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Science in medicine,Advances in stem cell therapy,for spinal cord injury. Andrea J Mothe and Charles H Tator, Toronto Western Research Institute and Krembil Neuroscience Centre Toronto Western Hospital Toronto Ontario Canada. Spinal cord injury SCI is a devastating condition producing great personal and societal costs. and for which there is no effective treatment Stem cell transplantation is a promising thera. peutic strategy though much preclinical and clinical research work remains Here we briefly. describe SCI epidemiology pathophysiology and experimental and clinical stem cell strategies. Research in stem cell biology and cell reprogramming is rapidly advancing with the hope of mov. ing stem cell therapy closer to helping people with SCI We examine issues important for clinical. translation and provide a commentary on recent developments including termination of the first. human embryonic stem cell transplantation trial in human SCI. Introduction Clinical trial design and management of SCI. Spinal cord injury SCI is a devastating condition with sudden Assessment of therapy in patients has improved markedly due. loss of sensory motor and autonomic function distal to the level to the development of the American Spinal Injury Association. of trauma Despite major advances in the medical and surgical ASIA grading scale and quantitative scores of sensory and. care of SCI patients no effective treatment exists for the neu motor function now used worldwide to assess the severity of SCI. rological deficits of major SCI 1 Current treatment includes and response to treatment 1 The ASIA Impairment Scale AIS. surgery to decompress and stabilize the injury prevention of ranges from A to E where A is a complete SCI and E denotes. secondary complications management of any that do occur normal sensory and motor function Acute treatment often. and rehabilitation Unfortunately neurological recovery is lim involves surgical management such as decompression spi. ited and most SCI patients still face substantial neurological nal stabilization or realignment of displaced vertebrae 14 to. dysfunction and lifelong disability Stem cell therapy offers sev prevent further injury from impingement on the spinal cord. eral highly attractive strategies for spinal cord repair including Acutely injured patients often require intensive care monitoring. replacement of damaged neuronal and glial cells remyelination to treat cardiovascular instability and respiratory insufficiency. of spared axons restoration of neuronal circuitry bridging of Currently there is limited pharmacotherapy for SCI patients. lesion cavities production of neurotrophic factors antiinflam Methylprednisolone demonstrated some neuroprotective effects. matory cytokines and other molecules to promote tissue spar in early experimental and clinical studies 15 16 but its use is. ing and neovascularization and a permissive environment for controversial because of limited efficacy and harmful side effects. plasticity and axonal regeneration This review builds on several Many SCI centers have stopped using steroids 17 Other neu. excellent previous reviews 2 8 and discusses the incidence and roprotective agents with promising results in experimental ani. pathophysiology of SCI as well as the key experimental and clini mals are now being investigated in clinical SCI trials including. cal stem cell strategies for SCI riluzole a sodium channel blocker and minocycline an antiin. flammatory agent 1 18 However neuroprotective agents alone. Epidemiology etiology incidence and prevalence of SCI may be insufficient to promote repair in major SCI where there. Worldwide the annual incidence of SCI is 15 40 cases per mil is extensive tissue loss. lion people 9 In Canada the Rick Hansen Institute estimates. there are currently 85 000 people living with SCI with more Pathophysiology of SCI. than 4 000 new cases per year 10 and in the United States the The most frequent type of traumatic SCI is acute compression of. Christopher and Dana Reeve Foundation estimates a prevalence the spinal cord 12 Usually some neurological tissue is preserved. of over 1 million patients with SCI and more than 12 000 new particularly in the subpial region 19 20 The primary mechani. cases each year 11 cal trauma causes necrosis edema hemorrhage and vasospasm A. The primary causes of traumatic SCI are motor vehicle crash cascade of secondary pathophysiological mechanisms is induced. es sports and recreation injuries falls at home and trauma at including ischemia apoptosis fluid and electrolyte disturbances. work 12 In young adults males are four times more likely than excitotoxicity lipid peroxidation production of free radicals and. females to sustain an SCI 13 Injury incidence shows a bimodal an inflammatory response resulting in further damage due to. distribution with the highest incidence in adolescents and young swelling and blood flow reduction 21 Ultimately a large fluid. adults with more than half aged 16 30 years old 10 The second filled cavity or cyst forms in the center of the cord surrounded by. incidence peak is in older adults primarily as a result of falls and a subpial rim containing some preserved axons many of which are. the aging population has increased the average age of injury demyelinated Figure 1 Hypertrophic astrocytes macrophages. and other cells secrete extracellular matrix and inhibitory mol. Conflict of interest The authors have declared that no conflict of interest exists ecules that constitute the glial scar resulting in a physical and. Citation for this article J Clin Invest 2012 122 11 3824 3834 doi 10 1172 JCI64124 chemical barrier to regeneration 22. 3824 The Journal of Clinical Investigation http www jci org Volume 122 Number 11 November 2012. science in medicine, Pathophysiology of SCI The diagram shows a composite of patho. physiological events occurring after SCI including the acute e g. edema and hemorrhage subacute e g inflammation and chronic. e g cavitation phases The primary and secondary injury mecha. nisms involve edema hemorrhage inflammation apoptosis necrosis. excitotoxicity lipid peroxidation electrolyte imbalance ischemia vaso. spasm and blood vessel occlusion Oligodendrocytes and neurons die. resulting in axonal demyelination and disruption of synaptic transmis. sion In the subacute and chronic phases a fluid filled lentiform shaped. cavity or cyst forms in the center of the cord with surrounding hyper. trophic astrocytes and macrophages These and other cells secrete. extracellular matrix and inhibitory molecules such as chondroitin sul. fate proteoglycans CSPG which compose the glial scar resulting in. a physical and chemical barrier to regeneration, of ES cells mesenchymal stem cells MSCs such as BM derived. stromal cells BMSCs neural stem progenitor cells NSPCs. and induced pluripotent stem cells iPSCs Figure 2 Trans. plantation of other cell types including Schwann cells olfactory. ensheathing glia genetically modified neurotrophin expressing. fibroblasts and activated macrophages have been the subject of. other recent reviews 2 4 7 8,Definition and rationale for stem cells.
A stem cell by definition continuously proliferates and asymmet. rically divides to self renew and generate daughter cells commit. ted to differentiation In contrast progenitor cells demonstrate a. limited proliferative capacity and differentiation potential Several. mechanisms for recovery have been proposed depending on the. cell type including replacement of oligodendrocytes or neurons. remyelination of spared axons restoration of neuronal circuitry. enhanced preservation of host neuronal and glial cells increased. expression of neurotrophins cytokines by transplanted or host. cells promotion of angiogenesis bridging of cysts or cavities. reduced inflammation or gliosis stimulation of endogenous pre. cursor cells and creation of a favorable environment for plastic. ity and axonal regeneration Figure 3 In most studies the exact. mechanisms of improvement were not completely defined. Some experimental rat models of SCI reproduce the typical. pathology of human SCI including the extradural compression ES cells. contusion and crush models in rats 23 SCI is classified depend ES cells are pluripotent cells derived from the inner cell mass of. ing on the time elapsed from the initial injury acute within sever developing blastocyst embryos that can differentiate into nearly. al days of SCI subacute one to two weeks after injury or chronic all cell types 26 Human ES cells are typically obtained from pre. four weeks or more after injury As discussed below experimental implantation or blastocyst stage embryos created during in vitro. cell transplantation strategies have generally been more effective fertilization procedures and can also be generated by somatic cell. in the subacute stage compared with the acute stage or the chronic nuclear transfer or parthenogenetic activation of eggs Trans. stage characterized by glial scarring and other inhibitory factors planted ES cells will form teratomas and thus ES cells must be. predifferentiated prior to grafting Protocols have been developed. General features of cell therapy for SCI to differentiate ES cells into neural precursors 27 30 and spe. Cell therapy is a promising strategy for SCI and preclinical mod cific neuronal 30 32 and glial lineages 33 34 Predifferentiated. els demonstrate that cell transplantation can ameliorate some mouse ES cells transplanted into the injured rat spinal cord dif. secondary events through neuroprotection and also restore lost ferentiated into neurons and glia and showed partial functional. tissue through regeneration Pioneering work in cell therapy recovery 35 As noted above SCI causes extensive demyelination. began in the late 1970s when Aguayo s group showed that periph and oligodendrocytes are particularly vulnerable to apoptosis. eral nerve grafts promoted regeneration of CNS axons 24 and ES cells predifferentiated into oligodendrocyte progenitor cells. Reier s group showed that grafted fetal spinal cord supported OPCs remyelinated spared axons and improved recovery when. regrowth of host axons 25 Since then numerous experimental transplanted subacutely into the injured rat spinal cord 36 37. cell transplantation strategies have produced regeneration and The advantage of ES cells is that they can be propagated in. partial recovery 2 7 Here we describe several stem cell based vitro almost indefinitely since they retain high telomerase activ. strategies for experimental and clinical SCI including the use ity However it has been difficult to generate high purity lineage. The Journal of Clinical Investigation http www jci org Volume 122 Number 11 November 2012 3825. science in medicine,Sources of stem cells for transplantation into. the injured spinal cord This illustration shows,various tissue sources of stem cells including. NSPCs iPSCs SKPs MSCs ES cells ESC,and direct conversion methods to yield neural. cells for transplantation NSPCs can be iso,lated from the fetal and adult brain and spinal. cord and differentiated into progenitor cells,such as OPCs and mature oligodendrocytes.
or astrocytes or neurons depending on culture,conditions and exposure to growth factors ES. cells follow a default pathway to neural cells,and specific conditions can promote OPC gen. eration MSCs can be derived from a variety of,tissues including BM umbilical cord adipose. tissue muscle and dental pulp from decidu,ous baby teeth In culture MSCs have shown. properties of neural cells Fibroblasts from,the skin can be reprogrammed using various.
methods into iPSCs which are then directed,along a neural lineage Recent studies have. directly converted fibroblasts to neurons and,NSPCs bypassing the pluripotent stage. specific cell lines without karyotypic abnormalities The concerns NSPCs are found in both fetal and adult CNS 38 The isolation. with transplantation of ES cell derived neural cells for SCI are the of adult neural stem cells in mammals was first reported in 1992. ethical issues of cell derivation and the possibility of tumorigen by Reynolds and Weiss 39 NSPCs reside within specific niches in. esis due to incomplete or aberrant differentiation resulting in the the adult CNS including the subventricular zone lining the lateral. formation of nonneural cells Table 1 ventricles of the forebrain 40 41 the dentate gyrus of the hip. Based on promising preclinical data of human ES cell derived pocampus 42 and the region of the central canal of the spinal. OPC transplants in rodent SCI models 36 37 the US Food and cord 43 Multipotential self renewing NSPCs can be isolated and. Drug Administration FDA approved the first human ES cell trial cultured from the adult rodent spinal cord when the cultured tis. in 2009 This phase I safety trial in SCI sponsored by Geron Corp sue includes regions of the central canal 44 45 We have shown. began in 2010 after further preclinical safety data were obtained that these NSPCs primarily differentiate into oligodendrocytes in. concerning abnormal cyst formation in transplanted animals The vitro 46 and in vivo 47 48 Transplantation of these NPSCs. GRNOPC1 cell line human ES cell derived OPC was transplant into SCI rats promoted functional recovery with neuroprotective. ed subacutely one to two weeks after injury directly into the spi and neuroregenerative effects 49 51 Most studies with trans. nal cord of ASIA A patients with complete thoracic SCI Patients planted NSPCs have shown modest recovery of the injured spi. received 2 million cells and were immunosuppressed for the first nal cord 3 7 although allodynia was associated with astrocytic. two months following transplantation In 2011 Geron discon differentiation of grafted NSPCs 49 Adult mouse brain derived. tinued this trial due to funding challenges No safety issues were NSPCs transplanted into the injured rat spinal cord with con. reported in the five patients who received GRNOPC1 transplants comitant infusion of growth factors promoted oligodendrocyte. but complete results have not been published Table 2 differentiation of the grafted NSPCs remyelination and improved. locomotor function 52 53 NSPCs derived from fetal rat spinal. NSPCs cord differentiated into neurons that integrated into the injured. NSPCs are multipotent cells committed to the neural lineage cord and improved recovery 54 and transplanted NSPCs com. that can self renew and be readily expanded in vitro NSPCs bined with valproic acid administration promoted neuronal differ. are typically grown as free floating neurospheres in serum free entiation resulting in restoration of disrupted neuronal circuitry. medium supplemented with EGF and FGF 2 Neurospheres and enhanced recovery 55 NSPCs have also demonstrated some. are 3D aggregates comprising a mixture primarily of progeni immunomodulatory and pathotropic ability by homing toward. tor cells a small percentage of stem cells and small numbers of damaged tissue 56 57 as well as secreting various neurotrophic. more differentiated cell types over multiple passages in culture factors and cytokines 58 60. The neural stem cells respond to the growth factors in the cul Most experimental SCI studies with NSPC transplants have. ture medium and selectively proliferate in suspension to form involved rodent cells because human stem cells were either not. neurospheres When these cells are plated in growth factor free available or difficult to grow Human NSPCs have been isolated. medium containing serum they differentiate into neurons oli from fetal brain and spinal cord from aborted fetuses 61 65. godendrocytes and astrocytes and from adult brain from surgical biopsy specimens and post. 3826 The Journal of Clinical Investigation http www jci org Volume 122 Number 11 November 2012. science in medicine, Potential mechanisms of spinal cord repair following stem cell trans. plantation The diagram shows some of the potential mechanisms of. repair after transplantation of stem cells into the injured cord Potential. mechanisms include replacement of oligodendrocytes or neurons by. transplanted cells shown in green remyelination of spared axons. restoration of neuronal circuitry by a new synapse with a transplanted. neuron that gives rise to a newly regenerated axon enhanced preser. vation of host neuronal and glial cells for example by secreted neuro. trophins from transplanted cells promotion of angiogenesis bridging. of the cyst cavity by transplanted cells reduction of inflammation or. gliosis stimulation of endogenous precursor cells and creation of a. favorable environment for plasticity and axonal regeneration. nosuppression Thus human NSPCs have certain drawbacks. including ethical concerns about fetal derived cells difficulties. in expanding adult derived cells to clinically sufficient numbers. and unavailability of autologous sources,Skin derived precursors. An accessible potentially autologous source of precursor cells. for transplantation is skin derived precursors SKPs residing. within the dermis of rodents and humans as described by Miller. and other groups 75 77 SKPs are generated during embryo. genesis persist into adulthood and share characteristics with. embryonic neural crest stem cells producing both mesodermal. progeny and peripheral neurons and Schwann cells 78 SKP. derived Schwann cells transplanted into SCI rats showed lesion. sparing remyelination of spared axons with peripheral myelin. and unlike other sources of Schwann cells provided a conducive. environment for axonal growth into the lesion but with limited. functional recovery 79,HSCs and MSCs, Adult BM contains several different stem cell populations of non.
neural origin including HSCs and MSCs HSCs are self renewing. adult stem cells found mainly in the BM that differentiate into. blood and immune cells In the early 1960s James Till and Ernest. mortem tissue 66 69 Recently we demonstrated that self McCulloch observed that BM cells injected into irradiated mice. renewing multipotent NSPCs can be passaged from the adult grew as colonies of cells in their spleens and each colony grew. human spinal cord of organ transplant donors and that these from a single cell 80 now known as a stem cell These Canadian. cells differentiate into both neurons and glia following trans scientists are recognized as the founders of HSC research HSC. plantation into rats with SCI 70 Stem cells isolated from the transplantation has now been used for decades to treat blood can. human fetal brain were transplanted into NOD SCID mice cers and other blood disorders 81. with SCI and the grafted cells expressed neural differentiation HSCs are identified based on their expression of distinct cell. markers and improved recovery 71 72 Extensive neuronal surface markers and nonadherence to plastic in culture Typical. differentiation of human fetal NSPC grafts was reported after ly erythrocytes and platelets are separated from BM yielding the. transplantation into the adult rat spinal cord 73 In addi mononuclear cell fractions MNCs comprising HSCs and nonhe. tion human fetal brain NSPCs modified to express galectin 1 matopoietic cells including monocytes macrophages endothelial. transplanted subacutely into the contused cervical spinal cord progenitor cells and small numbers of MSCs The advan. of adult common marmosets produced significantly greater grip tages of HSCs or BM derived mononuclear cells BM MNCs. strength than controls 74 are that they can be autologously derived and that they have a. A registry of government and privately supported clinical tri record of safety in humans The drawbacks are that HSCs are rare. als from all countries is available http www clinicaltrials gov 1 in 100 000 cells from BM and pose major risks with graft rejec. Table 2 summarizes completed trials of stem cell therapy for tion and graft versus host disease GvHD Subacute intraspinal. SCI Table 3 indicates ongoing trials Recently Stem Cells Inc transplantation of HSCs was shown to promote functional recov. started a phase I II safety efficacy trial in Switzerland involv ery after compression SCI in mice 82 83 For clinical transla. ing transplantation of human fetal brain stem cells into ASIA tion HSCs are commonly harvested from peripheral blood fol. A C patients with thoracic SCI Currently this is the only human lowing cytokine administration which mobilizes the HSCs and. trial involving NSPCs for SCI and these patients require immu the MNC fraction is administered. The Journal of Clinical Investigation http www jci org Volume 122 Number 11 November 2012 3827. science in medicine, Summary of advantages and disadvantages of potential stem cell types for SCI. ES cells NSPCs SKPs HSCs BM MNCs MSCs iPSCs iNPCs,Fetal Adult BM Other. derived sources,Availability Yes Yes No Yes Yes Yes Yes Yes Yes. Ease of isolation No No No Yes Yes Yes Yes No Yes, Autologous donors No No No Yes Yes Yes Yes Yes Yes. Ethical considerations Yes Yes No No No No No No No. Differentiation Pluripotent Neural Neural Nonneural Nonneural Nonneural Pluripotent Neural. potential and and and,peripheral potentially potentially.
myelin only neural neural, Tumorigenicity Yes Some No Unknown No No Unknown Yes Unknown. Pathotropism Unknown Yes Yes Unknown Yes Yes Yes Unknown Unknown. Efficacy in preclinical Yes in some Inconsistent Yes Yes Yes Inconsistent Yes Yes for Unknown. studies studies in many but few in some in many preclones. Safety in human Yes for ES Stem Cells Untested Untested Yes Yes Yes Untested Untested. trials cell derived Inc, The most common nonneural cell type for transplantation in there are reported adverse effects of MSCs such as increased. experimental SCI is the BMSC BMSCs are isolated from the MNC recurrence of hematological malignancies and enhanced tumor. fraction of BM and expanded in culture based on their adherence growth and metastases 90 101 102. to tissue culture plastic and expression of distinct cell surface There are a number of completed and currently ongoing SCI. antigens that do not include HSC markers The major advantage clinical trials involving autologous BM MNC or BMSC transplan. of MSCs is that they can be autologously transplanted and that tation as summarized in Tables 2 and 3 There are other reports. they express a variety of neurotrophic factors that are beneficial of small numbers of patients treated with MSC transplants show. for repair Other important features are their low immunogenic ing no adverse effects 103 104 Collectively evidence suggests. ity and their reported immunomodulatory properties ref 84 and that even transient MSC engraftment may exert favorable effects. Table 1 MSCs are widespread throughout a variety of tissues through secretion of cytokines and other paracrine factors that. 85 including Wharton jelly of the umbilical cord adipose tis engage and recruit recipient cells in tissue repair 105. sue adult muscle and the dental pulp of deciduous baby teeth. Recently predifferentiated adipose derived MSCs were transplant iPSCs. ed into SCI rats resulting in some functional recovery perhaps iPSCs are generated by reprogramming mature fully differ. due to paracrine effects of grafted cells wrapping demyelinated entiated cells into a pluripotent state The advantage of iPSCs. host axons and promoting their protection 86 Umbilical cord is that easily accessible cells such as skin from an SCI patient. derived HSCs or MSCs are attractive because this tissue is readily could be reprogrammed differentiated and transplanted. accessible and frequently discarded and MSCs are less prone to iPSCs were developed in 2006 by Takahashi and Yamanaka. rejection as evidenced by a lower risk of developing GvHD ref 87 who showed that mouse somatic cells such as fibroblasts. and Table 1 Compared with adult sources the number of MSCs could be reprogrammed to pluripotency with retroviral expres. or HSCs obtained from cord blood or placental tissues is small sion of the transcription factors OCT4 SOX2 KLF4 and. although they can be readily expanded and tissue can be frozen c MYC 106 iPSCs can also be generated from human somatic. and used later for isolation 88 cells 107 108 The ability to generate pluripotent cells from. Transplantation of BMSCs for SCI has been previously adult somatic cells without the need for an embryo was a major. reviewed 2 3 6 89 90 Many studies have examined BMSCs development in stem cell biology. in SCI rodents with some showing improved locomotor recov Puri and Nagy recently compared ES cells and iPSCs 109 iPSCs. ery 91 93 while others did not 51 94 95 likely due to dif share many key properties with ES cells including morphology. ferences in culture conditions Several studies have also shown pluripotency self renewal and gene expression During expansion. MSC differentiation into neural lineages in vitro although in and prolonged passage human ES cell lines frequently acquire. vivo this is controversial 88 90 Cumulative evidence suggests abnormal karyotypes and genetic amplification associated with. the therapeutic effects of MSCs are likely due to secretion of oncogenic transformation which is also the case with iPSC lines. neurotrophins angiogenesis and antiinflammatory actions 60 109 One of the main problems with generation of iPSCs is the. 93 96 97 HSCs and MSCs have also shown variable efficacy expression of reprogramming factors associated with teratoma. when transplanted intravenously or intrathecally demonstrat formation 110 For this reason several alternative delivery meth. ing pathotropism 98 100 Despite these potential benefits ods have been developed for reprogramming that do not require. 3828 The Journal of Clinical Investigation http www jci org Volume 122 Number 11 November 2012. Summary of completed clinical trials of stem cell therapy for SCI. Stem cell type Country sponsor Study status Phase No of patients Time of transplant Route of Comments. reference ASIA scale after injury cell delivery, ES cell derived USA Geron Terminated 11 2011 I ASIA A 10 enrolled Subacute Intraspinal No safety issue reported but complete results. OPCs GRNOPC1 NCT01217008 5 transplanted 1 2 weeks single dose not published. unpublished, Autologous BM MNCs Brazil Completed 81 I ASIA A C 10 median Chronic Intrathecal via LP No adverse effects but patients only followed. age 34 mean 3 years single dose for 12 weeks efficacy not reported. Autologous BM MNCs Czech Republic Completed 129 I II ASIA A 20 aged 19 41 Subacute Intraarterial or No complications reported 5 6 patients who. 10 30 days intravenous received cells intraarterially reported. chronic improvement 5 7 acute but only 1 13,2 17 months chronic patients reported improvement.
Autologous BM MNCs Korea Completed 130 I II ASIA A 35 15 57 Acute 2 weeks Intraspinal Some improvement reported in acute. subacute 2 8 weeks single dose and subacute groups but not chronic. chronic 8 weeks, Autologous BM MNCs Ecuador Completed 131 I II 8 aged 27 44 Acute Intraspinal No adverse effects reported. 5 days 6 months spinal canal or improvement in bladder function. chronic 5 21 years intravenous,single dose, Autologous BMSCs Korea Completed 132 I II ASIA A B 10 aged 34 61 Chronic Intraspinal 3 patients showed improvement in upper. 1 month followed by limb recovery with MRI and,intrathecal via LP electrophysiological changes. Autologous BMSCs Egypt Cairo Completed 12 2008 I II ASIA scale 80 aged 10 36 Chronic Not indicated No published reports. University NCT00816803 not indicated 10 months 3 years. Autologous MSCs Korea RNL Bio Completed 133 I ASIA A C 8 aged 19 60 2 months Intravenous No serious adverse events during 3 month. adipose derived Company Ltd NCT01274975 single dose follow up were reported. Autologous BMSCs India Completed 8 2010 I II ASIA A 12 aged 20 55 Acute 2 weeks Intrathecal for acute No published reports. International NCT01186679 subacute 2 8 weeks and subacute. Stemcell chronic 6 months intraspinal for,Services Ltd chronic. Published results of clinical trials if available are referenced Clinical trials currently recruiting or ongoing or recently completed are identified with the NCT number www clinicaltrials gov LP lumbar puncture. The Journal of Clinical Investigation http www jci org Volume 122 Number 11 November 2012. science in medicine, Summary of ongoing clinical trials of stem cell therapy for SCI.
Stem cell type Country sponsor Study status Phase ASIA scale No of patients Time of transplant Route of Comments. reference after injury cell delivery, Human fetal brain Switzerland Recruiting I II ASIA A C 12 estimated Chronic Intraspinal Cells used in Batten disease phase I trial. NSPCs Hu CNS SC StemCells Inc initiated 3 2011 enrollment eligible 3 12 months single dose no safety issues reported estimated. NCT01321333 ages 18 60 completion date 3 2016, Autologous BMSCs USA TCA Ongoing not I ASIA A 10 aged 18 65 2 weeks Intrathecal via Estimated completion date 6 2012. science in medicine,Cellular Therapy recruiting LP single dose. LLC initiated 7 2010,NCT01162915, Autologous BMSCs Brazil Hospital Ongoing not I ASIA A 20 Not indicated Intraspinal Estimated completion date 1 2013. Sao Rafael recruiting aged 18 50,NCT01325103, Umbilical cord China Spinal Cord Ongoing not I II ASIA A 20 enrolled Chronic 1 year Intraspinal 3 groups cord blood cell dose comparison.
blood MNCs Injury Network recruiting aged 18 60 2 groups cord blood cells combined with. initiated methylprednisolone cord blood cells with. 9 2010 methylprednisolone and oral lithium,NCT01354483 estimated completion date 8 2013. MSCs umbilical China General Recruiting I II ASIA scale 60 estimated Interval time Not indicated Estimated enrollment 20 acute patients. cord derived Hospital of Chinese initiated 1 2011 not indicated enrollment not indicated acute 20 chronic 10 patients rehabilitation only. Armed Police Forces NCT01393977 eligible ages and chronic 10 patients no treatment estimated. 20 50 transplants completion date 5 2012, Autologous BMSCs USA Memorial Recruiting I II ASIA A D 10 estimated Chronic Intravenous Estimated completion date 10 2014. Hermann Healthcare initiated 4 2011 children enrollment 6 months 4 years. System NCT01328860 eligible ages 1 15, Umbilical cord China Spinal Cord Ongoing not I II ASIA A 60 enrolled Acute subacute Intraspinal 4 groups cord blood cell transplant. blood MNCs Injury Network recruiting aged 18 65 4 weeks single dose combined with oral lithium cord blood cells. initiated 9 2011 lithium and placebo control estimated. NCT01471613 completion date 5 2013, Autologous BMSCs China Guangzhou Recruiting I II ASIA A B 20 estimated 2 weeks 1 year Combined Estimated completion date 6 2014. General Hospital of initiated 10 2011 enrollment intravenous and. Guangzhou Military NCT01446640 eligible ages intrathecal via LP. Command 16 60, Autologous BMSCs India TotipotentRX Recruiting I II ASIA A C 15 estimated Chronic Not indicated Estimated study completion date 10 2013.
Cell Therapy Pvt Ltd initiated 10 2011 enrollment eligible 6 months 8 years. The Journal of Clinical Investigation http www jci org Volume 122 Number 11 November 2012. NCT01490242 ages 18 60, Published results of clinical trials if available are referenced Clinical trials currently recruiting or ongoing or recently completed are identified with the NCT number. science in medicine, permanent transgene integrations such as adenovirus the piggy gramming This alternative approach to cellular reprogramming. Bac transposon and direct protein transduction 109 111 These for autologous cell replacement therapies avoids complications. reprogramming factors are needed to initiate but not sustain associated with the use of human pluripotent stem cells 118. somatic cell transformation into iPSCs which is very important such as tumorigenicity However more work needs to be done to. from a therapeutic standpoint However for clinical translation elucidate the process of direct conversion. the development of reproducible protocols for iPSC differentia. tion to specific neural lineages with complete elimination of resid Summary of challenges for clinical translation of stem. ual pluripotent stem cells is necessary cell therapy for SCI. Recently it was demonstrated that NSPCs can be derived from Clinical translation of stem cell therapy for SCI still faces enor. human iPSCs but human iPSC differentiation to neural lineag mous challenges although much has been learned from previ. es occurs at a much lower frequency than with ES cells 112 ous SCI and other trials However most have been phase I trials. Also some types of iPSC derived neural cells have an increased conducted with small numbers of patients without controls. likelihood of tumor formation after transplantation into the and thus assessment of efficacy is not possible 1 Enrolling. CNS Thus safe iPSC derived clones will need to be screened sufficient numbers of SCI patients for clinical trials has been. and selected 113 114 Experimental studies using preselected difficult because of differing severity and level of injury age of. safe iPSC derived neurospheres transplanted subacutely after patient and associated injuries Generally for cell transplanta. contusion SCI showed remyelination axonal outgrowth of sero tion trials the target SCI population has been ASIA A patients. tonergic fibers and promotion of locomotor recovery 114 In to avoid causing further damage but these patients may have. contrast transplantation of unsafe iPS derived neurospheres minimal ability to recover and demonstration of effectiveness. resulted in robust teratoma formation and sudden loss of loco is impaired due to insensitive outcome measures For example. motor function 114 Transplantation of murine iPSC derived short length axonal regeneration would be undetected in tho. astrocytes into SCI rats resulted in allodynia 115 Recently racic injuries Some of the obstacles the Geron trial encountered. Okano and colleagues grafted human iPSC derived neuro were the need to screen large numbers of patients the need to. spheres into the injured mouse spinal cord and demonstrated inject a large number of cells 2 million per patient and a rela. improved locomotor recovery with synapse formation between tively long wait time to ascertain clinical efficacy more than six. host and grafted cells expression of neurotrophic factors angio months The process of creating clinically acceptable ES cell. genesis axonal regrowth and increased myelination 116 No derived cells is costly and the same challenges apply to iPSC. tumor formation occurred in the grafted mice with the prese derived cells Recent developments with direct conversion meth. lected clones Also a recent study showed that transplanted ods indicate great potential for clinical stem cell therapy but. human iPSC derived self renewing neuroepithelial like stem more work is needed In contrast there are 50 years of research. cells differentiated into neuronal progeny in the injured mouse in the adult stem cell field with HSCs which are routinely used. spinal cord and restored synaptic connections contributing to to treat patients with leukemia and related bone blood cancers. improved motor function 117 Many clinical case reports describing MSC therapy for stroke. multiple sclerosis and in orthopedic conditions have been pub. Direct conversion to neural cells lished 125 128 Given the large amount of preclinical data and. Recently direct conversion of a cell into a different cell type bypass the safety record it is understandable that so many clinical tri. ing the pluripotent stage was shown For example hematopoi als have used MSC based therapies However answers will not. etic cells were generated directly from human dermal fibroblasts come from small uncoordinated phase I trials Also for rea. without establishing pluripotency via the ectopic expression of sons outlined in consensus panels it is important for patients. hematopoietic transcription factors 118 and mouse embryonic to avoid experimental therapy outside of a formal clinical trial. fibroblasts were directly reprogrammed to cardiomyocytes 119 The complexities of attenuating the tissue damage and second. Several studies demonstrated direct conversion of mouse and ary complications due to trauma and reconstructing the cyto. human skin or liver cells into neurons termed induced neuronal architecture of the injured spinal cord are very challenging but. cells with the combinatorial expression of neural lineage spe hopefully the rapid advances being made in stem cell biology. cific transcription factors 120 122 The reprogramming factors will result in effective experimental and clinical trials of stem. appear to lead to a switch in lineage fate rather than an induction cell therapy for SCI. of hybrid phenotypes although the induced neuronal cells retain a. small but detectable epigenetic memory of their donor cells 120 Acknowledgments. The interconversion between adult cells from ontogenically dif We thank the Canadian Paraplegic Association Ontario branch. ferent lineages by an induced transdifferentiation process without the Christopher and Dana Reeve Foundation Physicians Services. the need for establishing pluripotency provides a novel tool for Incorporated the Ontario Neurotrauma Foundation and Krembil. adult cell fate modification 123 Foundation SCI NET new emerging team for a grant for finan. Wernig and colleagues showed recently that mouse embry cial support We also thank the reviewers for their helpful sugges. onic fibroblasts can be directly converted to self renewing neural tions and the editors of JCI. precursor cells that generate both neurons and glia and can be. expanded in large numbers 124 The next step will be to deter Address correspondence to Charles H Tator Toronto Western. mine whether similar induced neural precursor cells iNPCs can Research Institute and Krembil Neuroscience Centre Toronto. be generated from adult human fibroblasts and whether these are Western Hospital 399 Bathurst Street Toronto ON Canada M5T. safe These new developments in stem cell biology suggest that 2S8 Phone 416 603 5889 Fax 416 603 5745 E mail charles. pluripotency is no longer a prerequisite for somatic cell repro tator uhn on ca. The Journal of Clinical Investigation http www jci org Volume 122 Number 11 November 2012 3831. science in medicine, 1 Tator CH Review of treatment trials in human 49 6 377 391 44 Kulbatski I Mothe AJ Keating A Hakamata Y. spinal cord injury issues difficulties and recom 23 Tator C Poon P Acute clip impact compression Kobayashi E Tator CH Oligodendrocytes and. mendations Neurosurgery 2006 59 5 957 982 model In Chen J Xu ZC Xiao Ming X Zhang JH radial glia derived from adult rat spinal cord pro. 2 Fehlings MG Vawda R Cellular treatments for spi eds Animal Models of Acute Neurological Injuries New genitors morphological and immunocytochemical. nal cord injury the time is right for clinical trials York New York USA Humana Press 2009 449 460 characterization J Histochem Cytochem 2007. Neurotherapeutics 2011 8 4 704 720 24 Richardson PM McGuinness UM Aguayo AJ 55 3 209 222. 3 Tetzlaff W et al A systematic review of cellular Axons from CNS neurons regenerate into PNS 45 Martens DJ Seaberg RM van der Kooy D In vivo. transplantation therapies for spinal cord injury grafts Nature 1980 284 5753 264 265 infusions of exogenous growth factors into the. 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Johnson WE Bone marrow for the treatment of Thomson JA In vitro differentiation of transplant genitors morphological and immunocytochemical. spinal cord injury mechanisms and clinical appli able neural precursors from human embryonic characterization J Histochem Cytochem 2007. cation Stem Cells 2011 29 2 169 178 stem cells Nat Biotechnol 2001 19 12 1129 1133 55 3 209 222. 7 Enzmann GU Benton RL Talbott JF Cao Q Whit 28 Tropepe V Hitoshi S Sirard C Mak TW Rossant 47 Mothe AJ Tator CH Transplanted neural stem. temore SR Functional considerations of stem cell J van der Kooy D Direct neural fate specification progenitor cells generate myelinating oligoden. transplantation therapy for spinal cord repair from embryonic stem cells a primitive mammalian drocytes and Schwann cells in spinal cord demy. 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USA Christopher and Dana Reeve Foundation 2009 enrichment of spinal motor neurons derived from Stem Cells 2009 27 3 733 743. 12 Tator CH Epidemiology and general characteristics human and monkey embryonic stem cells PLoS 51 Parr AM et al Transplanted adult spinal cord. of the spinal cord injury patient In Benzel EC ed One 2009 4 8 e6722 derived neural stem progenitor cells promote early. Contemporary Management Of Spinal Cord Injury 33 Brustle O et al Embryonic stem cell derived glial functional recovery after rat spinal cord injury. Park Ridge Illinois USA American Association of precursors a source of myelinating transplants Neuroscience 2008 155 3 760 770. 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