|Year : 2015 | Volume
| Issue : 1 | Page : 56-71
|Stem cell therapy in spinal trauma: Does it have scientific validity?
Harvinder Singh Chhabra, Kanchan Sarda
Spine Service, Indian Spinal Injuries Centre, Vasant Kunj, New Delhi, India
Click here for correspondence address and email
|Date of Web Publication||10-Nov-2014|
| Abstract|| |
Stem cell-based interventions aim to use special regenerative cells (stem cells) to facilitate neuronal function beyond the site of the injury. Many studies involving animal models of spinal cord injury (SCI) suggest that certain stem cell-based therapies may restore function after SCI. Currently, in case of spinal cord injuries, new discoveries with clinical implications have been continuously made in basic stem cell research, and stem cell-based approaches are advancing rapidly toward application in patients. There is a huge base of preclinical evidence in vitro and in animal models which suggests the safety and clinical efficacy of cellular therapies after SCI. Despite this, data from clinical studies is not very encouraging and at times confounding. Here, we have attempted to cover preclinical and clinical evidence base dealing with safety, feasibility and efficacy of cell based interventions after SCI. The limitations of preclinical data and the reasons underlying its failure to translate in a clinical setting are also discussed. Based on the evidence base, it is suggested that a multifactorial approach is required to address this situation. Need for standardized, stringently designed multi-centric clinical trials for obtaining validated proof of evidence is also highlighted.
Keywords: Spinal cord injury, stem cells, neurologic recovery, clinical trials
MeSH terms: Spinal cord injury, stem cell research, clinical trial
|How to cite this article:|
Chhabra HS, Sarda K. Stem cell therapy in spinal trauma: Does it have scientific validity?. Indian J Orthop 2015;49:56-71
| Introduction|| |
Spinal cord injury (SCI) is the most devastating ailment that can afflict mankind. A complete injury causes permanent loss of sensation and movement in the affected limbs and trunk, loss of bowel, bladder and sexual functions, thus causing extreme psychological stress.  It not only causes disability, but also has a profound impact on the social and economic prospects of the individual and the whole family.  The high aggregated costs of treatment and prolonged hospitalizations are an economic burden not only tfigo the individual's family, but also to the society.
Accidents are the main cause for SCI and youth in their prime of life are the most commonly affected.  Till date, there is no established therapeutic intervention capable of restoring significant neurological function after SCI. With recent advances in stem cell research there has been a tremendous hope for the development of new treatments for many serious diseases amongst researchers, clinicians and the individuals suffering from such diseases. Rigorous scientific and medical evidence is a must to harness the potential of these cells to create a standard mode of therapy which may then be offered as a clinical alternative to other existing standard therapies. In the following passages, we attempt to cover the evidence base for regeneration and repair after SCI. Both preclinical and clinical studies have been critically analyzed for graft survival, axonal regeneration, safety and sensory and motor functional recovery. Finally, we discuss the necessity for multi-disciplinary approaches using combinatorial strategies to achieve robust cellular regeneration associated with neurological and functional improvement.
Pathophysiology of the spinal cord
Spinal cord injury is caused by direct mechanical damage to the spinal cord that usually results in complete or incomplete loss of neural functions such as mobility and sensory function.  The nature and extent of the injury varies widely, depending on the site of injury and its severity. A primary injury refers to a mechanical trauma to the spinal cord leading to a disruption of the spinal cord tissue. SCI can result from contusion, compression, penetration or maceration of the spinal cord.  The most common injury mechanism is contusion of the spinal cord at the moment of injury, and the prolonged compression caused by vertebral bony structures and soft tissues that have become dislodged.  During the injury process, the spinal cord might be hyper-bent, over-stretched, rotated, and lacerated,  but the white matter is usually spared.  The primary injury to the spine triggers a number of pathophysiological processes, which may lead to a prolonged secondary injury phase.  These pathophysiological processes are the key determinants of the final extent of neurological deficits. , The secondary phase can be divided into the immediate (≤2 h), acute (≥2-48 h), sub-acute (≤14 days) intermediate (≤6 months) and chronic stages (≥6 months) of SCI. The pathophysiological processes, which are most affected relate to three major bodily systems - the nervous system, the immune system and the vascular system. 
The pathophysiological changes that occur within these different phases are distinct. (1) Acute phase: Edema, ischemia, hemorrhage, reactive oxygen species production and lipid peroxidation, glutamate-mediated excitotoxicity, ionic dysregulation, blood-spinal-cord barrier permeability, inflammation, demyelination, neuronal cell death, and neurogenic shock. (2) Sub-acute phase: Macrophage infiltration, microglial activity, astrocyte activity and scar formation, and initiation of neovascularization. (3) Chronic phase: Wallerian degeneration More Details, glial scar maturation, cyst and syrinx formation, cavity formation, and schwannosis. The end of spontaneous post-SCI changes is identified as a pathophysiological phenomenon with solid glial scar formation, syrinx formation, and neuronal apoptosis. There is retraction and demyelination of spared axons, which may induce permanent loss of sensorimotor functions that is unresponsive to treatment.  To select the best time-point for therapeutic cell transplantation, an understanding of the timeline of secondary damage cascades is important. 
The persistence of secondary injury mechanisms leads to further neuronal cell death and the interruption of the descending and ascending axonal tracts culminating in glial scarring. The scar forms a hostile environment for axon regeneration due to secretion of molecular inhibitors of axon growth as well as physical impenetrability.  The intrinsic capacity for regrowth of CNS axons over long distances if provided permissive environment suggests that the failure of CNS neurons to regenerate is due to the defects lying in the environment rather than within the CNS neurons.  A multitude of regenerative (cell growth and survival) as well as nonregenerative (physical and biochemical) events need to function in tandem to restore functionality of the neuron. 
Targets for repair
Based on the pathophysiology of SCI, several targets for intervention have been proposed to minimize damage and promote repair and regeneration. , The same are summarized in [Figure 1]. Based on these targets several physicochemical and cellular strategies have been employed at preclinical and/or clinical level to evaluate their safety and efficacy [Figure 2].
|Figure 1: Schematic diagram showing targets for Intervention after spinal cord injury (SCI): Potential targets for repair and regeneration after SCI are listed in the left pane and the proposed approaches to achieve these targets are listed in their right|
Click here to view
|Figure 2: Strategies to promote regeneration after spinal cord injury (SCI). The cellular and molecular events which result in the creation of a hostile environment for axon repair following SCI are delineated. The strategies (1– 4) employed to promote neuronal repair and regeneration by providing a permissive environment along with the level at which they act|
Click here to view
In order to promote functional recovery, stem cell transplantation must suppress the inflammatory response, inhibit neuronal apoptosis and necrosis, enhance neuronal regeneration, and promote axon regeneration and remyelination. 
| Materials and Methods|| |
We searched MEDLINE for the search term "(stem cell OR stem OR hematopoietic OR mesenchymal) AND (SCI OR hemisection OR contusion injury OR dorsal column injury OR complete transection OR corticospinal tract injury) from 1 st January 2000 to 28 th February 2014. Our initial search retrieved 2076 articles, of these 1494 were animal studies, and 981 were human studies. If required, recovered papers were reviewed for further relevant references. Further cross-referencing was undertaken with EMBASE, Cochrane Library, ongoing trials databases and Google and Google Scholar to corroborate findings and resolve discrepancies, if any.
Cell transplantation after SCI may promote neuronal regeneration and function by (1) Secreting neurotrophic molecules at the lesion site; (2) acting as a scaffold for axonal regeneration; (3) replacing the lost/damaged cells. 
A number of cell populations have been tested for their safety and efficacy after SCI. These include
- Embryonic cells
- Umbilical cord cells
- Mesenchymal cells
- Hematopoietic cells
- Olfactory ensheathing glial cells
- Progenitor cells
- Schwann cells (SCs)
- Induced pluripotent stem cells (iPSCs).
A large volume of preclinical evidence exists indicating the efficacy of cell transplantation in case of animal models of SCI and is discussed below.
Embryonic stem cells
Embryonic stem cells (ESCs) are pluripotent stem cells derived from the inner cell mass of the early embryo.  They can replicate indefinitely and differentiate into all three germ layers and generate all cell types of the body. ESCs were the first population of cells tested for its regenerative potential. The cells could differentiate into neuronal cell types both in vitro and in vivo in animal models. However, due to their capability to differentiate into all cell types they were found to be tumorigenic.  In recent times, instead of direct transplantation, derivatives of these cells have been used to analyze their potential for neuronal regeneration. Several groups have derived neural progenitor/stem cells, motor neurons, oligodendrocyte progenitor cells, and olfactory ensheathing cells (OECs) from ESCs in vitro, and then transplanted these cells into various animal models to study restoration of neural function. The transplanted population in these cases have a restricted potential to differentiate and are generally progenitor cell populations derived from the pluripotent ESC. The use of such restricted population thus reduces the risk of tumorigenesis. Such stem cell-derived neuronal progenitor cells (NPCs) are hailed to be a promising population for neuronal repair. Such NPCs may possess variable characteristics depending on how they were derived.
Kumagai et al.  generated two primary and secondary neurospheres from the ESCs and demonstrated that only the secondary neurospheres were effective in promoting functional recovery in the rodent sub-acute SCI model. This functional recovery was attributed to paracrine secretion from the transplanted gliogenic neurospheres rather than direct cell replacement. Other populations derived from ESCs include motor neurons,  neural stem cells (NSC),  NPCs,  GABAergic neurons,  oligodendrocyte progenitor cell (OPC) populations.  These populations have demonstrated various degrees of functional restoration in animal models. [Table 1] describes in brief the cell populations derived and their effect upon transplantation in animal models.
|Table 1: Cell population derived from ESCs and their effect upon transplantation in animal models|
Click here to view
Due to the efficacy of neuronal regeneration and neuronal function promotion by the ESC derived NSCs, a variety of engineered ESC-NSC populations have been developed for SCI by several groups. These include, ESC-NSC expressing neural cell adhesion molecule L1.  Transplantation of L1-overexpressing substrate adherent ESC-derived neural aggregates into a mouse SCI model resulted in an increased number of surviving cells, enhanced neuronal differentiation, reduced glial differentiation, and increased tyrosine hydroxylase expression as compared to wild type cell aggregates. 
Similarly, engineered cell population expressing neurogenins, a family of a basic helix-loop-helix transcription factors involved in specifying neuronal differentiation, have been reported by several groups. Perrin et al. and Shapiro et al. utilized Neurogenin-2 expressing ESC-derived NPCs and reported full restoration of weight support and significant improvement of functional motor recovery in rats after severe spinal cord compression injury. Partial restoration of serotonin 5HT1A receptor expression, which plays a major role in locomotion and is particularly affected after SCI, was also observed. ,
Successful differentiation of human ESC-derived NPCs (hESC-NPCs) with collagen scaffolds into neurons and glia was observed in the hemisection rat model.  The transplanted cells also promoted hindlimb locomotor recovery and sensory responses with observed migration of transplanted stem cells toward the lesion site.  Niapour et al. reported that co-transplantation of hESC-NPCs and SCs resulted in significant motor function recovery as compared to control and single transplantation groups.  This study suggested that the co-transplantation might be a feasible strategy to enhance neuronal differentiation and suppress glial differentiation and thus promote functional recovery.
Embryonic Stem Cell-derived populations have been utilized for combinatorial strategies also. Combination of motor neuron progenitors along with ESC-OPCs in a complete transection SCI rat model  resulted in significantly better BBB scores with significantly higher amplitude of motor evoked potential (MEP) in electrophysiological evaluation as compared to individual populations. Salehi et al., in another combinatorial study, transplanted OECs and ESC - derived motoneurons into contused SCI rats.  They reported significantly better regeneration and functional restoration as compared to that observed when individual populations were transplanted. Illes et al. have reported the presence of intrinsically active neurons (IANs) in neuronal populations derived from mouse ESCs. They proposed that presence of such IAN populations in cell grafts may be a prerequisite to attain functional activity following interventions involving transplantation of neural tissues.  Lee TH has reported a substantial improvement of motor function due to transplantation of mouse ESCs in a rat model of clip-compression SCI. 
Induced pluripotent stem cells
Although ESCs possess great potential due to their ability to differentiate into all cell types that are useful for therapeutic purposes, such as transplantation, they raise significant ethical concern as most of the ESCs arise from human embryos. Recent discovery that somatic cells can be reprogrammed to a pluripotent state may be used to circumvent these concerns. The reprogrammed cells called iPSCs, exhibit functional similarities to ESCs and present an exciting area of research.
These cells have been used to derive cell populations equivalent to those derived by ESCs and tested in case of SCI.
Like ESCs, long term self-renewing rosette-type NSC population has been derived from iPSC (lt-iPSC-NSCs).  This population possesses stable neuronal and glial differentiation ability and capacity of generating functional mature neurons in vitro.  Upon transplantation into the mouse SCI model, enhanced remyelination and axonal regeneration along with survival of endogenous neurons was observed.  iPSC derived GABAgeric neurons have been tested in the hemisection rat model and were found to significantly reverse decreased paw withdrawal thresholds.  This indicates that this may be a potential solution for the loss of sensory function after SCI.
In a recent study, Sareen et al. have reported survival, migration and integration of human neural progenitor cells generated from iPSCs in nude rats. The authors have proposed that the iPSC derived NPC may be an alternative to human fetal tissue derived NPCs. 
Mesenchymal stem cells (MSCs)
Mesenchymal stem cells are stromal cells that have the ability to self-renew and also exhibit multilineage differentiation. This self-renewing, multipotent stem cell population was initially identified from the bone marrow (BM). According to the statement of International Society for Cellular Therapy, the definition of multipotent MSCs must (1) Adhere to plastic when cultured in standard conditions; (2) they must express CD105, CD73, and CD90, and lack the expression of CD45, CD34, CD14, or CD11b, CD79a, or CD19 and HLA-DR surface molecules; and (3) they must be able to differentiate to osteoblasts, adipocytes and chondroblasts in vitro. MSCs have been reported to differentiate into osteoblasts, chondrocytes, adipocytes, neural cells and myoblasts, in vitro. , Due to their multipotent nature, source availability and comparative safety, these cells have been advocated as a promising cell source for repair. MSCs have been reported to evince spontaneous neuronal differentiation when implanted into both irradiated mice , and humans.  Furthermore, allogeneic MSCs were reported to be well tolerated after intradermal injection in horses. , Mezey et al.  and Brazelton et al.  infused BM cells intraperitoneally in rats and have reported neuronal differentiation in the brain of host animals.
Transplantation of MSCs in SCI animal models has been reported to promote sensorimotor function recovery and bladder function recovery via neural lineage differentiation, neurotrophic paracrine effects and posttrauma inflammation regulation. ,, Abrams et al. observed that the injury-induced sensitivity to mechanical stimuli was significantly attenuated upon MSC injection in contusion SCI rats.  They also reported improvement of locomotor function in SCI rats after transplantation of MSCs.
The major limitations in the therapeutic in vivo application of MSCs for SCI is their low survival rate after graft, the lack of neural differentiation, glial scar formation, cystic cavity formation, the inhibitory cellular environment and the transplantation time-point. ,,
Furthermore, significant effects on the outcome are observed depending upon the route of transplantation of MSCs. Intravenous (IV) transplantation of MSCs was reported to result in significantly better BBB motor score as compared to intralesional transplantation in SCI rats.  Similarly, IV cell administration in severe contusive SCI rats in acute and sub-acute phase resulted in significant locomotor recovery.  Intrathecal co-administration of NPCs and MSCs did not lead to any migration to the injury site. 
Implantation of MSCs into the spinal cord or lesion site has not been reported to promote neuronal differentiation.  However, Boido et al. have reported, significantly reduced lesion volume and improved hindlimb sensorimotor functions after transplantation of mouse MSCs into the lesion cavity of compression SCI mouse model.  Similar results have been reported by Gu et al. after transplantation of BM MSCs into the epicenter of the injured spinal cord of rats  In such cases, it is hypothesized that the engrafted MSCs may generate a favorable environment for functional recovery through modulating the post-SCI inflammatory response and by having neurotrophic paracrine activity.  The therapeutic effects of MSC transplantation on the sensorimotor deficits in animal SCI models have been clearly confirmed by a large number of studies. ,,,
In order to overcome the limitations of direct MSC transplantation, several strategies have been employed that include pretransplantation neural differentiation, neurotrophic gene transduction, glial cell co-transplantation, and tissue engineering. ,,, Rostral and caudal injection of neural modified human bone-marrow derived MSCs to the T-8 lesion immediately after SCI in the rat model resulted in significantly improved locomotor function. ,,,,,,,, Transplantation of neurally differentiated rat MSCs (NMSCs) into the epicenter of a contusive lesion resulted in the recovery of motor function as well as significantly shortened initial latency, N1 latency and P1 latency of the SSEPs. , Co-transplantation of autologous neural differentiated and undifferentiated MSCs in the contusion lesion cavity at T8-T9 level of rats' spinal cord reported a significantly higher BBB score as compared to controls. 
Genetically modified MScs have been also been tested in some in vivo studies. Populations tested include MSCs over expressing basic fibroblast growth factor (bFGF),  and Neurotrophin-3 (NT-3) gene. 
Song et al. have demonstrated improvement of hind limbs' motor function after allograft of bone MSCs in rats with acute injury to their spinal nerve.  In another study, Yin et al. have reported the antiapoptotic effect of MSC transplantation in adult rats after spinal cord ischemia-reperfusion injury. This suggests that MSCs may affect cell regeneration and repair through control of apoptosis following SCI. 
One of the major barriers to spinal cord regeneration is the glial scar, which hampers the movement of regenerating cells and does not support the survival of implanted cells and their neural differentiation. Biological scaffolds are now gaining importance for providing substratum as well as neurotropins to aid cell survival, differentiation and proliferation. Platelet-rich plasma scaffolds in combination with BDNF have been shown to support survival and neural differentiation of human MSCs.  Gelatin sponge (GS) scaffold system, which was constructed by ensheathing GS with a thin film of poly-(lactide-co-glycolide) (PLGA), also has been reported to support rat MSC adherence, survival and proliferation in vitro, and in the rat SCI model, the seeded scaffolds were shown to attenuate inflammation, promote angiogenesis, and reduce cavity formation.  Other scaffolds and cell combinations tested include PLGA scaffolds system and human MSCs,  a combination of Matrigel and neural-induced adipose-derived MSCs (NMSCs).  In recent times, the use of fibrin scaffold along with MSC injection has been reported to result in the formation of longitudinally-aligned layers of MSCs growing over the spinal cord lesion site. This was associated with migration of host neurites into the MSC architecture. Such a strategy provides control over cell integration into the tissue after intraspinal injections hence enhancing localization of the cell graft. 
Sources of MSCs other than BM have also been identified by researchers, such as, adipose tissue,  amniotic fluid,  placenta, , umbilical cord blood (UCB), , and in several fetal tissues including liver, lung, and spleen.  Of these the MSCs from UCB and adipose tissue are sources choice with many advantages such as ease of collection, availability and proliferative capacity.
Neural stem/progenitor cells
Neural stem/progenitor cells (NS/PCs) were first demonstrated in the subventricular zone of the mouse in 1989  and were isolated from the mouse striatal tissue and subventricular zone for the first time in 1992.  These cells were capable of self-renewal and generating the main phenotypes (neurons, astrocytes, and oligodendrocytes) of CNS cells in vitro and in vivo.  After transplantation into the injured spinal cord, NS/PCs generate mature neural phenotypes and provide neural functional recovery in some SCI models. 
Neural stem/progenitor cells have been transplanted in vivo for studying their therapeutic potential after SCI. In most cases, in vivo transplanted NSCs have shown a preferential capability of differentiating into glial lineages, especially astrocytes.  The direct transplantation of NSCs or NPCs has not been always efficient for functional recovery after SCI. Transplantation of fetal NPCs, derived from fetal rats, into the dorsal column lesion site of adult rats, resulted in only a minor sensory function improvement with no restoration of the motor function recovery.  Pretreatment of human NSCs with bFGF, heparin, and laminin before transplantation into the contusion lesion of rats led to an optimized survival rate, neuronal and oligodendroglia differentiation, and improved trunk stability.  Tarasenko et al.  reported that the spinal cord microenvironment can probably change the differentiating fate of grafted NSCs. Transplantation of NS/PCs obtained from myelin-deficient shiverer mutant mice (shi-NS/PC) into the lesion site of rats demonstrated that the remyelination capability of wt-NS/PCs was vital to motor and electrophysiological functional recovery.  Transplantation of the Olig2 expressing NSC into the contused spinal cord has been reported to increase the volume of spared white matter and reduce the cavity volume. This was associated with thickened myelin sheath which may be due to differentiation of NSCs into oligodendrocytes. 
Injection of a combination of NSCs and OECs into the spinal cord lesion of rats has been reported to lead to hindlimb locomotor functional recovery.  Salazar et al. have reported a significant improvement in locomotor recovery in early chronic SCI mouse model after NSC transplantation.  They have also demonstrated that the transplanted NSCs differentiated into oligodendrocytes and neurons and that astrocytic differentiation was rare. The authors also reported the integration of transplanted human NSCs with host cells. Emgard et al. have reported a neuroprotective effect of human spinal cord derived neural precursor cells in two different rat models of SCI.  In a recent study, Nemati et al. transplanted adult monkey NSCs into a contusion model of SCI in the rhesus monkey and reported homing of MSCs to the lesion and improved hindlimb performance. 
Olfactory ensheathing cells
Olfactory ensheathing cells permit growing axons from neurons of the nasal cavity olfactory mucosa to re-enter the olfactory bulb (OB) of the brain and form synapses with second-order neurons.  These cells are present in the olfactory epithelium and are considered as a special class of glial cells which exist in both the peripheral nerve system (PNS) and CNS, and share certain features and functions with astrocytes as well as SCs.  By virtue of their cell-specific properties, OECs are more likely to rescue neural function in the injured spinal cord as compared with SCs.
Recent studies have shown that rodent OECs can support axonal regrowth when transplanted into experimental models of SCI  and are also able to form myelin sheaths around regenerated or demyelinated axons, thereby permitting rapid saltatory conduction to occur. , It has therefore been proposed that OECs may be suitable cells for transplant-mediated repair of spinal cord trauma or nonrepairing foci of demyelination (such as may occur in chronic multiple sclerosis). These data indicate that transplanted OECs have a repair repertoire that is similar to that of SCs, but may have advantages over these because of their ability to migrate and integrate within areas of astrocytosis that are characteristic of damaged CNS. , Following transplantation into a localized electrolytic lesion of the corticospinal tract in adult rats, OECs supported unbranched, regenerative growth of corticospinal axons and restoration of a corticospinal-dependent paw-reaching function.  OECs promoted regeneration after complete transection of the spinal cord  and restored rapid and secure conduction across the transected dorsal columns of the rat spinal cord  with recovery of motor function.  Human OECs were also shown to remyelinate the demyelinated spinal cord of the rat.  Other groups have shed doubt on the functional improvements induced by OECs grafts, and have suggested that they are caused by a trophic support mechanism and not the birth of new neurons, which means that the therapeutic potential of OECs after SCI may be limited. , Centenaro et al.  and Aoki et al.  in their olfactory tissue transplantation studies suggest that OECs may be of limited use in promoting recovery after SCI.
The disparity in the results reported by different groups may be attributed to the cell population used, donor, injury models, graft preparation, time of transplantation and the transplantation procedure. ,,,
To address the issue of the time of transplantation or "transplantation window", Muñoz-Quiles et al.  compared the motor function recovery after OB derived OEC (OB-OEC) transplantation into completed transection injured rats among sub-acute chronic and nontreatment groups. They reported a 10% higher percentage of recovery in sub-acute transplantation group than the chronic group with motor axons growing beyond into the lesion site, indicating a rostral to caudal the lesion site crossing phenomenon.  Based on these finding Li and Lepski in their review, proposed that sub-acute or chronic cellular transplantation to bypass the acute phase after spinal trauma combined with scar ablation may be a potentially effective strategy to achieve regeneration and/or repair after SCI. 
Another factor that determines the survival and fate of the transplanted tissue is in vitro culture conditions. OECs with longer preculture times were found to be less effective as compared to those with shorter preculture times. 
Although the application of OECs for regeneration after SCI has been questioned, several studies support the potential of OECs to be protective/regenerative in nature.  OECs have been combined with cAMP treatment ,,, and laser puncture,  genetically modified for NT-3 production, and co-transplanted with other cell types  in order to boost the efficacy of OEC transplantation. Although most of such combinations have resulted in better efficacy as compared to OECs alone, a few have failed to do so. Co-transplantation of OECs with MSCs did not lead to any significant synergistic effects on neural function improvement as compared to OEC alone. ,,
Schwann cells were discovered by Theodor Schwann in 1839 and were found to provide myelination of peripheral axons. Schwann cell precursors (SCP) were found in developing stem cells within neural crest. When connected to nervous fibers, SCs or precursors lead to myelination of peripheral axons.  In the human and large animals, SCI leads to the formation of a cavity and a glial scar. Due to this, the ends of the regenerating axons at the edge of the scar become dysmorphic and cannot progress further leading to termination of axon regrowth.  It has been demonstrated that after SCI, if these injured neurons are grafted into a peripheral neural environment, which facilitates growth and remyelination, they can recover their morphology and electrophysiological function.  SCs are an important part of the PNS and are vital for the myelination of peripheral axons. Park et al. have reported that transplantation of SCs into a demyelinated spinal cord slice, in vitro, promotes survival and secretion of neurotrophic factors which may aid intrinsic neuronal regeneration.  SC transplantation has also been reported to lead to remyelination of demyelinated axons and axonal sprouting. 
In the past studies, SCs used were isolated from peripheral nerves and cultured in vitro to provide enough number of cells for the transplantation. In recent times, alternate sources for SCs have been used. The SCs have been derived from different stem cell populations or neural progenitors like, MSCs , adipose-derived stem cells,  and skin-derived precursors (SKPs).  Mesenchymal stem cell-derived SCs were tested by Park et al. and Xu et al. in vitro and were found to support axon remyelination and sprouting. , Biernaskie et al. derived SCs from SKPs which were isolated from the rodent or human skin.  Upon transplantation of these SKP-SCs in the murine contused model lesion site bridging effect, increased size of spared tissue, and reduced reactive gliosis was observed which was better in the SKP-SC group as compared to control and SKP only.  In addition, significant enhancement of locomotor recovery was observed although there was no restoration of sensory function. Therapeutic potential of SCP in an acute SCI model was tested by Agudo et al.  They reported a successful integration of the graft into the host tissue, and a robust bridging effect which extended rostrocaudally due to immediate cell injection into the lesion site after surgery.  However, no significant difference in motor function was observed between the SCP and control group.
Similar to other cell types, SCs have also been genetically modified and tested. SCs overexpressing chondroitin sulfate proteoglycans have been reported to suppress the expression of glial fibrillary acidic protein and chondroitin sulfate proteoglycan in reactive astrocytes, induce robust migration of astrocytes extending in parallel to the regenerated axons and remyelinate the axons. , Co-transplantation strategies and use of scaffolds and matrices have revealed that Matrigel and biodegradable scaffolds could promote cell survival and/or axon regeneration; however, functional activity was not significantly enhanced.  Co-transplantation of SC and MSC was found to be a promising strategy to enhance cell survival, axon regeneration and functional activity.  However, co-treatment of SC with cAMP enhancer and cAMP analog did not exhibit enhanced locomotor function as was reported previously. This could be attributed to experimental group arrangements, consistency of injury severity, appropriated statistics, and animal surgery. ,,, Kanno et al. have reported improved axonal regeneration and motor function following transplantation of SCs which were genetically modified to secrete neurotrophin in combination with chondroitinase. 
Based on the vast body of preclinical evidence, scientists and clinicians have been eager to explore the therapeutic effects of cell transplantation on spinal cord patients. Various cell types, different administration strategies, and different kinds of SCI patients have been involved in clinical trials or therapeutic settings. A plethora of patient testimonials and case studies have reported the clinical safety and efficacy of cell transplantation after SCI. However, there is a paucity of data from valid clinical trials. The data from such validated trials report several obstacles that are inherent to human studies including ethical issues differences in anatomy, and differences in underlying pathophysiological processes. Until now, no promising cell therapies that are safe and effective for SCI patients have been achieved.
Bone marrow transplantation for SCI has been the focus of attention in the last few years. There have been extensive preclinical studies which have demonstrated their potential role. Transplanted BMCs were found to improve neurological deficit in CNS injuries model by generating neural cells or myelin-producing cells , BMCs have been transplanted by direct injection into the injured spinal cord, , IV injection,  intrathecal injection  or injection into the spinal artery. 
The uses of BMCs for stem cell therapy in SCI subjects has more advantages compared with ESC use and therefore are more widely used. BM stem cell-based therapy is not associated with carcinogenesis, which sometimes occurs in ESC therapy,  Immunological rejection or graft-versus-host reactions, caused by allograft,  and extensive scientific data on BMCs has been accumulated from wide-ranging experiences in BM transplantation for hematological diseases.
Moreover, several hypotheses have been proposed to explain the role of BM stem cells in SCI models. First, BMCs improve neurologic deficit by generating either neural cells or myelin-producing cells. , Second, transplanted BMCs do not differentiate into neurons; rather, they work by guiding axonal regeneration by producing extracellular matrix. Third, transplanted BMCs promote compensatory mechanisms to reorganize neural network, and activate endogenous stem cells.  The studies have been summarized in [Table 2].
Preclinical studies suggest behavioral efficacy due transplantation of human UCB cells and suggest that benefits may come from secretion of factors by transplanted cells,  however, only a few small "open label" human studies have been conducted with varying claims of benefit. Currently, a planned SCI trial by China SCI network is being conducted (ClinicalTrials.gov Identifier: NCT01046786).
|Table 2: Summary of published clinical trials on cellular therapy for SCI|
Click here to view
The potential use of ESCs and iPSCs in clinical applications has vastly interested both researchers and clinicians. This has also has gained the attention of media. However, several issues remain to be addressed regarding their safety and efficacy. ,,, One of the most widely publicized trials has been the hESC OPCs, GRNOPC1, within patients who were suffering from complete thoracic level paraplegia with the loss of motor and sensory function. , To date, there are no serious adverse events in the long term followup reported, however, in November 2011, Geron announced that it had ended its SCI stem cell research program largely due to financial reasons. Though the concept of using ESC or iPSC derived cells for regeneration and repair is very tempting due to reasons of ease of availability and low immunological risks, still a vast body of preclinical evidence is needed before the therapeutic potential of these cells may be tested in a clinical setting.
Human trials published so far have had various flaws in design and documentation. Initiatives of various associations in educating clinicians as well as individuals regarding cellular therapies and clinical trial design in case of SCI go a long way in promoting moral, ethical and scientifically validated use of cellular interventions. ,,,,
A stem cell clinical trial in SCI needs to address several open ended questions with respect to cell population (ESC derived progenitors, MSCs, OECs, etc.), cell dosage (number of cells and number of interventions), subject selection (acute vs. chronic, level of injury) and outcome measures. In our experience, we have not been able to duplicate the efficacy to stem cell interventions in case of chronic  as well as acute SCI (unpublished results). The current proof of evidence points in the direction of undertaking trials which include other repair strategies such as predifferentiation, scaffolds, growth factors, etc., along with cell transplantation to achieve repair and regeneration post-SCI. Transplanting partially differentiated "progenitor cell" populations may be more effective than the pluripotent or multipotent populations. Disparity in preclinical evidence data versus clinical evidence.
Despite huge base of preclinical evidence in support of restoration of neuronal function through cellular interventions, the clinical evidence has not been that encouraging. There still remains a huge gap between the "bench" and the "bedside" which remains to be bridged. The factors which contribute to this are:
- Difference in the injuries between the animal models and human SCI
- Choice of the animal model
- Cell population used
- Patient selection criteria
- Spontaneous recovery confounding interpretation of results
- Poor trial design
- Lack of standardized outcome measures in a clinical trial.
| Conclusion|| |
The list of experimental therapies that have been developed in animal models to improve functional outcomes after SCI is extensive. There is a vast body of preclinical evidence which supports the therapeutic potential of cell transplant in facilitating spinal cord regeneration and/or repair after SCI. However, preclinical studies have their inherent limitations dependent upon the mechanism of injury and the animal model used. Recent publications on the mechanisms involved in repair and regeneration post-SCI provide valuable insights regarding the potential barriers to regeneration after SCI. These need to be addressed by scientists and clinicians to define new strategies for achieving repair. Basic scientific research should be directed toward providing a rational basis for tailoring specific combinations of clinical therapies to different types of SCI. Functional regeneration should be the primary goal of any approach being tested, and it is important that this is tested by scientifically validated and universally accepted outcome measures and tools. Due to the involvement of multiple cell type and the complexity of SCI, it is becoming increasingly clear that a single approach may not be successful in achieving SCI repair.
In the current scenario, the need for multi-disciplinary involvement is essential as a single approach to achieve functionally effective axonal regrowth and sprouting may be ineffective due to the complex nature of SCI and the number of cell populations involved. A multi-factorial approach involving cell populations, scaffolding matrix, growth factor supplementation and scar removal is required to address this situation. Along with this, multi-centric studies involving standardized and validated approach, a stringent trial design with appropriate outcome measures and rehabilitation protocol are a must to understand and achieve the potential of cellular therapy in case of SCI. A clinical trial program with appropriate clinical trial design and ethical conduct is key for achieving this goal.
| References|| |
Liverman CT, Altevogt BM, Joy JE, editors. Spinal Cord Injury: Progress, Promise and Priorities. Washington, DC: National Academies Press; 2005.
Priebe MM, Chiodo AE, Scelza WM, Kirshblum SC, Wuermser LA, Ho CH. Spinal cord injury medicine 6. Economisc and societal issues in spinal cord injury. Arch Phys Med Rehabil 2007;88:S84-8.
Chhabra HS, Arora M. Demographic profile of traumatic spinal cord injuries admitted at Indian Spinal Injuries Centre with special emphasis on mode of injury: A retrospective study. Spinal Cord 2012;50:745-54.
Yip PK, Malaspina A. Spinal cord trauma and the molecular point of no return. Mol Neurodegener 2012;7:6.
Tarasenko YI, Gao J, Nie L, Johnson KM, Grady JJ, Hulsebosch CE, et al.
Human fetal neural stem cells grafted into contusion-injured rat spinal cords improve behavior. J Neurosci Res 2007;85:47-57.
Rowland JW, Hawryluk GW, Kwon B, Fehlings MG. Current status of acute spinal cord injury pathophysiology and emerging therapies: Promise on the horizon. Neurosurg Focus 2008;25:E2.
Bauchet L, Lonjon N, Perrin FE, Gilbert C, Privat A, Fattal C. Strategies for spinal cord repair after injury: A review of the literature and information. Ann Phys Rehabil Med 2009;52:330-51.
Kakulas BA. A review of the neuropathology of human spinal cord injury with emphasis on special features. J Spinal Cord Med 1999;22:119-24.
McDonald JW, Liu XZ, Qu Y, Liu S, Mickey SK, Turetsky D, et al.
Transplanted embryonic stem cells survive, differentiate and promote recovery in injured rat spinal cord. Nat Med 1999;5:1410-2.
Norenberg MD, Smith J, Marcillo A. The pathology of human spinal cord injury: Defining the problems. J Neurotrauma 2004;21:429-40.
Akiyama Y, Honmou O, Kato T, Uede T, Hashi K, Kocsis JD. Transplantation of clonal neural precursor cells derived from adult human brain establishes functional peripheral myelin in the rat spinal cord. Exp Neurol 2001;167:27-39.
Deumens R, Koopmans GC, Honig WM, Maquet V, Jérôme R, Steinbusch HW, et al
. Chronically injured corticospinal axons do not cross large spinal lesion gaps after a multifactorial transplantation strategy using olfactory ensheathing cell/olfactory nerve fibroblast-biomatrix bridges. J Neurosci Res 2006;83:811-20.
Su H, Wu Y, Yuan Q, Guo J, Zhang W, Wu W. Optimal time point for neuronal generation of transplanted neural progenitor cells in injured spinal cord following root avulsion. Cell Transplant 2011;20:167-76.
Yiu G, He Z. Glial inhibition of CNS axon regeneration. Nat Rev Neurosci 2006;7:617-27.
Zurita M, Otero L, Aguayo C, Bonilla C, Ferreira E, Parajón A, et al.
Cell therapy for spinal cord repair: Optimization of biologic scaffolds for survival and neural differentiation of human bone marrow stromal cells. Cytotherapy 2010;12:522-37.
Horner PJ, Gage FH. Regenerating the damaged central nervous system. Nature 2000;407:963-70.
Garbossa D, Boido M, Fontanella M, Fronda C, Ducati A, Vercelli A. Recent therapeutic strategies for spinal cord injury treatment: Possible role of stem cells. Neurosurg Rev 2012;35:293-311.
Pearse DD, Bunge MB. Designing cell- and gene-based regeneration strategies to repair the injured spinal cord. J Neurotrauma 2006;23:438-52.
Blair K, Wray J, Smith A. The liberation of embryonic stem cells. PLoS Genet 2011;7:e1002019.
Cao F, Lin S, Xie X, Ray P, Patel M, Zhang X, et al. In vivo
visualization of embryonic stem cell survival, proliferation, and migration after cardiac delivery. Circulation 2006;113:1005-14.
Kumagai G, Okada Y, Yamane J, Nagoshi N, Kitamura K, Mukaino M, et al.
Roles of ES cell-derived gliogenic neural stem/progenitor cells in functional recovery after spinal cord injury. PLoS One 2009;4:e7706.
Lowry N, Goderie SK, Adamo M, Lederman P, Charniga C, Gill J, et al.
Multipotent embryonic spinal cord stem cells expanded by endothelial factors and Shh/RA promote functional recovery after spinal cord injury. Exp Neurol 2008;209:510-22.
Falk A, Koch P, Kesavan J, Takashima Y, Ladewig J, Alexander M, et al.
Capture of neuroepithelial-like stem cells from pluripotent stem cells provides a versatile system for in vitro
production of human neurons. PLoS One 2012;7:e29597.
Hatami M, Mehrjardi NZ, Kiani S, Hemmesi K, Azizi H, Shahverdi A, et al.
Human embryonic stem cell-derived neural precursor transplants in collagen scaffolds promote recovery in injured rat spinal cord. Cytotherapy 2009;11:618-30.
Kim DS, Jung SJ, Nam TS, Jeon YH, Lee DR, Lee JS, et al.
Transplantation of GABAergic neurons from ESCs attenuates tactile hypersensitivity following spinal cord injury. Stem Cells 2010;28:2099-108.
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.
Fujimoto Y, Abematsu M, Falk A, Tsujimura K, Sanosaka T, Juliandi B, et al.
Treatment of a mouse model of spinal cord injury by transplantation of human induced pluripotent stem cell-derived longterm self-renewing neuroepithelial-like stem cells. Stem Cells 2012;30:1163-73.
Rossi SL, Nistor G, Wyatt T, Yin HZ, Poole AJ, Weiss JH, et al.
Histological and functional benefit following transplantation of motor neuron progenitors to the injured rat spinal cord. PLoS One 2010;5:e11852.
Kerr CL, Letzen BS, Hill CM, Agrawal G, Thakor NV, Sterneckert JL, et al.
Efficient differentiation of human embryonic stem cells into oligodendrocyte progenitors for application in a rat contusion model of spinal cord injury. Int J Neurosci 2010;120:305-13.
Sharp KG, Flanagan LA, Yee KM, Steward O. A re-assessment of a combinatorial treatment involving Schwann cell transplants and elevation of cyclic AMP on recovery of motor function following thoracic spinal cord injury in rats. Exp Neurol 2012;233:625-44.
Chen J, Bernreuther C, Dihné M, Schachner M. Cell adhesion molecule l1-transfected embryonic stem cells with enhanced survival support regrowth of corticospinal tract axons in mice after spinal cord injury. J Neurotrauma 2005;22:896-906.
Cui YF, Xu JC, Hargus G, Jakovcevski I, Schachner M, Bernreuther C. Embryonic stem cell-derived L1 overexpressing neural aggregates enhance recovery after spinal cord injury in mice. PLoS One 2011;6:e17126.
Perrin FE, Boniface G, Serguera C, Lonjon N, Serre A, Prieto M, et al.
Grafted human embryonic progenitors expressing neurogenin-2 stimulate axonal sprouting and improve motor recovery after severe spinal cord injury. PLoS One 2010;5:e15914.
Shapiro S, Kubek M, Siemers E, Daly E, Callahan J, Putty T. Quantification of thyrotropin-releasing hormone changes and serotonin content changes following graded spinal cord injury.J Surg Res. 1995:59:393-8
Niapour A, Karamali F, Nemati S, Taghipour Z, Mardani M, Nasr-Esfahani MH, et al.
Cotransplantation of human embryonic stem cell-derived neural progenitors and schwann cells in a rat spinal cord contusion injury model elicits a distinct neurogenesis and functional recovery. Cell Transplant 2012;21:827-43.
Erceg S, Ronaghi M, Oria M, Roselló MG, Aragó MA, Lopez MG, et al.
Transplanted oligodendrocytes and motoneuron progenitors generated from human embryonic stem cells promote locomotor recovery after spinal cord transection. Stem Cells 2010;28:1541-9.
Salehi M, Pasbakhsh P, Soleimani M, Abbasi M, Hasanzadeh G, Modaresi MH, et al.
Repair of spinal cord injury by co-transplantation of embryonic stem cell-derived motor neuron and olfactory ensheathing cell. Iran Biomed J 2009;13:125-35.
Illes S, Jakab M, Beyer F, Gelfert R, Couillard-Despres S, Schnitzler A, et al.
Intrinsically active and pacemaker neurons in pluripotent stem cell-derived neuronal populations. Stem Cell Reports 2014;2:323-36.
Lee TH. Functional effect of mouse embryonic stem cell implantation after spinal cord injury. J Exerc Rehabil 2013;9:230-3.
Sareen D, Gowing G, Sahabian A, Staggenborg K, Paradis R, Avalos P, et al
. Human neural progenitor cells generated from induced pluripotent stem cells can survive, migrate, and integrate in the rodent spinal cord. J Comp Neurol 2014.
Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, et al.
Multilineage potential of adult human mesenchymal stem cells. Science 1999;284:143-7.
Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR, et al.
Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 2002;418:41-9.
Brazelton TR, Rossi FM, Keshet GI, Blau HM. From marrow to brain: Expression of neuronal phenotypes in adult mice. Science 2000;290:1775-9.
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.
Mezey E, Key S, Vogelsang G, Szalayova I, Lange GD, Crain B. Transplanted bone marrow generates new neurons in human brains. Proc Natl Acad Sci U S A 2003;100:1364-9.
Carrade DD, Affolter VK, Outerbridge CA, Watson JL, Galuppo LD, Buerchler S, et al
. Intradermal injections of equine allogeneic umbilical cord-derived mesenchymal stem cells are well tolerated and do not elicit immediate or delayed hypersensitivity reactions. Cytotherapy 2011;13:1180-92.
Krampera M, Glennie S, Dyson J, Scott D, Laylor R, Simpson E, et al.
Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide. Blood 2003;101:3722-9.
Nakajima H, Uchida K, Guerrero AR, Watanabe S, Sugita D, Takeura N, et al.
Transplantation of mesenchymal stem cells promotes an alternative pathway of macrophage activation and functional recovery after spinal cord injury. J Neurotrauma 2012;29:1614-25.
Karaoz E, Kabatas S, Duruksu G, Okcu A, Subasi C, Ay B, et al.
Reduction of lesion in injured rat spinal cord and partial functional recovery of motility after bone marrow derived mesenchymal stem cell transplantation. Turk Neurosurg 2012;22:207-17.
Park WB, Kim SY, Lee SH, Kim HW, Park JS, Hyun JK. The effect of mesenchymal stem cell transplantation on the recovery of bladder and hindlimb function after spinal cord contusion in rats. BMC Neurosci 2010;11:119.
Abrams MB, Dominguez C, Pernold K, Reger R, Wiesenfeld-Hallin Z, Olson L, et al.
Multipotent mesenchymal stromal cells attenuate chronic inflammation and injury-induced sensitivity to mechanical stimuli in experimental spinal cord injury. Restor Neurol Neurosci 2009;27:307-21.
Mothe AJ, Bozkurt G, Catapano J, Zabojova J, Wang X, Keating A, et al.
Intrathecal transplantation of stem cells by lumbar puncture for thoracic spinal cord injury in the rat. Spinal Cord 2011;49:967-73.
Boido M, Garbossa D, Fontanella M, Ducati A, Vercelli A. Mesenchymal stem cell transplantation reduces glial cyst and improves functional outcome after spinal cord compression. World Neurosurg 2014;81:183-90.
Gu W, Zhang F, Xue Q, Ma Z, Lu P, Yu B. Transplantation of bone marrow mesenchymal stem cells reduces lesion volume and induces axonal regrowth of injured spinal cord. Neuropathology 2010;30:205-17.
Kang ES, Ha KY, Kim YH. Fate of transplanted bone marrow derived mesenchymal stem cells following spinal cord injury in rats by transplantation routes. J Korean Med Sci 2012;27:586-93.
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.
Hu SL, Luo HS, Li JT, Xia YZ, Li L, Zhang LJ, et al.
Functional recovery in acute traumatic spinal cord injury after transplantation of human umbilical cord mesenchymal stem cells. Crit Care Med 2010;38:2181-9.
Cho SR, Kim YR, Kang HS, Yim SH, Park CI, Min YH, et al.
Functional recovery after the transplantation of neurally differentiated mesenchymal stem cells derived from bone barrow in a rat model of spinal cord injury. Cell Transplant 2009;18:1359-68.
Pedram MS, Dehghan MM, Soleimani M, Sharifi D, Marjanmehr SH, Nasiri Z. Transplantation of a combination of autologous neural differentiated and undifferentiated mesenchymal stem cells into injured spinal cord of rats. Spinal Cord 2010;48:457-63.
Liu WG, Wang ZY, Huang ZS. Bone marrow-derived mesenchymal stem cells expressing the bFGF transgene promote axon regeneration and functional recovery after spinal cord injury in rats. Neurol Res 2011;33:686-93.
Zhang YJ, Zhang W, Lin CG, Ding Y, Huang SF, Wu JL, et al.
Neurotrophin-3 gene modified mesenchymal stem cells promote remyelination and functional recovery in the demyelinated spinal cord of rats. J Neurol Sci 2012;313:64-74.
Zeng X, Zeng YS, Ma YH, Lu LY, Du BL, Zhang W, et al.
Bone marrow mesenchymal stem cells in a three-dimensional gelatin sponge scaffold attenuate inflammation, promote angiogenesis, and reduce cavity formation in experimental spinal cord injury. Cell Transplant 2011;20:1881-99.
Fang KM, Chen JK, Hung SC, Chen MC, Wu YT, Wu TJ, et al.
Effects of combinatorial treatment with pituitary adenylate cyclase activating peptide and human mesenchymal stem cells on spinal cord tissue repair. PLoS One 2010;5:e15299.
Oh JS, Kim KN, An SS, Pennant WA, Kim HJ, Gwak SJ, et al.
Cotransplantation of mouse neural stem cells (mNSCs) with adipose tissue-derived mesenchymal stem cells improves mNSC survival in a rat spinal cord injury model. Cell Transplant 2011;20:837-49.
Park HW, Cho JS, Park CK, Jung SJ, Park CH, Lee SJ, et al.
Directed induction of functional motor neuron-like cells from genetically engineered human mesenchymal stem cells. PLoS One 2012;7:e35244.
Alexanian AR, Fehlings MG, Zhang Z, Maiman DJ. Transplanted neurally modified bone marrow-derived mesenchymal stem cells promote tissue protection and locomotor recovery in spinal cord injured rats. Neurorehabil Neural Repair 2011;25:873-80.
Song Q, Xu R, Zhang Q, Ma M, Zhao X. Therapeutic effect of transplanting bone mesenchymal stem cells on the hind limbs′ motor function of rats with acute spinal cord injury. Int J Clin Exp Med 2014;7:262-7.
Yin F, Guo L, Meng CY, Liu YJ, Lu RF, Li P, et al.
Transplantation of mesenchymal stem cells exerts anti-apoptotic effects in adult rats after spinal cord ischemia-reperfusion injury. Brain Res 2014;1561:1-10.
Kang KN, Kim da Y, Yoon SM, Lee JY, Lee BN, Kwon JS, et al.
Tissue engineered regeneration of completely transected spinal cord using human mesenchymal stem cells. Biomaterials 2012;33:4828-35.
Park SS, Lee YJ, Lee SH, Lee D, Choi K, Kim WH, et al.
Functional recovery after spinal cord injury in dogs treated with a combination of Matrigel and neural-induced adipose-derived mesenchymal Stem cells. Cytotherapy 2012;14:584-97.
Hyatt AJ, Wang D, van Oterendorp C, Fawcett JW, Martin KR. Mesenchymal stromal cells integrate and form longitudinally-aligned layers when delivered to injured spinal cord via a novel fibrin scaffold. Neurosci Lett 2014 569:12-7.
In ′t Anker PS, Scherjon SA, Kleijburg-van der Keur C, de Groot-Swings GM, Claas FH, Fibbe WE, et al
. Isolation of mesenchymal stem cells of fetal or maternal origin from human placenta. Stem Cells 2004;22:1338-45.
Fukuchi Y, Nakajima H, Sugiyama D, Hirose I, Kitamura T, Tsuji K. Human placenta-derived cells have mesenchymal stem/progenitor cell potential. Stem Cells 2004;22:649-58.
Romanov YA, Svintsitskaya VA, Smirnov VN. Searching for alternative sources of postnatal human mesenchymal stem cells: Candidate MSC-like cells from umbilical cord. Stem Cells 2003;21:105-10.
Judas GI, Ferreira SG, Simas R, Sannomiya P, Benício A, da Silva LF, et al.
Intrathecal injection of human umbilical cord blood stem cells attenuates spinal cord ischaemic compromise in rats. Interact Cardiovasc Thorac Surg 2014;18:757-62.
Campagnoli C, Roberts IA, Kumar S, Bennett PR, Bellantuono I, Fisk NM. Identification of mesenchymal stem/progenitor cells in human first-trimester fetal blood, liver, and bone marrow. Blood 2001;98:2396-402.
Temple S. Division and differentiation of isolated CNS blast cells in microculture. Nature 1989;340:471-3.
Reynolds BA, Weiss S. Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 1992;255:1707-10.
Reubinoff BE, Itsykson P, Turetsky T, Pera MF, Reinhartz E, Itzik A, et al.
Neural progenitors from human embryonic stem cells. Nat Biotechnol 2001;19:1134-40.
Cao QL, Zhang YP, Howard RM, Walters WM, Tsoulfas P, Whittemore SR. Pluripotent stem cells engrafted into the normal or lesioned adult rat spinal cord are restricted to a glial lineage. Exp Neurol 2001;167:48-58.
Webber DJ, Bradbury EJ, McMahon SB, Minger SL. Transplanted neural progenitor cells survive and differentiate but achieve limited functional recovery in the lesioned adult rat spinal cord. Regen Med 2007;2:929-45.
Yan J, Xu L, Welsh AM, Hatfield G, Hazel T, Johe K, et al.
Extensive neuronal differentiation of human neural stem cell grafts in adult rat spinal cord. PLoS Med 2007;4:e39.
Yasuda A, Tsuji O, Shibata S, Nori S, Takano M, Kobayashi Y, et al.
Significance of remyelination by neural stem/progenitor cells transplanted into the injured spinal cord. Stem Cells 2011;29:1983-94.
Hwang DH, Kim BG, Kim EJ, Lee SI, Joo IS, Suh-Kim H, et al.
Transplantation of human neural stem cells transduced with Olig2 transcription factor improves locomotor recovery and enhances myelination in the white matter of rat spinal cord following contusive injury. BMC Neurosci 2009;10:117.
Wang G, Ao Q, Gong K, Zuo H, Gong Y, Zhang X. Synergistic effect of neural stem cells and olfactory ensheathing cells on repair of adult rat spinal cord injury. Cell Transplant 2010;19:1325-37.
Salazar DL, Uchida N, Hamers FP, Cummings BJ, Anderson AJ. Human neural stem cells differentiate and promote locomotor recovery in an early chronic spinal cord injury NOD-scid mouse model. PLoS One 2010;5:E12272.
Emgård M, Piao J, Aineskog H, Liu J, Calzarossa C, Odeberg J, et al.
Neuroprotective effects of human spinal cord-derived neural precursor cells after transplantation to the injured spinal cord. Exp Neurol 2014;253:138-45.
Nemati SN, Jabbari R, Hajinasrollah M, Zare Mehrjerdi N, Azizi H, Hemmesi K, et al
. Transplantation of adult monkey neural stem cells into a contusion spinal cord injury model in rhesus macaque monkeys. Cell J 2014;16:117-30.
Ramón-Cueto A, Avila J. Olfactory ensheathing glia: Properties and function. Brain Res Bull 1998;46:175-87.
Li Y, Carlstedt T, Berthold CH, Raisman G. Interaction of transplanted olfactory-ensheathing cells and host astrocytic processes provides a bridge for axons to regenerate across the dorsal root entry zone. Exp Neurol 2004;188:300-8.
Lakatos A, Barnett SC, Franklin RJ. Olfactory ensheathing cells induce less host astrocyte response and chondroitin sulphate proteoglycan expression than Schwann cells following transplantation into adult CNS white matter. Exp Neurol 2003;184:237-46.
Barnett SC, Alexander CL, Iwashita Y, Gilson JM, Crowther J, Clark L, et al.
Identification of a human olfactory ensheathing cell that can effect transplant-mediated remyelination of demyelinated CNS axons. Brain 2000;123:1581-8.
Yamamoto M, Raisman G, Li D, Li Y. Transplanted olfactory mucosal cells restore paw reaching function without regeneration of severed corticospinal tract fibres across the lesion. Brain Res 2009;1303:26-31.
Ramón-Cueto A, Cordero MI, Santos-Benito FF, Avila J. Functional recovery of paraplegic rats and motor axon regeneration in their spinal cords by olfactory ensheathing glia. Neuron 2000;25:425-35.
Imaizumi T, Lankford KL, Kocsis JD, Hashi K. The role of transplanted astrocytes for the regeneration of CNS axons. No To Shinkei 2001;53:632-8.
Kato T, Honmou O, Uede T, Hashi K, Kocsis JD. Transplantation of human olfactory ensheathing cells elicits remyelination of demyelinated rat spinal cord. Glia 2000;30:209-18.
Lu P, Yang H, Culbertson M, Graham L, Roskams AJ, Tuszynski MH. Olfactory ensheathing cells do not exhibit unique migratory or axonal growth-promoting properties after spinal cord injury. J Neurosci 2006;26:11120-30.
Collazos-Castro JE, Muñetón-Gómez VC, Nieto-Sampedro M. Olfactory glia transplantation into cervical spinal cord contusion injuries. J Neurosurg Spine 2005;3:308-17.
Centenaro LA, Jaeger Mda C, Ilha J, de Souza MA, Kalil-Gaspar PI, Cunha NB, et al.
Olfactory and respiratory lamina propria transplantation after spinal cord transection in rats: Effects on functional recovery and axonal regeneration. Brain Res 2011;1426:54-72.
Aoki M, Kishima H, Yoshimura K, Ishihara M, Ueno M, Hata K, et al.
Limited functional recovery in rats with complete spinal cord injury after transplantation of whole-layer olfactory mucosa: Laboratory investigation. J Neurosurg Spine 2010;12:122-30.
Richter MW, Fletcher PA, Liu J, Tetzlaff W, Roskams AJ. Lamina propria and olfactory bulb ensheathing cells exhibit differential integration and migration and promote differential axon sprouting in the lesioned spinal cord. J Neurosci 2005;25:10700-11.
Zhang SX, Huang F, Gates M, White J, Holmberg EG. Histological repair of damaged spinal cord tissue from chronic contusion injury of rat: A LM observation. Histol Histopathol 2011;26:45-58.
Zhang SX, Huang F, Gates M, Holmberg EG. Scar ablation combined with LP/OEC transplantation promotes anatomical recovery and P0-positive myelination in chronically contused spinal cord of rats. Brain Res 2011;1399:1-14.
Muñoz-Quiles C, Santos-Benito FF, Llamusí MB, Ramón-Cueto A. Chronic spinal injury repair by olfactory bulb ensheathing glia and feasibility for autologous therapy. J Neuropathol Exp Neurol 2009;68:1294-308.
Li J, Lepski G. Cell transplantation for spinal cord injury: A systematic review. Biomed Res Int 2013;2013:786475.
Novikova LN, Lobov S, Wiberg M, Novikov LN. Efficacy of olfactory ensheathing cells to support regeneration after spinal cord injury is influenced by method of culture preparation. Exp Neurol 2011;229:132-42.
Ziegler MD, Hsu D, Takeoka A, Zhong H, Ramón-Cueto A, Phelps PE, et al.
Further evidence of olfactory ensheathing glia facilitating axonal regeneration after a complete spinal cord transection. Exp Neurol 2011;229:109-19.
Tharion G, Indirani K, Durai M, Meenakshi M, Devasahayam SR, Prabhav NR, et al.
Motor recovery following olfactory ensheathing cell transplantation in rats with spinal cord injury. Neurol India 2011;59:566-72.
Stamegna JC, Felix MS, Roux-Peyronnet J, Rossi V, Féron F, Gauthier P, et al
. Nasal OEC transplantation promotes respiratory recovery in a subchronic rat model of cervical spinal cord contusion. Exp Neurol 2011;229:120-31.
Mackay-Sim A, St John JA. Olfactory ensheathing cells from the nose: Clinical application in human spinal cord injuries. Exp Neurol 2011;229:174-80.
Bretzner F, Plemel JR, Liu J, Richter M, Roskams AJ, Tetzlaff W. Combination of olfactory ensheathing cells with local versus systemic cAMP treatment after a cervical rubrospinal tract injury. J Neurosci Res 2010;88:2833-46.
Bohbot A. Olfactory ensheathing glia transplantation combined with LASERPONCTURE in human spinal cord injury: Results measured by electromyography monitoring. Cell Transplant 2010;19:179-84.
Amemori T, Jendelová P, Rùzicková K, Arboleda D, Syková E. Co-transplantation of olfactory ensheathing glia and mesenchymal stromal cells does not have synergistic effects after spinal cord injury in the rat. Cytotherapy 2010;12:212-25.
Ao Q, Wang AJ, Chen GQ, Wang SJ, Zuo HC, Zhang XF. Combined transplantation of neural stem cells and olfactory ensheathing cells for the repair of spinal cord injuries. Med Hypotheses 2007;69:1234-7.
Tofaris GK, Patterson PH, Jessen KR, Mirsky R. Denervated Schwann cells attract macrophages by secretion of leukemia inhibitory factor (LIF) and monocyte chemoattractant protein-1 in a process regulated by interleukin-6 and LIF. J Neurosci 2002;22:6696-703.
Dickson TC, Chung RS, McCormack GH, Staal JA, Vickers JC. Acute reactive and regenerative changes in mature cortical axons following injury. Neuroreport 2007;18:283-8.
Di Giovanni S. Molecular targets for axon regeneration: Focus on the intrinsic pathways. Expert Opin Ther Targets 2009;13:1387-98.
Park HW, Lim MJ, Jung H, Lee SP, Paik KS, Chang MS. Human mesenchymal stem cell-derived Schwann cell-like cells exhibit neurotrophic effects, via distinct growth factor production, in a model of spinal cord injury. Glia 2010;58:1118-32.
Biernaskie J, Sparling JS, Liu J, Shannon CP, Plemel JR, Xie Y, et al.
Skin-derived precursors generate myelinating Schwann cells that promote remyelination and functional recovery after contusion spinal cord injury. J Neurosci 2007;27:9545-59.
Xu Y, Liu L, Li Y, Zhou C, Xiong F, Liu Z, et al.
Myelin-forming ability of Schwann cell-like cells induced from rat adipose-derived stem cells in vitro
. Brain Res 2008;1239:49-55.
Xu Y, Liu Z, Liu L, Zhao C, Xiong F, Zhou C, et al.
Neurospheres from rat adipose-derived stem cells could be induced into functional Schwann cell-like cells in vitro
. BMC Neurosci 2008;9:21.
Biernaskie JA, McKenzie IA, Toma JG, Miller FD. Isolation of skin-derived precursors (SKPs) and differentiation and enrichment of their Schwann cell progeny. Nat Protoc 2006;1:2803-12.
Agudo M, Woodhoo A, Webber D, Mirsky R, Jessen KR, McMahon SB. Schwann cell precursors transplanted into the injured spinal cord multiply, integrate and are permissive for axon growth. Glia 2008;56:1263-70.
Deng LX, Hu J, Liu N, Wang X, Smith GM, Wen X, et al.
GDNF modifies reactive astrogliosis allowing robust axonal regeneration through Schwann cell-seeded guidance channels after spinal cord injury. Exp Neurol 2011;229:238-50.
Patel V, Joseph G, Patel A, Patel S, Bustin D, Mawson D, et al.
Suspension matrices for improved Schwann-cell survival after implantation into the injured rat spinal cord. J Neurotrauma 2010;27:789-801.
Ban DX, Ning GZ, Feng SQ, Wang Y, Zhou XH, Liu Y, et al.
Combination of activated Schwann cells with bone mesenchymal stem cells: The best cell strategy for repair after spinal cord injury in rats. Regen Med 2011;6:707-20.
Bunge MB, Pearse DD. Response to the report, "A re-assessment of a combinatorial treatment involving Schwann cell transplants and elevation of cyclic AMP on recovery of motor function following thoracic spinal cord injury in rats" by Sharp et al.
(this volume). Exp Neurol 2012;233:645-8.
Scott S, Kranz JE, Cole J, Lincecum JM, Thompson K, Kelly N, et al.
Design, power, and interpretation of studies in the standard murine model of ALS. Amyotroph Lateral Scler 2008;9:4-15.
Kanno H, Pressman Y, Moody A, Berg R, Muir EM, Rogers JH, et al.
Combination of engineered Schwann cell grafts to secrete neurotrophin and chondroitinase promotes axonal regeneration and locomotion after spinal cord injury. J Neurosci 2014;34:1838-55.
Chopp M, Zhang XH, Li Y, Wang L, Chen J, Lu D, et al.
Spinal cord injury in rat: Treatment with bone marrow stromal cell transplantation. Neuroreport 2000;11:3001-5.
Imaizumi T, Lankford KL, Waxman SG, Greer CA, Kocsis JD. Transplanted olfactory ensheathing cells remyelinate and enhance axonal conduction in the demyelinated dorsal columns of the rat spinal cord. J Neurosci 1998;18:6176-85.
Ramón-Cueto A, Plant GW, Avila J, Bunge MB. Long-distance axonal regeneration in the transected adult rat spinal cord is promoted by olfactory ensheathing glia transplants. J Neurosci 1998;18:3803-15.
Lu J, Féron F, Ho SM, Mackay-Sim A, Waite PM. Transplantation of nasal olfactory tissue promotes partial recovery in paraplegic adult rats. Brain Res 2001;889:344-57.
Clarkson ED, Zawada WM, Adams FS, Bell KP, Freed CR. Strands of embryonic mesencephalic tissue show greater dopamine neuron survival and better behavioral improvement than cell suspensions after transplantation in parkinsonian rats. Brain Res 1998;806:60-8.
Ramer LM, Au E, Richter MW, Liu J, Tetzlaff W, Roskams AJ. Peripheral olfactory ensheathing cells reduce scar and cavity formation and promote regeneration after spinal cord injury. J Comp Neurol 2004;473:1-15.
Au E, Roskams AJ. Olfactory ensheathing cells of the lamina propria in vivo
and in vitro
. Glia 2003;41:224-36.
Sasaki M, Honmou O, Akiyama Y, Uede T, Hashi K, Kocsis JD. Transplantation of an acutely isolated bone marrow fraction repairs demyelinated adult rat spinal cord axons. Glia 2001;35:26-34.
Burns AS, Lee BS, Ditunno JF Jr, Tessler A. Patient selection for clinical trials: The reliability of the early spinal cord injury examination. J Neurotrauma 2003;20:477-82.
Ichim TE, Solano F, Lara F, Paris E, Ugalde F, Rodriguez JP, et al.
Feasibility of combination allogeneic stem cell therapy for spinal cord injury: A case report. Int Arch Med 2010;3:30.
Kishk NA, Gabr H, Hamdy S, Afifi L, Abokresha N, Mahmoud H, et al.
Case control series of intrathecal autologous bone marrow mesenchymal stem cell therapy for chronic spinal cord injury. Neurorehabil Neural Repair 2010;24:702-8.
Bhanot Y, Rao S, Ghosh D, Balaraju S, Radhika CR, Satish Kumar KV. Autologous mesenchymal stem cells in chronic spinal cord injury. Br J Neurosurg 2011;25:516-22.
Park HC, Shim YS, Ha Y, Yoon SH, Park SR, Choi BH, et al.
Treatment of complete spinal cord injury patients by autologous bone marrow cell transplantation and administration of granulocyte-macrophage colony stimulating factor. Tissue Eng 2005;11:913-22.
Karamouzian S, Nematollahi-Mahani SN, Nakhaee N, Eskandary H. Clinical safety and primary efficacy of bone marrow mesenchymal cell transplantation in subacute spinal cord injured patients. Clin Neurol Neurosurg 2012;114:935-9.
Syková E, Homola A, Mazanec R, Lachmann H, Konrádová SL, Kobylka P, et al.
Autologous bone marrow transplantation in patients with subacute and chronic spinal cord injury. Cell Transplant 2006;15:675-87.
Yoon SH, Shim YS, Park YH, Chung JK, Nam JH, Kim MO, et al.
Complete spinal cord injury treatment using autologous bone marrow cell transplantation and bone marrow stimulation with granulocyte macrophage-colony stimulating factor: Phase I/II clinical trial. Stem Cells 2007;25:2066-73.
Jarocha D, Milczarek O, Kawecki Z, Wendrychowicz A, Kwiatkowski S, Majka M. Preliminary study of autologous bone marrow nucleated cells transplantation in children with spinal cord injury. Stem Cells Transl Med 2014;3:395-404.
Huang H, Chen L, Wang H, Xi H, Gou C, Zhang J, et al.
Safety of fetal olfactory ensheathing cell transplantation in patients with chronic spinal cord injury. A 38-month followup with MRI. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 2006;20:439-43.
Lima C, Pratas-Vital J, Escada P, Hasse-Ferreira A, Capucho C, Peduzzi JD. Olfactory mucosa autografts in human spinal cord injury: A pilot clinical study. J Spinal Cord Med 2006;29:191-203.
Chhabra HS, Lima C, Sachdeva S, Mittal A, Nigam V, Chaturvedi D, et al.
Autologous olfactory [corrected] mucosal transplant in chronic spinal cord injury: An Indian Pilot Study. Spinal Cord 2009;47:887-95.
Mackay-Sim A, Féron F, Cochrane J, Bassingthwaighte L, Bayliss C, Davies W, et al.
Autologous olfactory ensheathing cell transplantation in human paraplegia: A 3-year clinical trial. Brain 2008;131:2376-86.
Lammertse DP, Jones LA, Charlifue SB, Kirshblum SC, Apple DF, Ragnarsson KT, et al.
Autologous incubated macrophage therapy in acute, complete spinal cord injury: Results of the phase 2 randomized controlled multicenter trial. Spinal Cord 2012;50:661-71.
Zhou XH, Ning GZ, Feng SQ, Kong XH, Chen JT, Zheng YF, et al.
Transplantation of autologous activated Schwann cells in the treatment of spinal cord injury: Six cases, more than five years of followup. Cell Transplant 2012;21 Suppl 1:S39-47.
Saberi H, Moshayedi P, Aghayan HR, Arjmand B, Hosseini SK, Emami-Razavi SH, et al.
Treatment of chronic thoracic spinal cord injury patients with autologous Schwann cell transplantation: An interim report on safety considerations and possible outcomes. Neurosci Lett 2008;443:46-50.
Amr SM, Gouda A, Koptan WT, Galal AA, Abdel-Fattah DS, Rashed LA, et al.
Bridging defects in chronic spinal cord injury using peripheral nerve grafts combined with a chitosan-laminin scaffold and enhancing regeneration through them by co-transplantation with bone-marrow-derived mesenchymal stem cells: Case series of 14 patients. J Spinal Cord Med 2014;37:54-71.
Sahni V, Kessler JA. Stem cell therapies for spinal cord injury. Nat Rev Neurol 2010;6:363-72.
Martins-Taylor K, Xu RH. Concise review: Genomic stability of human induced pluripotent stem cells. Stem Cells 2012;30:22-7.
Bretzner F, Gilbert F, Baylis F, Brownstone RM. Target populations for first-in-human embryonic stem cell research in spinal cord injury. Cell Stem Cell 2011;8:468-75.
Lebkowski J. GRNOPC1: The world′s first embryonic stem cell-derived therapy. Interview with Jane Lebkowski. Regen Med 2011;6:11-3.
Blight A, Curt A, Ditunno JF, Dobkin B, Ellaway P, Fawcett J, et al.
Position statement on the sale of unproven cellular therapies for spinal cord injury: The international campaign for cures of spinal cord injury paralysis. Spinal Cord 2009;47:713-4.
Lammertse D, Tuszynski MH, Steeves JD, Curt A, Fawcett JW, Rask C, et al.
Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP panel: Clinical trial design. Spinal Cord 2007;45:232-42.
Steeves JD, Lammertse D, Curt A, Fawcett JW, Tuszynski MH, Ditunno JF, et al.
Guidelines for the conduct of clinical trials for spinal cord injury (SCI) as developed by the ICCP panel: Clinical trial outcome measures. Spinal Cord 2007;45:206-21.
Tuszynski MH, Steeves JD, Fawcett JW, Lammertse D, Kalichman M, Rask C, et al.
Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP Panel: Clinical trial inclusion/exclusion criteria and ethics. Spinal Cord 2007;45:222-31.
Harvinder Singh Chhabra
Indian Spinal Injuries Centre, Sector C, Vasant Kunj, New Delhi - 110 070
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2]
[Table 1], [Table 2]
|This article has been cited by|
||Autologous bone marrow cell transplantation in acute spinal cord injury—an Indian pilot study
| ||H S Chhabra,K Sarda,M Arora,R Sharawat,V Singh,A Nanda,G M Sangodimath,V Tandon |
| ||Spinal Cord. 2016; 54(1): 57 |
|[Pubmed] | [DOI]|
||Controversies and Potential Risk of Mesenchymal Stem Cells Application
| ||Islam Elboghdady,Hamid Hassanzadeh,Benjamin E. Stein,Howard S. An |
| ||Seminars in Spine Surgery. 2015; |
|[Pubmed] | [DOI]|
| Article Access Statistics|
| Viewed||2537 |
| Printed||55 |
| Emailed||1 |
| PDF Downloaded||321 |
| Comments ||[Add] |
| Cited by others ||2 |