Skip to main content

Advertisement

Log in

Stem cell therapy in spinal trauma: Does it have scientific validity?

  • Symposium-ICL-2014
  • Published:
Indian Journal of Orthopaedics Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Liverman CT, Altevogt BM, Joy JE, editors. Spinal Cord Injury: Progress, Promise and Priorities. Washington, DC: National Academies Press; 2005.

    Google Scholar 

  2. 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.

    Article  PubMed  Google Scholar 

  3. 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.

    Article  PubMed  CAS  Google Scholar 

  4. Yip PK, Malaspina A. Spinal cord trauma and the molecular point of no return. Mol Neurodegener 2012;7:6.

    Article  PubMed  PubMed Central  Google Scholar 

  5. 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.

    Article  PubMed  CAS  Google Scholar 

  6. 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.

  7. 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.

    Article  PubMed  CAS  Google Scholar 

  8. 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.

    Article  PubMed  CAS  Google Scholar 

  9. 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.

    Article  PubMed  CAS  Google Scholar 

  10. Norenberg MD, Smith J, Marcillo A. The pathology of human spinal cord injury: Defining the problems. J Neurotrauma 2004;21:429–40.

    Article  PubMed  Google Scholar 

  11. 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.

    Article  PubMed  CAS  Google Scholar 

  12. 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.

    Article  PubMed  CAS  Google Scholar 

  13. 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.

    Article  PubMed  Google Scholar 

  14. Yiu G, He Z. Glial inhibition of CNS axon regeneration. Nat Rev Neurosci 2006;7:617–27.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. 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.

    Article  PubMed  CAS  Google Scholar 

  16. Horner PJ, Gage FH. Regenerating the damaged central nervous system. Nature 2000;407:963–70.

    Article  PubMed  CAS  Google Scholar 

  17. 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.

    Article  PubMed  CAS  Google Scholar 

  18. Pearse DD, Bunge MB. Designing cell-and gene-based regeneration strategies to repair the injured spinal cord. J Neurotrauma 2006;23:438–52.

    Article  PubMed  CAS  Google Scholar 

  19. Blair K, Wray J, Smith A. The liberation of embryonic stem cells. PLoS Genet 2011;7:e1002019.

  20. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  21. 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.

  22. 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.

    Article  PubMed  CAS  Google Scholar 

  23. 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.

    Article  CAS  Google Scholar 

  24. 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.

    Article  PubMed  CAS  Google Scholar 

  25. 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.

    Article  PubMed  CAS  Google Scholar 

  26. 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. 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.

    Article  PubMed  CAS  Google Scholar 

  28. 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.

    Article  CAS  Google Scholar 

  29. 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.

    Article  PubMed  CAS  Google Scholar 

  30. 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.

    Article  PubMed  CAS  Google Scholar 

  31. 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.

    Article  PubMed  Google Scholar 

  32. 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.

    Article  CAS  Google Scholar 

  33. 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.

    Article  CAS  Google Scholar 

  34. 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

    Article  PubMed  CAS  Google Scholar 

  35. 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.

    Article  PubMed  Google Scholar 

  36. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  37. 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.

    PubMed  CAS  Google Scholar 

  38. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Lee TH. Functional effect of mouse embryonic stem cell implantation after spinal cord injury. J Exerc Rehabil 2013;9:230–3.

    Article  PubMed  PubMed Central  Google Scholar 

  40. 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.

    Google Scholar 

  41. 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.

    Article  PubMed  CAS  Google Scholar 

  42. 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.

    Article  PubMed  CAS  Google Scholar 

  43. Brazelton TR, Rossi FM, Keshet GI, Blau HM. From marrow to brain: Expression of neuronal phenotypes in adult mice. Science 2000;290:1775–9.

    Article  PubMed  CAS  Google Scholar 

  44. 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.

    Article  PubMed  CAS  Google Scholar 

  45. 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. 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.

    Article  PubMed  Google Scholar 

  47. 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.

    Article  PubMed  CAS  Google Scholar 

  48. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  49. 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.

    PubMed  Google Scholar 

  50. 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. 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.

    PubMed  Google Scholar 

  52. 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.

    Article  PubMed  CAS  Google Scholar 

  53. 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.

    Article  PubMed  Google Scholar 

  54. 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.

    Article  PubMed  Google Scholar 

  55. 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. 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.

    Article  PubMed  CAS  Google Scholar 

  57. 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.

    Article  PubMed  Google Scholar 

  58. 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.

    Article  PubMed  Google Scholar 

  59. 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.

    Article  PubMed  CAS  Google Scholar 

  60. 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.

    Article  PubMed  CAS  Google Scholar 

  61. 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.

    Article  PubMed  CAS  Google Scholar 

  62. 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.

    Article  PubMed  Google Scholar 

  63. 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.

    Article  CAS  Google Scholar 

  64. 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.

    Article  PubMed  Google Scholar 

  65. 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.

    Article  CAS  Google Scholar 

  66. 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.

    Article  PubMed  Google Scholar 

  67. 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.

    PubMed  PubMed Central  Google Scholar 

  68. 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.

    Article  PubMed  CAS  Google Scholar 

  69. 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.

    Article  PubMed  CAS  Google Scholar 

  70. 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.

    Article  PubMed  CAS  Google Scholar 

  71. 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. 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.

    Article  PubMed  Google Scholar 

  73. 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.

    Article  PubMed  CAS  Google Scholar 

  74. 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.

    Article  PubMed  Google Scholar 

  75. 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.

    Article  PubMed  Google Scholar 

  76. 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.

    Article  PubMed  CAS  Google Scholar 

  77. Temple S. Division and differentiation of isolated CNS blast cells in microculture. Nature 1989;340:471–3.

    Article  PubMed  CAS  Google Scholar 

  78. Reynolds BA, Weiss S. Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 1992;255:1707–10.

    Article  PubMed  CAS  Google Scholar 

  79. 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.

    Article  PubMed  CAS  Google Scholar 

  80. 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.

    Article  PubMed  CAS  Google Scholar 

  81. 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.

    Article  PubMed  CAS  Google Scholar 

  82. 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.

    Article  CAS  Google Scholar 

  83. 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.

    Article  PubMed  Google Scholar 

  84. 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. 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.

    Article  PubMed  Google Scholar 

  86. 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.

  87. 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.

    Article  PubMed  CAS  Google Scholar 

  88. 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.

    PubMed  PubMed Central  CAS  Google Scholar 

  89. Ramon-Cueto A, Avila J. Olfactory ensheathing glia: Properties and function. Brain Res Bull 1998;46:175–87.

    Article  PubMed  CAS  Google Scholar 

  90. 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.

    Article  PubMed  Google Scholar 

  91. 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.

    Article  PubMed  CAS  Google Scholar 

  92. 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.

    Article  PubMed  Google Scholar 

  93. 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.

    Article  PubMed  CAS  Google Scholar 

  94. Ramon-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.

    Article  PubMed  CAS  Google Scholar 

  95. 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.

    PubMed  CAS  Google Scholar 

  96. 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Collazos-Castro JE, Muneton-Gomez VC, Nieto-Sampedro M. Olfactory glia transplantation into cervical spinal cord contusion injuries. J Neurosurg Spine 2005;3:308–17.

    Article  PubMed  Google Scholar 

  99. 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.

    Article  PubMed  CAS  Google Scholar 

  100. 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.

    Article  PubMed  Google Scholar 

  101. 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. 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.

    PubMed  Google Scholar 

  103. 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.

    Article  PubMed  CAS  Google Scholar 

  104. Munoz-Quiles C, Santos-Benito FF, Llamusí MB, Ramon-Cueto A. Chronic spinal injury repair by olfactory bulb ensheathing glia and feasibility for autologous therapy. J Neuropathol Exp Neurol 2009;68:1294–308.

    Article  PubMed  Google Scholar 

  105. Li J, Lepski G. Cell transplantation for spinal cord injury: A systematic review. Biomed Res Int 2013;2013:786475.

    PubMed  PubMed Central  Google Scholar 

  106. 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.

    Article  PubMed  Google Scholar 

  107. Ziegler MD, Hsu D, Takeoka A, Zhong H, Ramon-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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. 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.

    Article  PubMed  Google Scholar 

  109. 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.

    Article  PubMed  CAS  Google Scholar 

  110. 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.

    Article  PubMed  Google Scholar 

  111. 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.

    PubMed  CAS  Google Scholar 

  112. 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.

    Article  PubMed  Google Scholar 

  113. Amemori T, Jendelová P, Růzicková 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.

    Article  PubMed  CAS  Google Scholar 

  114. 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.

    Article  PubMed  CAS  Google Scholar 

  115. 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. 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.

    Article  PubMed  Google Scholar 

  117. Di Giovanni S. Molecular targets for axon regeneration: Focus on the intrinsic pathways. Expert Opin Ther Targets 2009;13:1387–98.

    Article  PubMed  Google Scholar 

  118. 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.

    Article  PubMed  Google Scholar 

  119. 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. 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.

    Article  PubMed  CAS  Google Scholar 

  121. 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  122. 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.

    Article  PubMed  CAS  Google Scholar 

  123. 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.

    Article  PubMed  CAS  Google Scholar 

  124. 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  126. 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.

    Article  PubMed  CAS  Google Scholar 

  127. 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.

    Article  PubMed  CAS  Google Scholar 

  128. 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.

    Article  PubMed  CAS  Google Scholar 

  129. 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. 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.

    Article  PubMed  CAS  Google Scholar 

  131. 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. Ramon-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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. 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.

    Article  PubMed  CAS  Google Scholar 

  134. 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.

    Article  PubMed  CAS  Google Scholar 

  135. 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.

    Article  PubMed  Google Scholar 

  136. Au E, Roskams AJ. Olfactory ensheathing cells of the lamina propria in vivo and in vitro. Glia 2003;41:224–36.

    Article  PubMed  Google Scholar 

  137. 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  138. 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.

    Article  PubMed  Google Scholar 

  139. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  140. 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.

    Article  PubMed  Google Scholar 

  141. 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.

    Article  PubMed  Google Scholar 

  142. 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.

    Article  PubMed  CAS  Google Scholar 

  143. 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.

    Article  PubMed  Google Scholar 

  144. 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.

    Article  PubMed  Google Scholar 

  145. 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.

    Article  PubMed  Google Scholar 

  146. 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  147. 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.

    PubMed  Google Scholar 

  148. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  149. 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.

    Article  PubMed  CAS  Google Scholar 

  150. 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  151. 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.

    Article  PubMed  CAS  Google Scholar 

  152. 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.

    Article  PubMed  Google Scholar 

  153. 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.

    Article  PubMed  CAS  Google Scholar 

  154. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  155. Sahni V, Kessler JA. Stem cell therapies for spinal cord injury. Nat Rev Neurol 2010;6:363–72.

    Article  PubMed  PubMed Central  Google Scholar 

  156. Martins-Taylor K, Xu RH. Concise review: Genomic stability of human induced pluripotent stem cells. Stem Cells 2012;30:22–7.

    Article  PubMed  CAS  Google Scholar 

  157. 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.

    Article  PubMed  CAS  Google Scholar 

  158. Lebkowski J. GRNOPC1: The world’s first embryonic stem cell-derived therapy. Interview with Jane Lebkowski. Regen Med 2011;6:11–3.

    Article  PubMed  Google Scholar 

  159. www.elearnSCI.org: A global educational initiatives [Spinal Cord, 2013]-PubMed-NCBI. Available from: http://www.ncbi.nlm.nih.gov/pubmed/?term=elearnSCI. [Last cited on 2014 Apr 02].

  160. 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.

    Article  PubMed  CAS  Google Scholar 

  161. 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.

    Article  PubMed  CAS  Google Scholar 

  162. 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.

    Article  PubMed  CAS  Google Scholar 

  163. 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.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Harvinder Singh Chhabra.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chhabra, H.S., Sarda, K. Stem cell therapy in spinal trauma: Does it have scientific validity?. IJOO 49, 54–71 (2015). https://doi.org/10.4103/0019-5413.143913

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.4103/0019-5413.143913

Key words

MeSH terms

Navigation