Atormac
Neurology India
menu-bar5 Open access journal indexed with Index Medicus
  Users online: 3736  
 Home | Login 
About Editorial board Articlesmenu-bullet NSI Publicationsmenu-bullet Search Instructions Online Submission Subscribe Videos Etcetera Contact
  Navigate Here 
 Search
 
  
 Resource Links
  »  Similar in PUBMED
 »  Search Pubmed for
 »  Search in Google Scholar for
 »Related articles
  »  Article in PDF (567 KB)
  »  Citation Manager
  »  Access Statistics
  »  Reader Comments
  »  Email Alert *
  »  Add to My List *
* Registration required (free)  

 
  In this Article
 »  Abstract
 » Introduction
 » Historical Aspects
 » Adult Stem Cells
 »  Induced Pluripot...
 »  Fetal Neural Tra...
 » Embryonic Stem Cells
 »  Mesenchymal Stem...
 »  Induced Pluripot...
 » Clinical Trials
 » Extent of Misuse
 » Conclusions
 »  References
 »  Article Tables

 Article Access Statistics
    Viewed3031    
    Printed37    
    Emailed0    
    PDF Downloaded147    
    Comments [Add]    
    Cited by others 2    

Recommend this journal

 


 
Table of Contents    
REVIEW ARTICLE
Year : 2016  |  Volume : 64  |  Issue : 4  |  Page : 612-623

Cell therapy for neurological disorders: The elusive goal


1 Department of Neurosurgery, All India Institute of Medical Sciences, New Delhi; National Brain Research Centre, Manesar, Haryana, India
2 National Brain Research Centre, Manesar, Haryana, India

Date of Web Publication5-Jul-2016

Correspondence Address:
Prof. Prakash N Tandon
National Brain Research Centre, Manesar - 122 051, Haryana
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.185418

Rights and Permissions

 » Abstract 

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


How to cite this article:
Tandon PN, Seth P. Cell therapy for neurological disorders: The elusive goal. Neurol India 2016;64:612-23

How to cite this URL:
Tandon PN, Seth P. Cell therapy for neurological disorders: The elusive goal. Neurol India [serial online] 2016 [cited 2019 Oct 22];64:612-23. Available from: http://www.neurologyindia.com/text.asp?2016/64/4/612/185418



 » Introduction Top


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.


 » Historical Aspects Top


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.


 » Adult Stem Cells Top


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.


 » Induced Pluripotent Stem Cells Top


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.


 » Fetal Neural Transplant Top


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.


 » Embryonic Stem Cells Top


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.


 » Mesenchymal Stem Cells Top


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.


 » Induced Pluripotent Stem Cells Top


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.


 » Clinical Trials Top


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.
Table 1: Outcome of clinical trials using mesenchymal stem cells

Click here to view


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.


 » Extent of Misuse Top


  • As mentioned earlier, Martin Enserink in a thought provoking paper “Selling the Stem Cell Dream” quoted, “If you suffer from an incurable neurological disease such as MS, PD, HD, ALS in a procedure that takes just a few hours and costs $23,000, the Preventive Medicine Centre in Rotterdam will inject stem cells obtained from umbilical cord blood into your blood stream and under your skin.”[150] It is alarming that not only is there little or no evidence for the procedures and their efficacy, the experts say that in many cases there are no published animal studies to suggest that they might work in humans. The paper provides a list of several such companies around the world, e.g. Cells-4-Health (Netherland); Em Cell (Kiev, Ukrain); Huang (Shijingshan, China); Beijing Xishan Institute for Neuroregeneration and Functional Recovery (Beijing, China); Institute of Regenerative Medicine (St. John, Barbados); Advanced Cell Therapy (Worcestor, Mas, USA—12 centres around the world); Medra (California, Co, operating from Dominician Republic); X-cell centre (Cologne, Germany). These companies advertise stem-cell based treatment for conditions such as diabetes, AD, ALS, and erectile dysfunction
  • Patients who received the stem-cell procedure during an operation at a hospital in Innsbruck, Austria, are now engaging in a legal battle against the hospital in a scandal that goes right to the heart of the country's health ministry [152]
  • In China, fetal brain tissue has been transplanted into the lesion of more than 400 patients with spinal cord injury. Anecdotal reports have been the only basis for assuming that the procedure is safe and effective. Dabkin et al.,[153] undertook an independent observational study of 7 chronic spinal cord injured patients undergoing surgery in Beijing. They found several lacunae in the research protocol. Complications, including meningitis, occurred in 5 patients. No clinically useful sensorimotor disability or autonomic improvements were found. In the absence of valid protocols for these clinical trials, physicians should not recommend this procedure to patients
  • 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. Notwithstanding this fact, the above mentioned clinics claim to have treated thousands of patients with some “spectacular” results. Some companies are “preying on desperate patients” says Irving Weissman—a pioneer of stem cell biology
  • Kiatpongsan and Sip [147] in their paper reinforce this view that “Many advertisements for medical procedures that have never been proven efficacious in appropriately designed clinical trials.” To date, proven therapeutic applications for stem cells have been mainly for blood and immunological disorders
  • Law enforcing or regulatory agencies in the United States have shut down several stem cell clinics. A series of British Broadcasting Company documentaries revealed unethical trade practices that involved sale of human fetuses sourced from Ukraine to stem cell tourism clinics in the Caribbean. This forced the closure of the Institute of Regenerative Medicine of Barbados, one of the major clinic in this “business”
  • David Cyranoski [154] quotes Paul Knoepfler of University of California, Davis, regarding stem cells that “No clinical trials have shown any evidence of efficacy.” “Patient testimonials cited by the people setting the treatments have little, if any, meaning.”“I feel that we must protect patients from risky treatments advanced by overzealous, even greedy entrepreneurs” reported Bettie Sue Masters—a biochemist at the University of Texas Health Science Centre in San Antonio. Some clinics recruit patients in the United States and then direct them for overseas treatment. One such example is the Stem Cell Treatment Institute in San Diego that treats its patients in Mexico. RNL Bio, a stem cell company that has its headquarters in Seoul, has its affiliate clinics in the United States, where fat samples of patients are collected and sent to Seoul. The manipulated cells are not approved for reinjection in the United States or South Korea, and so patients typically travel to China or Japan for the procedure. RNL has since 2006 sent more than 10,000 patients to clinics in Japan and China to receive injections. Two patients who underwent this procedure in Japan died
  • Chinese Health Ministry's efforts to ban the clinical use of unapproved stem cell treatments failed to control the situation. “Businesses around the country continue to charge thousands of dollars for these unproven therapies. They attract thousands of medical tourists from overseas. The number of such companies in China in 2009 was believed to be about 100.” As per reports published in Nature, stem-cell experts contacted by Nature insist that such therapies are not ready for clinics and say that some of them may even endanger the patient's health.[155],[156]



 » Conclusions Top


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.

 
 » References Top

1.
Wilson EB. The cell in development and heredity. New York: The Macmillan Company; 1925.  Back to cited text no. 1
    
2.
Nowell PC, Cole LJ, Habermeyer JG, Roan PL. Growth and continued function of rat marrow cells in X-radiated mice. Cancer Res 1956;16:258-61.  Back to cited text no. 2
    
3.
Till JE, McCulloch CE. A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat Res 1961;14:213-22.  Back to cited text no. 3
    
4.
Spangrude GJ, Heimfeld S, Weissman IL. Purification and characterization of mouse hematopoietic stem cells. Science 1988;241:58-62.  Back to cited text no. 4
    
5.
Weissman IL. Stem cells: Units of development, units of regeneration, and units in evolution. Cell 2000;100:157-68.  Back to cited text no. 5
    
6.
Martin GR. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci USA 1981;78:7634-8.  Back to cited text no. 6
    
7.
Evans MJ, Kaufman MH. Establishment in culture of pluripotential cells from mouse embryos. Nature 1981;292:154-6.  Back to cited text no. 7
    
8.
Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, et al. Embryonic stem cell lines derived from human blastocysts. Science 1998;282:1145-7.  Back to cited text no. 8
    
9.
Tabar V, Panagiotakos G, Greenberg ED, Chan BK, Sadelain M, Gutin PH, et al. Migration and differentiation of neural precursors derived from human embryonic stem cells in the rat brain. Nat Biotechnol 2005;23:601-6.  Back to cited text no. 9
    
10.
Keirstead HS, Nistor G, Bernal G, Totoiu M, Cloutier F, Sharp K, et al. Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury. J Neurosci 2005;25:4694-705.  Back to cited text no. 10
    
11.
Zhang SC, Wernig M, Duncan ID, Brustle O, Thomson JA. In vitro differentiation of transplantable neural precursors from human embryonic stem cells. Nat Biotechnol 2001;19:1129-33.  Back to cited text no. 11
    
12.
Park CH, Minn YK, Lee JY, Choi DH, Chang MY, Shim JW, et al.In vitro and in vivo analyses of human embryonic stem cell-derived dopamine neurons. J Neurochem 2005;92:1265-76.  Back to cited text no. 12
    
13.
Perrier AL, Tabar V, Barberi T, Rubio ME, Bruses J, Topf N, et al. Derivation of midbrain dopamine neurons from human embryonic stem cells. Proc Natl Acad Sci USA 2004;101:12543-8.  Back to cited text no. 13
    
14.
Gage FH, Coates PW, Palmer TD, Kuhn HG, Fisher LJ, Suhonen JO, et al. Survival and differentiation of adult neuronal progenitor cells transplanted to the adult brain. Proc Natl Acad Sci USA 1995;92:11879-83.  Back to cited text no. 14
    
15.
McKay R. Stem cells in the central nervous system. Science 1997;276:66-71.  Back to cited text no. 15
    
16.
Lie DC, Dziewczapolski G, Willhoite AR, Kaspar BK, Shults CW, Gage FH. The adult substantia nigra contains progenitor cells with neurogenic potential. J Neurosci 2002;22:6639-49.  Back to cited text no. 16
    
17.
Young HE, Black AC Jr. Adult stem cells. Anat Rec A Discov Mol Cell Evol Biol 2004;276:75-102.  Back to cited text no. 17
    
18.
Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 2007;318:1917-20.  Back to cited text no. 18
    
19.
Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007;131:861-72.  Back to cited text no. 19
    
20.
Yamanaka S. Strategies and new developments in the generation of patient-specific pluripotent stem cells. Cell Stem Cell 2007;1:39-49.  Back to cited text no. 20
    
21.
Thompson WG. Successful brain grafting. Fetal Tissue Transplant Med, New York Med 1890:701-2.  Back to cited text no. 21
    
22.
Das GD, Altman J. Studies on the transplantation of developing neural tissue in the mammalian brain. I. Transplantation of cerebellar slabs into the cerebellum of neonate rats. Brain Res 1972;38:233-49.  Back to cited text no. 22
    
23.
Bjorklund A, Katzman R, Stenevi U, West KA. Development and growth of axonal sprouts from noradrenaline and 5-hydroxytryptamine neurons in the rat spinal cord. Brain Res 1971;31:21-33.  Back to cited text no. 23
    
24.
Bjorklund A, Segal M, Stenevi U. Functional reinnervation of rat hippocampus by locus coeruleus implants. Brain Res 1979;170:409-26.  Back to cited text no. 24
    
25.
Bjorklund A, Stenevi U. Reconstruction of the nigrostriatal dopamine pathway by intracerebral nigral transplants. Brain Res 1979;177:555-60.  Back to cited text no. 25
    
26.
Bjorklund A, Dunnett SB, Stenevi U, Lewis ME, Iversen SD. Reinnervation of the denervated striatum by substantia nigra transplants: Functional consequences as revealed by pharmacological and sensorimotor testing. Brain Res 1980;199:307-33.  Back to cited text no. 26
    
27.
Lund RD, Hauschka SD. Transplanted neural tissue develops connections with host rat brain. Science 1976;193:582-4.  Back to cited text no. 27
    
28.
Tandon PN. Neural Transplantation: Current status and future perspective. Key-note Address, Indian Science Congress, Pune; 1988.  Back to cited text no. 28
    
29.
Tandon PN, Gopinath G, Mahapatra AK, Shelty AK. Neural transplantation in mammals: Our experience. Proc Indian Nat Sci Acad 1990;56:51-8.  Back to cited text no. 29
    
30.
Hitchcock ER, Clough CG, Hughes RC, Kenny BG. Transplantation in Parkinson's disease: Stereotactic implantation of adrenal medulla and foetal mesencephalon. Acta Neurochir Suppl (Wien) 1989;46:48-50.  Back to cited text no. 30
    
31.
Freed CR, Breeze RE, Rosenberg NL, Schneck SA, Well TH, Barrett JN, et al. Transplantation of human fetal dopamine cells for Parkinson's disease. Results at 1 year. Arch Neurol 1990;47:505-12.  Back to cited text no. 31
    
32.
Madrazo I, Franco-Bourland R, Ostrosky-Solis F, Aguilera M, Cuevas C, Zamorano C, et al. Fetal homotransplants (ventral mesencephalon and adrenal tissue) to the striatum of Parkinsonian subjects. Arch Neurol 1990;47:1281-5.  Back to cited text no. 32
    
33.
Tandon PN. Neural transplantation, CNS neuronal injury, and regeneration. Proc Indian Nat Sci Acad 1992;58(Part-B):1-16.  Back to cited text no. 33
    
34.
Sladek JR Jr., Shoulson I. Neural transplantation: A call for patience rather than patients. Science 1988;240:1386-8.  Back to cited text no. 34
    
35.
Bjorklund A. Neural transplantation - An experimental tool with clinical possibilities. Trends in neurosciences 1991;14:319-22.  Back to cited text no. 35
    
36.
Lindvall O. Prospects of transplantation in human neurodegenerative diseases. Trends in Neurosciences 1991;14:376-84.  Back to cited text no. 36
    
37.
Tandon PN, Gopinath G. Clinical use of neural transplants: The unsolved problems. In: Neural Transplantation, CNS Injury and Regeneration. Eds Marwah J, Teitelbaum H, Prasad KN: CRC Press, Florida; 1994. P 1-15.  Back to cited text no. 37
    
38.
Lindvall O, Brundin P, Widner H, Rehncrona S, Gustavii B, Frackowiak R, et al. Grafts of fetal dopamine neurons survive and improve motor function in Parkinson's disease. Science 1990;247:574-7.  Back to cited text no. 38
    
39.
Widner H, Tetrud J, Rehncrona S, Snow B, Brundin P, Gustavii B, et al. Bilateral fetal mesencephalic grafting in two patients with Parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). N Engl J Med 1992;327:1556-63.  Back to cited text no. 39
    
40.
Dunnett SB, Bjorklund A, Lindvall O. Cell therapy in Parkinson's disease-stop or go? Nat Rev Neurosci 2001;2:365-9.  Back to cited text no. 40
    
41.
Freed CR, Greene PE, Breeze RE, Tsai WY, DuMouchel W, Kao R, et al. Transplantation of embryonic dopamine neurons for severe Parkinson's disease. N Engl J Med 2001;344:710-9.  Back to cited text no. 41
    
42.
Olanow CW, Goetz CG, Kordower JH, Stotessl AJ, Sossi V, Brin MF, et al. A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson's disease. Ann Neurol 2003;54:403-14.  Back to cited text no. 42
    
43.
Evans JR, Mason SL, Barker RA. Current status of clinical trials of neural transplantation in Parkinson's disease. Prog Brain Res 2012;200:169-98.  Back to cited text no. 43
    
44.
Olanow CW, Rascol O, Hauser R, Feigin PD, Jankovic J, Lang A, et al. A double-blind, delayed-start trial of rasagiline in Parkinson's disease. N Engl J Med 2009;361:1268-78.  Back to cited text no. 44
    
45.
Barker RA, Kuan WL. Graft-induced dyskinesias in Parkinson's disease: What is it all about? Cell Stem Cell 2010;7:148-9.  Back to cited text no. 45
    
46.
Politis M, Wu K, Loane C, Quinn NP, Brooks DJ, Rehncrona S, et al. Serotonergic neurons mediate dyskinesia side effects in Parkinson's patients with neural transplants. Sci Transl Med 2010;2:38ra46.  Back to cited text no. 46
    
47.
Ganz J, Lev N, Melamed E, Offen D. Cell replacement therapy for Parkinson's disease: How close are we to the clinic? Expert Rev Neurother 2011;11:1325-39.  Back to cited text no. 47
    
48.
Kordower JH, Chu Y, Hauser RA, Freeman TB, Olanow CW. Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson's disease. Nat Med 2008;14:504-6.  Back to cited text no. 48
    
49.
Kordower JH, Chu Y, Hauser RA, Olanow CW, Freeman TB. Transplanted dopaminergic neurons develop PD pathologic changes: A second case report. Mov Disord 2008;23:2303-6.  Back to cited text no. 49
    
50.
Li JY, Englund E, Holton JL, Soulet D, Hagell P, Lees AJ, et al. Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host-to-graft disease propagation. Nat Med 2008;14:501-3.  Back to cited text no. 50
    
51.
Barinaga M. New lead to brain neuron regeneration. Science 1998;282:1018-9.  Back to cited text no. 51
    
52.
Tandon PN. Neural stem cell research: A revolution in the making. Current Science 2001;80:507-14.  Back to cited text no. 52
    
53.
Dourin N. Stem Cell Technololgy and Other Innovative Therapies. Pontifical Academy of Sciences; 2007.  Back to cited text no. 53
    
54.
Roy NS, Cleren C, Singh SK, Yang L, Beal MF, Goldman SA. Functional engraftment of human ES cell-derived dopaminergic neurons enriched by coculture with telomerase-immortalized midbrain astrocytes. Nat Med 2006;12:1259-68.  Back to cited text no. 54
    
55.
Cho MS, Hwang DY, Kim DW. Efficient derivation of functional dopaminergic neurons from human embryonic stem cells on a large scale. Nat Protoc 2008;3:1888-94.  Back to cited text no. 55
    
56.
Alper J. Geron gets green light for human trial of ES cell-derived product. Nat Biotechnol 2009;27:213-4.  Back to cited text no. 56
    
57.
Friedmann T. Lessons for the stem cell discourse from the gene therapy experience. Perspect Biol Med 2005;48:585-91.  Back to cited text no. 57
    
58.
Baker M. Stem-cell pioneer bows out. Nature 2011;479:59.  Back to cited text no. 58
    
59.
Lorenz E, Congdon C, Uphoff D. Modification of acute irradiation injury in mice and guinea-pigs by bone marrow injections. Radiology 1952;58:863-77.  Back to cited text no. 59
    
60.
Ezine S, Weissman IL, Rouse RV. Bone marrow cells give rise to distinct cell clones within the thymus. Nature 1984;309:629-31.  Back to cited text no. 60
    
61.
Smith LG, Weissman IL, Heimfeld S. Clonal analysis of hematopoietic stem-cell differentiation in vivo. Proc Natl Acad Sci USA 1991;88:2788-92.  Back to cited text no. 61
    
62.
Baum CM, Weissman IL, Tsukamoto AS, Buckle AM, Peault B. Isolation of a candidate human hematopoietic stem-cell population. Proc Natl Acad Sci USA 1992;89:2804-8.  Back to cited text no. 62
    
63.
Uchida N, Weissman IL. Searching for hematopoietic stem cells: Evidence that Thy-1.1lo Lin- Sca-1+ cells are the only stem cells in C57BL/Ka-Thy-1.1 bonemarrow. J Exp Med 1992;175:175-84.  Back to cited text no. 63
    
64.
Weissman I. Stem Cell: Lessons from past, lessons for future. Pontifical Academy of Sciences; Vatican City; 2007. p. 49-58.  Back to cited text no. 64
    
65.
Ferrari G, Cusella-De Angelis G, Coletta M, Paolucci E, Stornaiuolo A, Cossu G, et al. Muscle regeneration by bone marrow-derived myogenic progenitors. Science 1998;279:1528-30.  Back to cited text no. 65
    
66.
Petersen BE, Bowen WC, Patrene KD, Mars WM, Sullivan AK, Murase N, et al. Bone marrow as a potential source of hepatic oval cells. Science 1999;284:1168-70.  Back to cited text no. 66
    
67.
Olmsted-Davis EA, Gugala Z, Camargo F, Gannon FH, Jackson K, Kienstra KA, et al. Primitive adult hematopoietic stem cells can function as osteoblast precursors. Proc Natl Acad Sci USA 2003;100:15877-82.  Back to cited text no. 67
    
68.
Mezey E, Chandross KJ, Harta G, Maki RA, McKercher SR. Turning blood into brain: Cells bearing neuronal antigens generated in vivo from bone marrow. Science 2000;290:1779-82.  Back to cited text no. 68
    
69.
Brazelton TR, Rossi FM, Keshet GI, Blau HM. From marrow to brain: Expression of neuronal phenotypes in adult mice. Science 2000;290:1775-9.  Back to cited text no. 69
    
70.
Woodbury D, Schwarz EJ, Prockop DJ, Black IB. Adult rat and human bone marrow stromal cells differentiate into neurons. J Neurosci Res 2000;61:364-70.  Back to cited text no. 70
    
71.
Zhao LR, Duan WM, Reyes M, Keene CD, Verfaillie CM, Low WC. Human bone marrow stem cells exhibit neural phenotypes and ameliorate neurological deficits after grafting into the ischemic brain of rats. Exp Neurol 2002;174:11-20.  Back to cited text no. 71
    
72.
Crain BJ, Tran SD, Mezey E. Transplanted human bone marrow cells generate new brain cells. J Neurol Sci 2005;233:121-3.  Back to cited text no. 72
    
73.
Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalaz XR, et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 2002;418:41-9.  Back to cited text no. 73
    
74.
Uccelli A, Moretta L, Pistoia V. Mesenchymal stem cells in health and disease. Nat Rev Immunol 2008;8:726-36.  Back to cited text no. 74
    
75.
Karp JM, Leng Teo GS. Mesenchymal stem cell homing: The devil is in the details. Cell Stem Cell 2009;4:206-16.  Back to cited text no. 75
    
76.
Si YL, Zhao YL, Hao HJ, Fu XB, Han WD. MSCs: Biological characteristics, clinical applications and their outstanding concerns. Ageing Res Rev 2011;10:93-103.  Back to cited text no. 76
    
77.
Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006;8:315-7.  Back to cited text no. 77
    
78.
Park HJ, Lee PH, Bang OY, Lee G, Ahn YH. Mesenchymal stem cells therapy exerts neuroprotection in a progressive animal model of Parkinson's disease. J Neurochem 2008;107:141-51.  Back to cited text no. 78
    
79.
Alvarez CV, Garcia-Lavandeira M, Garcia-Rendueles ME, Diaz-Rodriguez E, Garcia-Rendueles AR, Perez-Romero S, et al. Defining stem cell types: Understanding the therapeutic potential of ESCs, ASCs, and iPS cells. J Mol Endocrinol 2012;49:R89-111.  Back to cited text no. 79
    
80.
Atoui R, Chiu RC. Concise review: Immunomodulatory properties of mesenchymal stem cells in cellular transplantation: Update, controversies, and unknowns. Stem Cells Transl Med 2012;1:200-5.  Back to cited text no. 80
    
81.
Sanberg PR, Eve DJ, Metcalf C, Borlongan CV. Advantages and challenges of alternative sources of adult-derived stem cells for brain repair in stroke. Prog Brain Res 2012;201:99-117.  Back to cited text no. 81
    
82.
Rebelatto CK, Aguiar AM, Moretao MP, Senegaglia AC, Hansen P, Barchiki F, et al. Dissimilar differentiation of mesenchymal stem cells from bone marrow, umbilical cord blood, and adipose tissue. Exp Biol Med (Maywood) 2008;233:901-13.  Back to cited text no. 82
    
83.
Hodgkinson CP, Gomez JA, Mirotsou M, Dzau VJ. Genetic engineering of mesenchymal stem cells and its application in human disease therapy. Hum Gene Ther 2010;21:1513-26.  Back to cited text no. 83
    
84.
Wagner W, Wein F, Seckinger A, Frankhauser M, Wirkner U, Krause U, et al. Comparative characteristics of mesenchymal stem cells from human bone marrow, adipose tissue, and umbilical cord blood. Exp Hematol 2005;33:1402-16.  Back to cited text no. 84
    
85.
Ormerod BK, Palmer TD, Caldwell MA. Neurodegeneration and cell replacement. Philos Trans R Soc Lond B Biol Sci 2008;363:153-70.  Back to cited text no. 85
    
86.
van der Bogt KE, Schrepfer S, Yu J, Sheikh AY, Hoyt G, Govaert JA, et al. Comparison of transplantation of adipose tissue- and bone marrow-derived mesenchymal stem cells in the infarcted heart. Transplantation 2009;87:642-52.  Back to cited text no. 86
    
87.
Shahdadfar A, Fronsdal K, Haug T, Reinholt FP, Brinchmann JE. In vitro expansion of human mesenchymal stem cells: Choice of serum is a determinant of cell proliferation, differentiation, gene expression, and transcriptome stability. Stem Cells 2005;23:1357-66.  Back to cited text no. 87
    
88.
Wagner W, Ho AD. Mesenchymal stem cell preparations - Comparing apples and oranges. Stem Cell Rev 2007;3:239-48.  Back to cited text no. 88
    
89.
Kern S, Eichler H, Stoeve J, Kluter H, Bieback K. Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells 2006;24:1294-301.  Back to cited text no. 89
    
90.
Chang YJ, Shih DT, Tseng CP, Hsieh TB, Lee DC, Hwang SM. Disparate mesenchyme-lineage tendencies in mesenchymal stem cells from human bone marrow and umbilical cord blood. Stem Cells 2006;24:679-85.  Back to cited text no. 90
    
91.
Aleynik A, Gernavage KM, Mourad Y, Sherman LS, Liu K, Gubenko YA, et al. Stem cell delivery of therapies for brain disorders. Clin Transl Med 2014;3:24.  Back to cited text no. 91
    
92.
Liu Y, Wang L, Kikuiri T, Akiyama K, Chen C, Xu X, et al. Mesenchymal stem cell-based tissue regeneration is governed by recipient T lymphocytes via IFN-gamma and TNF-alpha. Nat Med 2011;17:1594-601.  Back to cited text no. 92
    
93.
Zhu D, Wallace EM, Lim R. Cell-based therapies for the preterm infant. Cytotherapy 2014;16:1614-28.  Back to cited text no. 93
    
94.
Karussis D, Karageorgiou C, Vaknin-Dembinsky A, Gowda-Kurkalli B, Gomori JM, Kassis I, et al. Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis. Arch Neurol 2010;67:1187-94.  Back to cited text no. 94
    
95.
Liu L, Eckert MA, Riazifar H, Kang DK, Agalliu D, Zhao W. From blood to the brain: Can systemically transplanted mesenchymal stem cells cross the blood-brain barrier? Stem Cells Int 2013;2013:435093.  Back to cited text no. 95
    
96.
Chen J, Li Y, Katakowski M, Chen X, Wang L, Lu D, et al. Intravenous bone marrow stromal cell therapy reduces apoptosis and promotes endogenous cell proliferation after stroke in female rat. J Neurosci Res 2003;73:778-86.  Back to cited text no. 96
    
97.
Hou D, Youssef EA, Brinton TJ, Zhang P, Rogers P, Price ET, et al. Radiolabeled cell distribution after intramyocardial, intracoronary, and interstitial retrograde coronary venous delivery: Implications for current clinical trials. Circulation 2005;112:I150-6.  Back to cited text no. 97
    
98.
Freyman T, Polin G, Osman H, Crary J, Lu M, Cheng L, et al. A quantitative, randomized study evaluating three methods of mesenchymal stem cell delivery following myocardial infarction. Eur Heart J 2006;27:1114-22.  Back to cited text no. 98
    
99.
Hofstetter CP, Schwarz EJ, Hess D, Widenfalk J, El Manira A, Prockop DJ, et al. Marrow stromal cells form guiding strands in the injured spinal cord and promote recovery. Proc Natl Acad Sci USA 2002;99:2199-204.  Back to cited text no. 99
    
100.
Kim SU, de Vellis J. Stem cell-based cell therapy in neurological diseases: A review. J Neurosci Res 2009;87:2183-200.  Back to cited text no. 100
    
101.
Bang OY, Lee JS, Lee PH, Lee G. Autologous mesenchymal stem cell transplantation in stroke patients. Ann Neurol 2005;57:874-82.  Back to cited text no. 101
    
102.
Osaka M, Honmou O, Murakami T, Nonaka T, Houkin K, Hamada H, et al. Intravenous administration of mesenchymal stem cells derived from bone marrow after contusive spinal cord injury improves functional outcome. Brain Res 2010;1343:226-35.  Back to cited text no. 102
    
103.
Gutierrez-Fernandez M, Rodriguez-Frutos B, Alvarez-Grech J, Vallejo-Cremades MT, Exposito-Alcaide M, Merino J, et al. Functional recovery after hematic administration of allogenic mesenchymal stem cells in acute ischemic stroke in rats. Neuroscience 2011;175:394-405.  Back to cited text no. 103
    
104.
Barzilay R, Kan I, Ben-Zur T, Bulvik S, Melamed E, Offen D. Induction of human mesenchymal stem cells into dopamine-producing cells with different differentiation protocols. Stem Cells Dev 2008;17:547-54.  Back to cited text no. 104
    
105.
Teng YD, Lavik EB, Qu X, Park KI, Ourednik J, Zurakowski D, et al. Functional recovery following traumatic spinal cord injury mediated by a unique polymer scaffold seeded with neural stem cells. Proc Natl Acad Sci USA 2002;99:3024-9.  Back to cited text no. 105
    
106.
Xu L, Yan J, Chen D, Welsh AM, Hazel T, Johe K, et al. Human neural stem cell grafts ameliorate motor neuron disease in SOD-1 transgenic rats. Transplantation 2006;82:865-75.  Back to cited text no. 106
    
107.
Ryu CH, Park KY, Hou Y, Jeong CH, Kim SM, Jeun SS. Gene therapy of multiple sclerosis using interferon beta-secreting human bone marrow mesenchymal stem cells. Biomed Res Int 2013;2013:696738.  Back to cited text no. 107
    
108.
Kaplan JM, Youd ME, Lodie TA. Immunomodulatory activity of mesenchymal stem cells. Curr Stem Cell Res Ther 2011;6:297-316.  Back to cited text no. 108
    
109.
Akiyama Y, Radtke C, Honmou O, Kocsis JD. Remyelination of the spinal cord following intravenous delivery of bone marrow cells. Glia 2002;39:229-36.  Back to cited text no. 109
    
110.
Vierbuchen T, Ostermeier A, Pang ZP, Kokubu Y, Sudhof TC, Wernig M. Direct conversion of fibroblasts to functional neurons by defined factors. Nature 2010;463:1035-41.  Back to cited text no. 110
    
111.
Lowry WE, Richter L, Yachechko R, Pyle AD, Tchieu J, Sridharan R, et al. Generation of human induced pluripotent stem cells from dermal fibroblasts. Proc Natl Acad Sci USA 2008;105:2883-8.  Back to cited text no. 111
    
112.
Krencik R, Weick JP, Liu Y, Zhang ZJ, Zhang SC. Specification of transplantable astroglial subtypes from human pluripotent stem cells. Nat Biotechnol 2011;29:528-34.  Back to cited text no. 112
    
113.
Hu BY, Du ZW, Zhang SC. Differentiation of human oligodendrocytes from pluripotent stem cells. Nat Protoc 2009;4:1614-22.  Back to cited text no. 113
    
114.
Wang S, Bates J, Li X, Schanz S, Chandler-Militello D, Levine C, et al. Human iPSC-derived oligodendrocyte progenitor cells can myelinate and rescue a mouse model of congenital hypomyelination. Cell Stem Cell 2013;12:252-64.  Back to cited text no. 114
    
115.
Jung YW, Hysolli E, Kim KY, Tanaka Y, Park IH. Human induced pluripotent stem cells and neurodegenerative disease: Prospects for novel therapies. Curr Opin Neurol 2012;25:125-30.  Back to cited text no. 115
    
116.
Zeng H, Guo M, Martins-Taylor K, Wang X, Zhang Z, Park JW, et al. Specification of region-specific neurons including forebrain glutamatergic neurons from human induced pluripotent stem cells. PLoS One 2010;5:e11853.  Back to cited text no. 116
    
117.
Kriks S, Shim JW, Piao J, Ganat JM, Wakeman DR, Xie Z, et al. Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson's disease. Nature 2011;480:547-551.  Back to cited text no. 117
    
118.
Liu H, Zhang SC. Specification of neuronal and glial subtypes from human pluripotent stem cells. Cell Mol Life Sci 2011;68:3995-4008.  Back to cited text no. 118
    
119.
Svendsen CN. Back to the future: How human induced pluripotent stem cells will transform regenerative medicine. Hum Mol Genet 2013;22:R32-8.  Back to cited text no. 119
    
120.
Bilic J, Izpisua Belmonte JC. Concise review: Induced pluripotent stem cells versus embryonic stem cells: Close enough or yet too far apart? Stem Cells 2012;30:33-41.  Back to cited text no. 120
    
121.
Blasco MA, Serrano M, Fernandez-Capetillo O. Genomic instability in iPS: Time for a break. EMBO J 2011;30:991-3.  Back to cited text no. 121
    
122.
Gore A, Li Z, Fung HL, Young JE, Agarwal S, Antosiewicz-Bourget J, et al. Somatic coding mutations in human induced pluripotent stem cells. Nature 2011;471:63-7.  Back to cited text no. 122
    
123.
Laurent LC, Ulitsky I, Slavin I, Tran H, Schork A, Morey R, et al. Dynamic changes in the copy number of pluripotency and cell proliferation genes in human ESCs and iPSCs during reprogramming and time in culture. Cell Stem Cell 2011;8:106-18.  Back to cited text no. 123
    
124.
Chin MH, Mason MJ, Xie W, Volinia S, Singer M, Peterson C, et al. Induced pluripotent stem cells and embryonic stem cells are distinguished by gene expression signatures. Cell Stem Cell 2009;5:111-23.  Back to cited text no. 124
    
125.
Feng Q, Lu SJ, Klimanskaya I, Gomes I, Kim D, Chung Y, et al. Hemangioblastic derivatives from human induced pluripotent stem cells exhibit limited expansion and early senescence. Stem Cells 2010;28:704-12.  Back to cited text no. 125
    
126.
Mayshar Y, Ben-David U, Lavon N, Biancotti JC, Yakir B, Clark AT, et al. Identification and classification of chromosomal aberrations in human induced pluripotent stem cells. Cell Stem Cell 2010;7:521-31.  Back to cited text no. 126
    
127.
Ross CA, Akimov SS. Human-induced pluripotent stem cells: Potential for neurodegenerative diseases. Hum Mol Genet 2014;23:R17-26.  Back to cited text no. 127
    
128.
Cyranoski D. Stem cells: 5 things to know before jumping on the iPS bandwagon. Nature 2008;452:406-8.  Back to cited text no. 128
    
129.
Camnasio S, Delli Carri A, Lombardo A, Grad I, Mariotti C, Castucci A, et al. The first reported generation of several induced pluripotent stem cell lines from homozygous and heterozygous Huntington's disease patients demonstrates mutation related enhanced lysosomal activity. Neurobiol Dis 2012;46:41-51.  Back to cited text no. 129
    
130.
Badger JL, Cordero-Llana O, Hartfield EM, Wade-Martins R. Parkinson's disease in a dish-Using stem cells as a molecular tool. Neuropharmacology 2014;76 Pt A: 88-96.  Back to cited text no. 130
    
131.
Gage FH, Temple S. Neural stem cells: Generating and regenerating the brain. Neuron 2013;80:588-601.  Back to cited text no. 131
    
132.
Jeon I, Lee N, Li JY, Park IH, Park KS, Moon J, et al. Neuronal properties, in vivo effects, and pathology of a Huntington's disease patient-derived induced pluripotent stem cells. Stem Cells 2012;30:2054-62.  Back to cited text no. 132
    
133.
Kaye JA, Finkbeiner S. Modeling Huntington's disease with induced pluripotent stem cells. Mol Cell Neurosci 2013;56:50-64.  Back to cited text no. 133
    
134.
Qiang L, Fujita R, Abeliovich A. Remodeling neurodegeneration: Somatic cell reprogramming-based models of adult neurological disorders. Neuron 2013;78:957-69.  Back to cited text no. 134
    
135.
Pedrosa E, Sandler V, Shah A, Carroll R, Chang C, Rockowitz S, et al. Development of patient-specific neurons in schizophrenia using induced pluripotent stem cells. J Neurogenet 2011;25:88-103.  Back to cited text no. 135
    
136.
Dimos JT, Rodolfa KT, Niakan KK, Weisenthal LM, Mitsumoto H, Chung W, et al. Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science 2008;321:1218-21.  Back to cited text no. 136
    
137.
Perlow MJ, Freed WJ, Hoffer BJ, Seiger A, Olson L, Wyatt RJ. Brain grafts reduce motor abnormalities produced by destruction of nigrostriatal dopamine system. Science 1979;204:643-7.  Back to cited text no. 137
    
138.
Freed WJ, Perlow MJ, Karoum F, Seiger A, Olson L, Hoffer BJ, et al. Restoration of dopaminergic function by grafting of fetal rat substantia nigra to the caudate nucleus: Long-term behavioral, biochemical, and histochemical studies. Ann Neurol 1980;8:510-9.  Back to cited text no. 138
    
139.
Backlund EO, Granberg PO, Hamberger B, Knutssen E, Martensson A, Sedvall G, et al. Transplantation of adrenal medullary tissue to striatum in Parkinsonism. First clinical trials. J Neurosurg 1985;62:169-73.  Back to cited text no. 139
    
140.
Madrazo I, Drucker-Colin R, Diaz V, Martinez-Mata J, Torres C, Becerril JJ. Open microsurgical autograft of adrenal medulla to the right caudate nucleus in two patients with intractable Parkinson's disease. N Engl J Med 1987;316:831-4.  Back to cited text no. 140
    
141.
Dunnett SB, Rosser AE. Challenges for taking primary and stem cells into clinical neurotransplantation trials for neurodegenerative disease. Neurobiol Dis 2014;61:79-89.  Back to cited text no. 141
    
142.
Mendez I, Vinuela A, Astradsson A, Mukhida K, Hallett P, Robertson H, et al. Dopamine neurons implanted into people with Parkinson's disease survive without pathology for 14 years. Nat Med 2008;14:507-9.  Back to cited text no. 142
    
143.
Lv YT, Zhang Y, Liu M, Qiuwaxi JN, Ashwood P, Cho SC, et al. Transplantation of human cord blood mononuclear cells and umbilical cord-derived mesenchymal stem cells in autism. J Transl Med 2013;11:196.  Back to cited text no. 143
    
144.
Sharma A, Badhe P, Mishra P. An improved case of autism as revealed by PET CT scan in patient transplanted with autologous bone marrow derived mononuclear cells. J Stem Cell Res Ther 2013, 3:139. doi:10.4172/2157-7633.1000139.  Back to cited text no. 144
    
145.
Tandon PN. Transplantation and stem cell research in neurosciences: Where does India stand? Neurol India 2009;57:706-14.  Back to cited text no. 145
[PUBMED]  Medknow Journal  
146.
Prasad K, Sharma A, Garg A, Mohanty S, Bhatnagar S, Johri S, et al. Intravenous autologous bone marrow mononuclear stem cell therapy for ischemic stroke: A multicentric, randomized trial. Stroke 2014;45:3618-24.  Back to cited text no. 146
    
147.
Kiatpongsan S, Sipp D. Medicine. Monitoring and regulating offshore stem cell clinics. Science 2009;323:1564-5.  Back to cited text no. 147
    
148.
Zhao T, Zhang ZN, Rong Z, Xu Y. Immunogenicity of induced pluripotent stem cells. Nature 2011;474:212-5.  Back to cited text no. 148
    
149.
Choi SA, Lee JY, Wang KC, Phi JH, Song SH, Song J, et al. Human adipose tissue-derived mesenchymal stem cells: Characteristics and therapeutic potential as cellular vehicles for prodrug gene therapy against brainstem gliomas. Eur J Cancer 2012;48:129-37.  Back to cited text no. 149
    
150.
Enserink M. Biomedicine. Selling the stem cell dream. Science 2006;313:160-3.  Back to cited text no. 150
    
151.
Mouhieddine TH, Kobeissy FH, Itani M, Nokkari A, Wang KK. Stem cells in neuroinjury and neurodegenerative disorders: Challenges and future neurotherapeutic prospects. Neural Regen Res 2014;9:901-6.  Back to cited text no. 151
[PUBMED]  Medknow Journal  
152.
Abbott A. Doctors accused of doing illegal stem-cell trials. Nature 2008;453:6-7.  Back to cited text no. 152
    
153.
Dobkin BH, Curt A, Guest J. Cellular transplants in China: Observational study from the largest human experiment in chronic spinal cord injury. Neurorehabil Neural Repair 2006;20:5-13.  Back to cited text no. 153
    
154.
Cyranoski D. Texas prepares to fight for stem cells. Nature 2011;477:377-8.  Back to cited text no. 154
    
155.
Cyranoski D. Stem-cell therapy takes off in Texas. Nature 2012;483:13-4.  Back to cited text no. 155
    
156.
Cyranoski D. China's stem-cell rules go unheeded. Nature 2012;484:149-50.  Back to cited text no. 156
    



 
 
    Tables

  [Table 1]

This article has been cited by
1 Cholinergic and dopaminergic neuronal differentiation of human adipose tissue derived mesenchymal stem cells
Hany El Sayed Marei,Aya El-Gamal,Asma Althani,Nahla Afifi,Ahmed Abd-Elmaksoud,Amany Farag,Carlo Cenciarelli,Caceci Thomas,Hasan Anwarul
Journal of Cellular Physiology. 2018; 233(2): 936
[Pubmed] | [DOI]
2 MicroRNA-138-5p regulates neural stem cell proliferation and differentiation in vitro by targeting TRIP6 expression
Juan Wang,Jixia Li,Jian Yang,Lianguo Zhang,Shane Gao,Fei Jiao,Maoli Yi,Jun Xu
Molecular Medicine Reports. 2017; 16(5): 7261
[Pubmed] | [DOI]



 

Top
Print this article  Email this article
   
Online since 20th March '04
Published by Wolters Kluwer - Medknow