],[19],[111] It is very promising to note that sufficient evidence exists to indicate that iPSCs can be transformed to various subtypes of neurons and glia—astrocytes, oligodendrocytes or even tyrosine hydroxylase (TH) positive (dopamine secreting) neurons, glutamatergic, gamma amino butyric acid (GABA) ergic, or motor neurons.[112],[113],[114],[115],[116],[117],[118] This led Svendsen to propose how human induced pluripotent cells will eventually transform regenerative medicine.[119] However, to use these cells for replacement therapy has its own problems regarding their integration with the host and, more so, for reconstituting the functional circuits. The risk of host-to-graft propagation of the disease would need attention. It has now been established that the iPSCs may be similar to, but not identical, to ESCs. In “Concise review: Induced Pluripotent Stem Cells versus Embryonic Stem Cells: Close enough or yet too far apart,” Bilic and Belmonte [120] stated that “Transcribed genes, epigenetic landscape, differentiation potential and mutational load show small but distinctive dissimilarities between these two cell types.” Takahashi et al., acknowledged that human iPSCs are not identical to human ESCs.[19] In addition, iPSCs also seem to be able to accumulate embryonic-stem-cell-dissimilar transcripts and chromatin marks that are not related to the cell of origin.[121],[122],[123] Bilic and Belmonte [120] independently recorded genomic instability and mutations appearing due to the imperfections in reprogramming procedure. Detailed genome-wide studies comparing ESC and iPSCs revealed small, but distinct, differences between the two. Even early and late passage human iPSCs are not identical.[124],[125] In addition, Bilic and Belmonte [120] reported the iPSC mutation to range from chromosomal aneuploidy, subchromosomal deletions, and duplications to single base mutation. They quoted a study by Mayshar et al.,[126] who reported as many as 20% cells to be having gross chromosomal aberrations, including complete trisomy (9% of total). The risks involved in using C-Myc for transformation that resulted in tumorigenesis were pointed out by several studies.[115],[119],[121] It is generally agreed that there are many biological and technological problems that need to be resolved prior to using iPSCs for clinical application.[115],[119],[124],[127] According to Jung et al.,[115] challenges, such as those ensuring clinical safety, should be overcome, and protocols of reprogramming and differentiation need to be optimized to increase the efficiency and to eliminate tumor formation. They reported tumor development in 3 out of 12 transplanted rats. The current protocols for transformation with all recent improvements are still lengthy, complex, and expensive and yield incompletely homogeneous population of neurons.[127] To use custom-made cells would take a ridiculous amount of money.[128] Autologous iPSC lines take several weeks to generate enough stem cells, and hence cannot be used for acute conditions such as trauma and stroke.[129] In addition to the use of iPSCs for replacement therapy, there are other prospects of utilizing the technique to model neurodegenerative disorders—so called disease-in-the dish—or the screening and testing of therapeutic compounds in vitro.[119],[130] Such reprogrammed cells derived from patients provide unique opportunities for exploring the basic developmental biology issues and the disease pathogenesis.[18],[19],[78],[79],[110],[115],[129],[131],[132],[133] Thus, cells from patients suffering from PD,[131] AD,[134] HD,[132] schizophrenia,[135] and ALS [136] have been transformed to disease-specific stem cells. It is hoped that these would not only provide better understanding of the pathogenesis and potential drug targets, but also opportunities for individualized therapy. This, however, will not be discussed here in further details.
Following the unequivocal demonstration of successful transplantation of fetal neural tissue in rodents in the 1970s,[22],[23],[25],[26],[27],[137],[138] the first human neural transplant using adrenal medulla was performed by Backlund et al.,[139] and Madrazo et al.[140] This was soon followed by the transplantation of human fetal ventral mesencephalic tissues by Hitchcock et al.,[30] in the striatum of patients with Parkinsonism More Details. As a consequence, thousands of Parkinson's patients (and many others with diverse neurological disorders) were submitted to fetal neural transplants with variable results. The outcome of such operations and the problems associated with these have been reviewed in several papers.[31],[37],[38],[40],[43],[46],[47],[141] Independent open-label studies initially reported beneficial effects in Parkinson's patients. However, two large double-blind placebo-controlled studies by Freed et al.,[41] and Olanow et al.,[42] failed to show any significant differences between patients who had undergone fetal ventral mesencephalic transplantation when compared to controls, even though the implanted dopaminergic cells were detected in the brain of the treated patients even after 10–14 years following the transplantation.[47],[142] As mentioned earlier, a simultaneous search for other alternatives suitable for cellular therapy resulted in the discovery of neural stem cells, ESCs, and adult cells such as bone-marrow-derived mesenchymal cells, hematopoietic cells, adipose tissue-derived cells, and cord-blood derived cells. Such tissue-specific stem cells could be derived from virtually every part of the body and coaxed to grow into neurons in vitro. Attempts to convert adult-cells into pluripotent cells ultimately resulted in the revolutionary technique of iPSCs, described earlier. Thus, the potential of cell-therapy for treatment of diverse neurological disorders has vastly expanded. These advances have also helped to overcome the ethical problems that were associated with the use of fetal neural transplants or blastocyst-derived ESCs. An excellent review of the experimental use of these cells in the animal models of PD, HD, ALS, MS, stroke, brain tumors, and spinal cord injury (SCI) is provided in a series of tables presented by Kim and de Vellis [100] and Kaplan et al.[108] This information has been updated during 2010–2014 for a variety of clinical trials using different sources of stem cells [Table 1]. A further search for such clinical trials in the US Government Clinical Trial Registry recently revealed a few more ongoing or completed trials using a variety of stem cells for treatment of neurological disorders such as the inborn errors of metabolism (NCT00176904, NCT00176917, and NCT00668564), cerebral palsy (NCT01193660), stroke (NCT00859014), multiple sclerosis (NCT00278655), and brain tumors (NCT00085202). Unfortunately, most of these studies had limited sample size; and, the available information is inadequate to arrive at a considered view of the therapeutic value. There are other smaller trials like Phase I/II trials on 37 patients of autism by Lv et al.,[143] and a single patient of autism by Sharma et al.,[144] primarily to evaluate the safety of stem cells for anti-inflammatory therapy. A number of research projects dealing with stem cell therapy, mostly related to MSCs, are being pursued by investigators in India, although only a few have dealt with central nervous system disorders.[145] A stem cell clinical trial registry has been established at the Indian Council of Medical Research (ICMR). Unfortunately, since it is not legally binding, not all ongoing or planned trials or therapeutic interventions are being documented. However, it is worth mentioning that the first Phase II multicenter randomized trial using intravenous autologous bone marrow stem cell therapy for ischemic stroke was reported from India by Prasad et al.[146] The study indicated that intravenous infusion of bone marrow SCs is safe, but without a considerable beneficial effect of treatment on stroke outcome.
Kiatpongsan and Sipp,[147] while surveying the clinical scenario, found many advertisements for medical procedures that have never been proven to be efficacious in appropriately designed clinical trials. They concluded by stating that “To date, proven therapeutic applications for stem cells have mainly been for blood and immunological disorders.” An important question that is often overlooked while assessing the functional improvement is the precise role played by the transplanted cells. The current review confirms our earlier studies with fetal neural transplant that the beneficial effect, if any, is not necessarily due to the replacement of the damaged or diseased cells, nor due to the reconstruction of the disrupted neural circuits.[30],[37] However, when it comes to neurological disorders, cell replacement is probably the least important. Cells from diverse sources can be transformed to release desired neurotransmitters (dopamine), neuroprotective factors, various cytokines and growth factors, and angiogenic factors. These may revive or stimulate the regeneration of endogenous neurons and even promote the growth of neurites and synaptogenesis. However, probably a more important role of the transplanted cells is their anti-inflammatory and immunoprotective role. They can promote myelination, improve vascularity, and are known to modify the blood brain barrier. In addition, they can be specifically transformed to deliver drugs or genes. A large number of studies testify this conclusion.[74],[78],[80],[81],[93],[94],[148],[149] These observations are true for all types of stem cells irrespective of their embryonic, fetal, or adult origin (ESCs, MSCs, iPSCs, or others). However, various types of stem cells have their particular advantages and disadvantages. Obviously, there is no “one size fit all.” In fact, MSCs from different sources—bone marrow, umbilical cord blood, adipose tissue, and skin—are not the same with respect to their therapeutic value. From this fairly extensive survey, it is obvious that cellular therapy using stem cells of diverse origin has the potential to treat a variety of neurological disorders. However, it is also clear that none of the reviewed studies would meet the criteria of class 1 evidence for use in the routine clinical practice. Enserink [150] in a thought provoking paper, “Selling the stem cell dream,” concluded by stating that “Amid all the hype about stem cells, it is easy to forget that very few cell-based therapies have proven their mettle in rigorous clinical trials.” Kim and de Vellis,[100] in a detailed review, “Stem cell based cell therapy in neurological disorders,” concluded that “There is an urgent need to address several issues before stem cell replacement therapy and gene therapy are widely accepted in clinical medicine.” Similarly, Sanberg [81] pointed out that, while there are a number of different types of stem cells that could prove to be useful, there are potential concerns associated with each one of them. Hodgkinson [83] provided an update of various clinical trials using MSCs [Table 1]. Among the 28 trials listed for various diseases during 2001–2009, only three were for neurological disorders (ALS, PD, and SCI); these were only feasibility studies. Commenting on the future directions, they concluded that “MSC therapy has been shown to be beneficial in the treatment of a diverse range of disorders. However, the routine use of MSCs in the clinic has been hampered due to their problems related to poor survival, engraftment and differentiation.” Alvarez [79] summarized the therapeutic potentials of ESCs, adult SCs, and iPSC cells in an attempt to define their potential. In the current scenario, approximately 3400 controlled clinical trials are registered as 'Cell Therapy' in the NIH database (http://clinical-trials.gov/). Of these, 1900 have now been completed, although only 125 have presented their results. Many of these clinical studies are Phase I trials relating to safety issues and many use autologous bone marrow-purified populations. A few hundred studies are using MSCs, although none have yet formally presented their results. Mouhieddine et al.,[151] stated that “Even with the exponential increase in our knowledge of stem cell formulation and manipulation, we are still far from fully understanding the intricate mechanisms in which these intriguing cells function.” Dunnett and Rosser [141] voiced the same concern in his words as “The current state of knowledge does not provide a 'let out' for unproven stem cell clinics operating without experimental evidence for efficacy in the absence of a randomized control trial.” They stated that “concern is related to the extent to which commercial pressures are driving a premature 'rush to clinic' in advance of sufficient pre-clinical evidence for safety and efficacy.” They advised against “stem-cell tourism.” Notwithstanding the absence of a scientifically acceptable proof of reliable, reproducible benefit of human stem cell therapy (other than for some hematological and immunological disorders), literally thousands of patients have been submitted to the yet “unproven” therapy.
This is not to say that stem cell therapy does not have any potential for clinical use, but only to point out that there is an urgent need for more critical basic studies. We have sufficient evidence from animal studies that there is “hope for help” for a wide range of incurable and devastating brain and spinal disorders; however, the methodology to exploit the technique to provide the desired benefit without incurring an unacceptable risk is still eluding us. The crucial question that plagues research in this field is why the benefits observed in animal models are not translating into humans? No doubt there are a host of other related questions, such as the source and type of stem cells to be used, the ideal technique to isolate and grow homogenous populations of stem cells, the culture media to be used, the number of cells required, their route of administration, the need for human leukocyte antigen matching in case of an allogenic graft, the risk of tumor development and host-to-graft transfer of disease, the premature ageing of transplanted cells, and their long-term survival and integration. Hence, an in-depth research is warranted in search of answers to these questions. It appears that we are “tantalizingly near and yet far-off” from our ultimate goal, the success of this therapy for human disorders of the nervous system. Acknowledgements The authors wish to express their grateful thanks to Ms. Priyanka of National Brain Research Centre for her help in arranging much of the material used in the review as well as in organizing the list of references. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
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