Advertisement

Cell and Tissue Research

, Volume 349, Issue 1, pp 349–362 | Cite as

Neural stem cells for spinal cord repair

  • Beatrice Sandner
  • Peter Prang
  • Francisco J. Rivera
  • Ludwig Aigner
  • Armin Blesch
  • Norbert Weidner
Review

Abstract

Spinal cord injury (SCI) causes the irreversible loss of spinal cord parenchyma including astroglia, oligodendroglia and neurons. In particular, severe injuries can lead to an almost complete neural cell loss at the lesion site and structural and functional recovery might only be accomplished by appropriate cell and tissue replacement. Stem cells have the capacity to differentiate into all relevant neural cell types necessary to replace degenerated spinal cord tissue and can now be obtained from virtually any stage of development. Within the last two decades, many in vivo studies in small animal models of SCI have demonstrated that stem cell transplantation can promote morphological and, in some cases, functional recovery via various mechanisms including remyelination, axon growth and regeneration, or neuronal replacement. However, only two well-documented neural-stem-cell-based transplantation strategies have moved to phase I clinical trials to date. This review aims to provide an overview about the current status of preclinical and clinical neural stem cell transplantation and discusses future perspectives in the field.

Keywords

Stem cell Remyelination Transplantation Axon Regeneration 

References

  1. Abematsu M, Tsujimura K, Yamano M, Saito M, Kohno K, Kohyama J, Namihira M, Komiya S, Nakashima K (2010) Neurons derived from transplanted neural stem cells restore disrupted neuronal circuitry in a mouse model of spinal cord injury. J Clin Invest 120:3255–3266PubMedGoogle Scholar
  2. Akiyama Y, Honmou O, Kato T, Uede T, Hashi K, Kocsis JD (2001) Transplantation of clonal neural precursor cells derived from adult human brain establishes functional peripheral myelin in the rat spinal cord. Exp Neurol 167:27–39PubMedGoogle Scholar
  3. Akiyama Y, Lankford K, Radtke C, Greer CA, Kocsis JD (2004) Remyelination of spinal cord axons by olfactory ensheathing cells and Schwann cells derived from a transgenic rat expressing alkaline phosphatase marker gene. Neuron Glia Biol 1:47–55PubMedGoogle Scholar
  4. Ankeny DP, McTigue DM, Jakeman LB (2004) Bone marrow transplants provide tissue protection and directional guidance for axons after contusive spinal cord injury in rats. Exp Neurol 190:17–31PubMedGoogle Scholar
  5. Archer DR, Cuddon PA, Lipsitz D, Duncan ID (1997) Myelination of the canine central nervous system by glial cell transplantation: a model for repair of human myelin disease. Nat Med 3:54–59PubMedGoogle Scholar
  6. Arsenijevic Y, Villemure JG, Brunet JF, Bloch JJ, Deglon N, Kostic C, Zurn A, Aebischer P (2001) Isolation of multipotent neural precursors residing in the cortex of the adult human brain. Exp Neurol 170:48–62PubMedGoogle Scholar
  7. Barnabe-Heider F, Frisen J (2008) Stem cells for spinal cord repair. Cell Stem Cell 3:16–24PubMedGoogle Scholar
  8. Basso DM, Beattie MS, Bresnahan JC (1996) Graded histological and locomotor outcomes after spinal cord contusion using the NYU weight-drop device versus transection. Exp Neurol 139:244–256PubMedGoogle Scholar
  9. Bernstein-Goral H, Bregman BS (1993) Spinal cord transplants support the regeneration of axotomized neurons after spinal cord lesions at birth: a quantitative double-labeling study. Exp Neurol 123:118–132PubMedGoogle Scholar
  10. Bernstein-Goral H, Bregman BS (1997) Axotomized rubrospinal neurons rescued by fetal spinal cord transplants maintain axon collaterals to rostral CNS targets. Exp Neurol 148:13–25PubMedGoogle Scholar
  11. Blakemore WF, Crang AJ (1985) The use of cultured autologous Schwann cells to remyelinate areas of persistent demyelination in the central nervous system. J Neurol Sci 70:207–223PubMedGoogle Scholar
  12. Bonner JF, Blesch A, Neuhuber B, Fischer I (2010) Promoting directional axon growth from neural progenitors grafted into the injured spinal cord. J Neurosci Res 88:1182–1192PubMedGoogle Scholar
  13. Bonner JF, Connors TM, Silverman WF, Kowalski DP, Lemay MA, Fischer I (2011) Grafted neural progenitors integrate and restore synaptic connectivity across the injured spinal cord. J Neurosci 31:4675–4686PubMedGoogle Scholar
  14. Bregman BS (1987a) Development of serotonin immunoreactivity in the rat spinal cord and its plasticity after neonatal spinal cord lesions. Brain Res 431:245–263PubMedGoogle Scholar
  15. Bregman BS (1987b) Spinal cord transplants permit the growth of serotonergic axons across the site of neonatal spinal cord transection. Brain Res 431:265–279PubMedGoogle Scholar
  16. Bregman BS, Reier PJ (1986) Neural tissue transplants rescue axotomized rubrospinal cells from retrograde death. J Comp Neurol 244:86–95PubMedGoogle Scholar
  17. Bregman BS, Kunkel-Bagden E, Reier PJ, Dai HN, McAtee M, Gao D (1993) Recovery of function after spinal cord injury: mechanisms underlying transplant-mediated recovery of function differ after spinal cord injury in newborn and adult rats. Exp Neurol 123:3–16PubMedGoogle Scholar
  18. Bregman BS, Diener PS, McAtee M, Dai HN, James C (1997) Intervention strategies to enhance anatomical plasticity and recovery of function after spinal cord injury. Adv Neurol 72:257–275PubMedGoogle Scholar
  19. Busch SA, Silver J (2007) The role of extracellular matrix in CNS regeneration. Curr Opin Neurobiol 17:120–127PubMedGoogle Scholar
  20. Callera F, Nascimento RX do (2006) Delivery of autologous bone marrow precursor cells into the spinal cord via lumbar puncture technique in patients with spinal cord injury: a preliminary safety study. Exp Hematol 34:130–131PubMedGoogle Scholar
  21. Cao QL, Zhang YP, Howard RM, Walters WM, Tsoulfas P, Whittemore SR (2001) Pluripotent stem cells engrafted into the normal or lesioned adult rat spinal cord are restricted to a glial lineage. Exp Neurol 167:48–58PubMedGoogle Scholar
  22. Cao QL, Howard RM, Dennison JB, Whittemore SR (2002) Differentiation of engrafted neuronal-restricted precursor cells is inhibited in the traumatically injured spinal cord. Exp Neurol 177:349–359PubMedGoogle Scholar
  23. Cao Q, Xu XM, Devries WH, Enzmann GU, Ping P, Tsoulfas P, Wood PM, Bunge MB, Whittemore SR (2005) Functional recovery in traumatic spinal cord injury after transplantation of multineurotrophin-expressing glial-restricted precursor cells. J Neurosci 25:6947–6957PubMedGoogle Scholar
  24. Cao Q, He Q, Wang Y, Cheng X, Howard RM, Zhang Y, DeVries WH, Shields CB, Magnuson DS, Xu XM, Kim DH, Whittemore SR (2010) Transplantation of ciliary neurotrophic factor-expressing adult oligodendrocyte precursor cells promotes remyelination and functional recovery after spinal cord injury. J Neurosci 30:2989–3001PubMedGoogle Scholar
  25. Caplan AI (2007) Adult mesenchymal stem cells for tissue engineering versus regenerative medicine. J Cell Physiol 213:341–347PubMedGoogle Scholar
  26. Castro RF, Jackson KA, Goodell MA, Robertson CS, Liu H, Shine HD (2002) Failure of bone marrow cells to transdifferentiate into neural cells in vivo. Science 297:1299PubMedGoogle Scholar
  27. Chernykh ER, Stupak VV, Muradov GM, Sizikov MY, Shevela EY, Leplina OY, Tikhonova MA, Kulagin AD, Lisukov IA, Ostanin AA, Kozlov VA (2007) Application of autologous bone marrow stem cells in the therapy of spinal cord injury patients. Bull Exp Biol Med 143:543–547PubMedGoogle Scholar
  28. Cho JS, Park HW, Park SK, Roh S, Kang SK, Paik KS, Chang MS (2009) Transplantation of mesenchymal stem cells enhances axonal outgrowth and cell survival in an organotypic spinal cord slice culture. Neurosci Lett 454:43–48PubMedGoogle Scholar
  29. Collins WF (1983) A review and update of experiment and clinical studies of spinal cord injury. Paraplegia 21:204–219PubMedGoogle Scholar
  30. Cummings BJ, Uchida N, Tamaki SJ, Salazar DL, Hooshmand M, Summers R, Gage FH, Anderson AJ (2005) Human neural stem cells differentiate and promote locomotor recovery in spinal cord-injured mice. Proc Natl Acad Sci USA 102:14069–14074PubMedGoogle Scholar
  31. Cummings BJ, Uchida N, Tamaki SJ, Anderson AJ (2006) Human neural stem cell differentiation following transplantation into spinal cord injured mice: association with recovery of locomotor function. Neurol Res 28:474–481PubMedGoogle Scholar
  32. Davies JE, Huang C, Proschel C, Noble M, Mayer-Proschel M, Davies SJ (2006) Astrocytes derived from glial-restricted precursors promote spinal cord repair. J Biol 5:7PubMedGoogle Scholar
  33. Dawson MR, Levine JM, Reynolds R (2000) NG2-expressing cells in the central nervous system: are they oligodendroglial progenitors? J Neurosci Res 61:471–479PubMedGoogle Scholar
  34. Deda H, Inci MC, Kurekci AE, Kayihan K, Ozgun E, Ustunsoy GE, Kocabay S (2008) Treatment of chronic spinal cord injured patients with autologous bone marrow-derived hematopoietic stem cell transplantation: 1-year follow-up. Cytotherapy 10:565–574PubMedGoogle Scholar
  35. Diener PS, Bregman BS (1998) Fetal spinal cord transplants support the development of target reaching and coordinated postural adjustments after neonatal cervical spinal cord injury. J Neurosci 18:763–778PubMedGoogle Scholar
  36. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop D, Horwitz E (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8:315–317PubMedGoogle Scholar
  37. Erceg S, Ronaghi M, Stojkovic M (2009) Human embryonic stem cell differentiation toward regional specific neural precursors. Stem Cells 27:78–87PubMedGoogle Scholar
  38. Evans MJ, Kaufman MH (1981) Establishment in culture of pluripotential cells from mouse embryos. Nature 292:154–156PubMedGoogle Scholar
  39. Fawcett JW, Curt A, Steeves JD, Coleman WP, Tuszynski MH, Lammertse D, Bartlett PF, Blight AR, Dietz V, Ditunno J, Dobkin BH, Havton LA, Ellaway PH, Fehlings MG, Privat A, Grossman R, Guest JD, Kleitman N, Nakamura M, Gaviria M, Short D (2007) Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP panel: spontaneous recovery after spinal cord injury and statistical power needed for therapeutic clinical trials. Spinal Cord 45:190–205PubMedGoogle Scholar
  40. Field P, Li Y, Raisman G (2003) Ensheathment of the olfactory nerves in the adult rat. J Neurocytol 32:317–324PubMedGoogle Scholar
  41. Franklin RJ (2002) Remyelination of the demyelinated CNS: the case for and against transplantation of central, peripheral and olfactory glia. Brain Res Bull 57:827–832PubMedGoogle Scholar
  42. Gage FH, Coates PW, Palmer TD, Kuhn HG, Fisher LJ, Suhonen JO, Peterson DA, Suhr ST, Ray J (1995) Survival and differentiation of adult neuronal progenitor cells transplanted to the adult brain. Proc Natl Acad Sci USA 92:11879–11883PubMedGoogle Scholar
  43. Gaillard A, Prestoz L, Dumartin B, Cantereau A, Morel F, Roger M, Jaber M (2007) Reestablishment of damaged adult motor pathways by grafted embryonic cortical neurons. Nat Neurosci 10:1294–1299PubMedGoogle Scholar
  44. Geffner LF, Santacruz P, Izurieta M, Flor L, Maldonado B, Auad AH, Montenegro X, Gonzalez R, Silva F (2008) Administration of autologous bone marrow stem cells into spinal cord injury patients via multiple routes is safe and improves their quality of life: comprehensive case studies. Cell Transplant 17:1277–1293PubMedGoogle Scholar
  45. Giger RJ, Hollis ER 2nd, Tuszynski MH (2010) Guidance molecules in axon regeneration. Cold Spring Harb Perspect Biol 2:a001867PubMedGoogle Scholar
  46. Gledhill RF, Harrison BM, McDonald WI (1973) Demyelination and remyelination after acute spinal cord compression. Exp Neurol 38:472–487PubMedGoogle Scholar
  47. Gregori N, Proschel C, Noble M, Mayer-Proschel M (2002) The tripotential glial-restricted precursor (GRP) cell and glial development in the spinal cord: generation of bipotential oligodendrocyte-type-2 astrocyte progenitor cells and dorsal-ventral differences in GRP cell function. J Neurosci 22:248–256PubMedGoogle Scholar
  48. Grill R, Murai K, Blesch A, Gage FH, Tuszynski MH (1997) Cellular delivery of neurotrophin-3 promotes corticospinal axonal growth and partial functional recovery after spinal cord injury. J Neurosci 17:5560–5572PubMedGoogle Scholar
  49. Gritti A, Parati EA, Cova L, Frolichsthal P, Galli R, Wanke E, Faravelli L, Morassutti DJ, Roisen F, Nickel DD, Vescovi AL (1996) Multipotential stem cells from the adult mouse brain proliferate and self-renew in response to basic fibroblast growth factor. J Neurosci 16:1091–1100PubMedGoogle Scholar
  50. Groopman J (2003) The Reeve effect. The New Yorker, Nov 10:82-93Google Scholar
  51. Groves AK, Barnett SC, Franklin RJ, Crang AJ, Mayer M, Blakemore WF, Noble M (1993) Repair of demyelinated lesions by transplantation of purified O-2A progenitor cells. Nature 362:453–455PubMedGoogle Scholar
  52. Han SS, Liu Y, Tyler-Polsz C, Rao MS, Fischer I (2004) Transplantation of glial-restricted precursor cells into the adult spinal cord: survival, glial-specific differentiation, and preferential migration in white matter. Glia 45:1–16PubMedGoogle Scholar
  53. Harris DT (2008) Cord blood stem cells: a review of potential neurological applications. Stem Cell Rev 4:269–274PubMedGoogle Scholar
  54. Hofstetter CP, Schwarz EJ, Hess D, Widenfalk J, El Manira A, Prockop DJ, Olson L (2002) Marrow stromal cells form guiding strands in the injured spinal cord and promote recovery. Proc Natl Acad Sci USA 99:2199–2204PubMedGoogle Scholar
  55. Hofstetter CP, Holmstrom NA, Lilja JA, Schweinhardt P, Hao J, Spenger C, Wiesenfeld-Hallin Z, Kurpad SN, Frisen J, Olson L (2005) Allodynia limits the usefulness of intraspinal neural stem cell grafts; directed differentiation improves outcome. Nat Neurosci 8:346–353PubMedGoogle Scholar
  56. Honmou O, Felts PA, Waxman SG, Kocsis JD (1996) Restoration of normal conduction properties in demyelinated spinal cord axons in the adult rat by transplantation of exogenous Schwann cells. J Neurosci 16:3199–3208PubMedGoogle Scholar
  57. Hooshmand MJ, Sontag CJ, Uchida N, Tamaki S, Anderson AJ, Cummings BJ (2009) Analysis of host-mediated repair mechanisms after human CNS-stem cell transplantation for spinal cord injury: correlation of engraftment with recovery. PLoS One 4:e5871PubMedGoogle Scholar
  58. Houle JD, Reier PJ (1988) Transplantation of fetal spinal cord tissue into the chronically injured adult rat spinal cord. J Comp Neurol 269:535–547PubMedGoogle Scholar
  59. Hu YF, Gourab K, Wells C, Clewes O, Schmit BD, Sieber-Blum M (2010) Epidermal neural crest stem cell (EPI-NCSC)–mediated recovery of sensory function in a mouse model of spinal cord injury. Stem Cell Rev 6:186–198PubMedGoogle Scholar
  60. Hulsebosch CE (2002) Recent advances in pathophysiology and treatment of spinal cord injury. Adv Physiol Educ 26:238–255PubMedGoogle Scholar
  61. Imaizumi T, Lankford KL, Kocsis JD (2000) Transplantation of olfactory ensheathing cells or Schwann cells restores rapid and secure conduction across the transected spinal cord. Brain Res 854:70–78PubMedGoogle Scholar
  62. Ishii K, Nakamura M, Dai H, Finn TP, Okano H, Toyama Y, Bregman BS (2006) Neutralization of ciliary neurotrophic factor reduces astrocyte production from transplanted neural stem cells and promotes regeneration of corticospinal tract fibers in spinal cord injury. J Neurosci Res 84:1669–1681PubMedGoogle Scholar
  63. Iwanami A, Kaneko S, Nakamura M, Kanemura Y, Mori H, Kobayashi S, Yamasaki M, Momoshima S, Ishii H, Ando K, Tanioka Y, Tamaoki N, Nomura T, Toyama Y, Okano H (2005) Transplantation of human neural stem cells for spinal cord injury in primates. J Neurosci Res 80:182–190PubMedGoogle Scholar
  64. Jin Y, Fischer I, Tessler A, Houle JD (2002) Transplants of fibroblasts genetically modified to express BDNF promote axonal regeneration from supraspinal neurons following chronic spinal cord injury. Exp Neurol 177:265–275PubMedGoogle Scholar
  65. Johansson CB, Svensson M, Wallstedt L, Janson AM, Frisen J (1999) Neural stem cells in the adult human brain. Exp Cell Res 253:733–736PubMedGoogle Scholar
  66. Johe KK, Hazel TG, Muller T, Dugich-Djordjevic MM, McKay RD (1996) Single factors direct the differentiation of stem cells from the fetal and adult central nervous system. Genes Dev 10:3129–3140PubMedGoogle Scholar
  67. Kakulas BA (1999) A review of the neuropathology of human spinal cord injury with emphasis on special features. J Spinal Cord Med 22:119–124PubMedGoogle Scholar
  68. Kalyani AJ, Rao MS (1998) Cell lineage in the developing neural tube. Biochem Cell Biol 76:1051–1068PubMedGoogle Scholar
  69. Karimi-Abdolrezaee S, Eftekharpour E, Wang J, Morshead CM, Fehlings MG (2006) Delayed transplantation of adult neural precursor cells promotes remyelination and functional neurological recovery after spinal cord injury. J Neurosci 26:3377–3389PubMedGoogle Scholar
  70. Keating A (2006) Mesenchymal stromal cells. Curr Opin Hematol 13:419–425PubMedGoogle Scholar
  71. Keirstead HS, Nistor G, Bernal G, Totoiu M, Cloutier F, Sharp K, Steward O (2005) Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury. J Neurosci 25:4694–4705PubMedGoogle Scholar
  72. Kobylka P, Ivanyi P, Breur-Vriesendorp BS (1998) Preservation of immunological and colony-forming capacities of long-term (15 years) cryopreserved cord blood cells. Transplantation 65:1275–1278PubMedGoogle Scholar
  73. Kohama I, Lankford KL, Preiningerova J, White FA, Vollmer TL, Kocsis JD (2001) Transplantation of cryopreserved adult human Schwann cells enhances axonal conduction in demyelinated spinal cord. J Neurosci 21:944–950PubMedGoogle Scholar
  74. Krabbe C, Zimmer J, Meyer M (2005) Neural transdifferentiation of mesenchymal stem cells—a critical review. APMIS 113:831–844PubMedGoogle Scholar
  75. Kumar AA, Kumar SR, Narayanan R, Arul K, Baskaran M (2009) Autologous bone marrow derived mononuclear cell therapy for spinal cord injury: a phase I/II clinical safety and primary efficacy data. Exp Clin Transplant 7:241–248PubMedGoogle Scholar
  76. Kunkel-Bagden E, Dai HN, Bregman BS (1992) Recovery of function after spinal cord hemisection in newborn and adult rats: differential effects on reflex and locomotor function. Exp Neurol 116:40–51PubMedGoogle Scholar
  77. Lammertse D, Tuszynski MH, Steeves JD, Curt A, Fawcett JW, Rask C, Ditunno JF, Fehlings MG, Guest JD, Ellaway PH, Kleitman N, Blight AR, Dobkin BH, Grossman R, Katoh H, Privat A, Kalichman M (2007) Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP panel: clinical trial design. Spinal Cord 45:232–242PubMedGoogle Scholar
  78. Levine JM, Reynolds R (1999) Activation and proliferation of endogenous oligodendrocyte precursor cells during ethidium bromide-induced demyelination. Exp Neurol 160:333–347PubMedGoogle Scholar
  79. Levine JM, Stincone F, Lee YS (1993) Development and differentiation of glial precursor cells in the rat cerebellum. Glia 7:307–321PubMedGoogle Scholar
  80. Levine JM, Reynolds R, Fawcett JW (2001) The oligodendrocyte precursor cell in health and disease. Trends Neurosci 24:39–47PubMedGoogle Scholar
  81. Li Y, Field PM, Raisman G (1997) Repair of adult rat corticospinal tract by transplants of olfactory ensheathing cells. Science 277:2000–2002PubMedGoogle Scholar
  82. Lu J, Feron F, Mackay-Sim A, Waite PM (2002) Olfactory ensheathing cells promote locomotor recovery after delayed transplantation into transected spinal cord. Brain 125:14–21PubMedGoogle Scholar
  83. Lu P, Tuszynski MH (2008) Growth factors and combinatorial therapies for CNS regeneration. Exp Neurol 209:313–320PubMedGoogle Scholar
  84. Lu P, Blesch A, Tuszynski MH (2004a) Induction of bone marrow stromal cells to neurons: differentiation, transdifferentiation, or artifact? J Neurosci Res 77:174–191PubMedGoogle Scholar
  85. Lu P, Yang H, Jones LL, Filbin MT, Tuszynski MH (2004b) Combinatorial therapy with neurotrophins and cAMP promotes axonal regeneration beyond sites of spinal cord injury. J Neurosci 24:6402–6409PubMedGoogle Scholar
  86. Lu P, Jones LL, Tuszynski MH (2005) BDNF-expressing marrow stromal cells support extensive axonal growth at sites of spinal cord injury. Exp Neurol 191:344–360PubMedGoogle Scholar
  87. Lu P, Yang H, Culbertson M, Graham L, Roskams AJ, Tuszynski MH (2006) Olfactory ensheathing cells do not exhibit unique migratory or axonal growth-promoting properties after spinal cord injury. J Neurosci 26:11120–11130PubMedGoogle Scholar
  88. Lu P, Jones LL, Tuszynski MH (2007) Axon regeneration through scars and into sites of chronic spinal cord injury. Exp Neurol 203:8–21PubMedGoogle Scholar
  89. Lu P, Wang L, Graham K, Banosi M, Brock A, Blesch A, Havten M, Tuszynski MH (2010) Embryonic spinal cord neurons from GFP rats extend axons over long distances and form synapses after adult spinal cord injury. Program no. 7621/Q18 2010 Neuroscience Meeting Planner. Society for Neuroscience, 2010 Online, San DiegoGoogle Scholar
  90. Maherali N, Hochedlinger K (2008) Guidelines and techniques for the generation of induced pluripotent stem cells. Cell Stem Cell 3:595–605PubMedGoogle Scholar
  91. Maherali N, Sridharan R, Xie W, Utikal J, Eminli S, Arnold K, Stadtfeld M, Yachechko R, Tchieu J, Jaenisch R, Plath K, Hochedlinger K (2007) Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution. Cell Stem Cell 1:55–70PubMedGoogle Scholar
  92. Marcus AJ, Woodbury D (2008) Fetal stem cells from extra-embryonic tissues: do not discard. J Cell Mol Med 12:730–742PubMedGoogle Scholar
  93. Martin GR (1981) Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci USA 78:7634–7638PubMedGoogle Scholar
  94. Mayer-Proschel M, Kalyani AJ, Mujtaba T, Rao MS (1997) Isolation of lineage-restricted neuronal precursors from multipotent neuroepithelial stem cells. Neuron 19:773–785PubMedGoogle Scholar
  95. Mayor S (2010) First patient enters trial to test safety of stem cells in spinal injury. BMJ 341:c5724PubMedGoogle Scholar
  96. McDonald JW, Liu XZ, Qu Y, Liu S, Mickey SK, Turetsky D, Gottlieb DI, Choi DW (1999) Transplanted embryonic stem cells survive, differentiate and promote recovery in injured rat spinal cord. Nat Med 5:1410–1412PubMedGoogle Scholar
  97. McKinnon RD, Waldron S, Kiel ME (2005) PDGF alpha-receptor signal strength controls an RTK rheostat that integrates phosphoinositol 3′-kinase and phospholipase Cgamma pathways during oligodendrocyte maturation. J Neurosci 25:3499–3508PubMedGoogle Scholar
  98. Mitsui T, Shumsky JS, Lepore AC, Murray M, Fischer I (2005) Transplantation of neuronal and glial restricted precursors into contused spinal cord improves bladder and motor functions, decreases thermal hypersensitivity, and modifies intraspinal circuitry. J Neurosci 25:9624–9636PubMedGoogle Scholar
  99. Mothe AJ, Tator CH (2008) Transplanted neural stem/progenitor cells generate myelinating oligodendrocytes and Schwann cells in spinal cord demyelination and dysmyelination. Exp Neurol 213:176–190PubMedGoogle Scholar
  100. Mujtaba T, Piper DR, Kalyani A, Groves AK, Lucero MT, Rao MS (1999) Lineage-restricted neural precursors can be isolated from both the mouse neural tube and cultured ES cells. Dev Biol 214:113–127PubMedGoogle Scholar
  101. Nakagawa M, Koyanagi M, Tanabe K, Takahashi K, Ichisaka T, Aoi T, Okita K, Mochiduki Y, Takizawa N, Yamanaka S (2008) Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol 26:101–106PubMedGoogle Scholar
  102. Neuhuber B, Timothy Himes B, Shumsky JS, Gallo G, Fischer I (2005) Axon growth and recovery of function supported by human bone marrow stromal cells in the injured spinal cord exhibit donor variations. Brain Res 1035:73–85PubMedGoogle Scholar
  103. Newman MB, Davis CD, Kuzmin-Nichols N, Sanberg PR (2003) Human umbilical cord blood (HUCB) cells for central nervous system repair. Neurotox Res 5:355–368PubMedGoogle Scholar
  104. Nistor GI, Totoiu MO, Haque N, Carpenter MK, Keirstead HS (2005) Human embryonic stem cells differentiate into oligodendrocytes in high purity and myelinate after spinal cord transplantation. Glia 49:385–396PubMedGoogle Scholar
  105. Nussbaum J, Minami E, Laflamme MA, Virag JA, Ware CB, Masino A, Muskheli V, Pabon L, Reinecke H, Murry CE (2007) Transplantation of undifferentiated murine embryonic stem cells in the heart: teratoma formation and immune response. FASEB J 21:1345–1357PubMedGoogle Scholar
  106. O'Donoghue K, Fisk NM (2004) Fetal stem cells. Best Pract Res Clin Obstet Gynaecol 18:853–875PubMedGoogle Scholar
  107. Ogawa Y, Sawamoto K, Miyata T, Miyao S, Watanabe M, Nakamura M, Bregman BS, Koike M, Uchiyama Y, Toyama Y, Okano H (2002) Transplantation of in vitro-expanded fetal neural progenitor cells results in neurogenesis and functional recovery after spinal cord contusion injury in adult rats. J Neurosci Res 69:925–933PubMedGoogle Scholar
  108. Okada S, Ishii K, Yamane J, Iwanami A, Ikegami T, Katoh H, Iwamoto Y, Nakamura M, Miyoshi H, Okano HJ, Contag CH, Toyama Y, Okano H (2005) In vivo imaging of engrafted neural stem cells: its application in evaluating the optimal timing of transplantation for spinal cord injury. FASEB J 19:1839–1841PubMedGoogle Scholar
  109. Okita K, Yamanaka S (2011) Induced pluripotent stem cells: opportunities and challenges. Philos Trans R Soc Lond B Biol Sci 366:2198–2207PubMedGoogle Scholar
  110. Pal R, Venkataramana NK, Bansal A, Balaraju S, Jan M, Chandra R, Dixit A, Rauthan A, Murgod U, Totey S (2009) Ex vivo-expanded autologous bone marrow-derived mesenchymal stromal cells in human spinal cord injury/paraplegia: a pilot clinical study. Cytotherapy 11:897–911PubMedGoogle Scholar
  111. Palmer TD, Ray J, Gage FH (1995) FGF-2-responsive neuronal progenitors reside in proliferative and quiescent regions of the adult rodent brain. Mol Cell Neurosci 6:474–486PubMedGoogle Scholar
  112. Palmer TD, Markakis EA, Willhoite AR, Safar F, Gage FH (1999) Fibroblast growth factor-2 activates a latent neurogenic program in neural stem cells from diverse regions of the adult CNS. J Neurosci 19:8487–8497PubMedGoogle Scholar
  113. Park DH, Lee JH, Borlongan CV, Sanberg PR, Chung YG, Cho TH (2011) Transplantation of umbilical cord blood stem cells for treating spinal cord injury. Stem Cell Rev 7:181–194PubMedGoogle Scholar
  114. Park HC, Shim YS, Ha Y, Yoon SH, Park SR, Choi BH, Park HS (2005) Treatment of complete spinal cord injury patients by autologous bone marrow cell transplantation and administration of granulocyte-macrophage colony stimulating factor. Tissue Eng 11:913–922PubMedGoogle Scholar
  115. Park IH, Zhao R, West JA, Yabuuchi A, Huo H, Ince TA, Lerou PH, Lensch MW, Daley GQ (2008) Reprogramming of human somatic cells to pluripotency with defined factors. Nature 451:141–146PubMedGoogle Scholar
  116. Pfeifer K, Vroemen M, Blesch A, Weidner N (2004) Adult neural progenitor cells provide a permissive guiding substrate for corticospinal axon growth following spinal cord injury. Eur J Neurosci 20:1695–1704PubMedGoogle Scholar
  117. Pfeifer K, Vroemen M, Caioni M, Aigner L, Bogdahn U, Weidner N (2006) Autologous adult rodent neural progenitor cell transplantation represents a feasible strategy to promote structural repair in the chronically injured spinal cord. Regen Med 1:255–266PubMedGoogle Scholar
  118. Phinney DG, Prockop DJ (2007) Concise review: mesenchymal stem/multipotent stromal cells: the state of transdifferentiation and modes of tissue repair—current views. Stem Cells 25:2896–2902PubMedGoogle Scholar
  119. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284:143–147PubMedGoogle Scholar
  120. Pojda Z, Machaj EK, Oldak T, Gajkowska A, Jastrzewska M (2005) Nonhematopoietic stem cells of fetal origin—how much of today's enthusiasm will pass the time test? Folia Histochem Cytobiol 43:209–212PubMedGoogle Scholar
  121. Polito A, Reynolds R (2005) NG2-expressing cells as oligodendrocyte progenitors in the normal and demyelinated adult central nervous system. J Anat 207:707–716PubMedGoogle Scholar
  122. Ramon-Cueto A, Avila J (1998) Olfactory ensheathing glia: properties and function. Brain Res Bull 46:175–187PubMedGoogle Scholar
  123. Ramon-Cueto A, Cordero MI, Santos-Benito FF, Avila J (2000) Functional recovery of paraplegic rats and motor axon regeneration in their spinal cords by olfactory ensheathing glia. Neuron 25:425–435PubMedGoogle Scholar
  124. Rao MS (1999) Multipotent and restricted precursors in the central nervous system. Anat Rec 257:137–148PubMedGoogle Scholar
  125. Rao MS, Mayer-Proschel M (1997) Glial-restricted precursors are derived from multipotent neuroepithelial stem cells. Dev Biol 188:48–63PubMedGoogle Scholar
  126. Rao MS, Noble M, Mayer-Proschel M (1998) A tripotential glial precursor cell is present in the developing spinal cord. Proc Natl Acad Sci USA 95:3996–4001PubMedGoogle Scholar
  127. Reubinoff BE, Pera MF, Fong CY, Trounson A, Bongso A (2000) Embryonic stem cell lines from human blastocysts: somatic differentiation in vitro. Nat Biotechnol 18:399–404PubMedGoogle Scholar
  128. Reynolds BA, Weiss S (1992) Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 255:1707–1710PubMedGoogle Scholar
  129. Rogers I, Yamanaka N, Bielecki R, Wong CJ, Chua S, Yuen S, Casper RF (2007) Identification and analysis of in vitro cultured CD45-positive cells capable of multi-lineage differentiation. Exp Cell Res 313:1839–1852PubMedGoogle Scholar
  130. Roy NS, Wang S, Jiang L, Kang J, Benraiss A, Harrison-Restelli C, Fraser RA, Couldwell WT, Kawaguchi A, Okano H, Nedergaard M, Goldman SA (2000) In vitro neurogenesis by progenitor cells isolated from the adult human hippocampus. Nat Med 6:271–277PubMedGoogle Scholar
  131. Saito F, Nakatani T, Iwase M, Maeda Y, Hirakawa A, Murao Y, Suzuki Y, Onodera R, Fukushima M, Ide C (2008) Spinal cord injury treatment with intrathecal autologous bone marrow stromal cell transplantation: the first clinical trial case report. J Trauma 64:53–59PubMedGoogle Scholar
  132. Salazar DL, Uchida N, Hamers FP, Cummings BJ, Anderson AJ (2010) Human neural stem cells differentiate and promote locomotor recovery in an early chronic spinal cord injury NOD-scid mouse model. PLoS One 5:e12272PubMedGoogle Scholar
  133. Salewski RP, Eftekharpour E, Fehlings MG (2010) Are induced pluripotent stem cells the future of cell-based regenerative therapies for spinal cord injury? J Cell Physiol 222:515–521PubMedGoogle Scholar
  134. Sanchez-Ramos J, Song S, Cardozo-Pelaez F, Hazzi C, Stedeford T, Willing A, Freeman TB, Saporta S, Janssen W, Patel N, Cooper DR, Sanberg PR (2000) Adult bone marrow stromal cells differentiate into neural cells in vitro. Exp Neurol 164:247–256PubMedGoogle Scholar
  135. Sasaki M, Lankford KL, Zemedkun M, Kocsis JD (2004) Identified olfactory ensheathing cells transplanted into the transected dorsal funiculus bridge the lesion and form myelin. J Neurosci 24:8485–8493PubMedGoogle Scholar
  136. Sharp J, Frame J, Siegenthaler M, Nistor G, Keirstead HS (2010) Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants improve recovery after cervical spinal cord injury. Stem Cells 28:152–163PubMedGoogle Scholar
  137. Sherwood AM, Dimitrijevic MR, McKay WB (1992) Evidence of subclinical brain influence in clinically complete spinal cord injury: discomplete SCI. J Neurol Sci 110:90–98PubMedGoogle Scholar
  138. Shihabuddin LS, Ray J, Gage FH (1997) FGF-2 is sufficient to isolate progenitors found in the adult mammalian spinal cord. Exp Neurol 148:577–586PubMedGoogle Scholar
  139. Sieber-Blum M, Grim M (2004) The adult hair follicle: cradle for pluripotent neural crest stem cells. Birth Defects Res Part C Embryo Today 72:162–172Google Scholar
  140. Sieber-Blum M, Hu Y (2008) Epidermal neural crest stem cells (EPI-NCSC) and pluripotency. Stem Cell Rev 4:256–260PubMedGoogle Scholar
  141. Sieber-Blum M, Grim M, Hu YF, Szeder V (2004) Pluripotent neural crest stem cells in the adult hair follicle. Dev Dyn 231:258–269PubMedGoogle Scholar
  142. Steeves JD, Lammertse D, Curt A, Fawcett JW, Tuszynski MH, Ditunno JF, Ellaway PH, Fehlings MG, Guest JD, Kleitman N, Bartlett PF, Blight AR, Dietz V, Dobkin BH, Grossman R, Short D, Nakamura M, Coleman WP, Gaviria M, Privat A (2007) Guidelines for the conduct of clinical trials for spinal cord injury (SCI) as developed by the ICCP panel: clinical trial outcome measures. Spinal Cord 45:206–221PubMedGoogle Scholar
  143. Steward O, Sharp K, Selvan G, Hadden A, Hofstadter M, Au E, Roskams J (2006) A re-assessment of the consequences of delayed transplantation of olfactory lamina propria following complete spinal cord transection in rats. Exp Neurol 198:483–499PubMedGoogle Scholar
  144. Sykova E, Homola A, Mazanec R, Lachmann H, Konradova SL, Kobylka P, Padr R, Neuwirth J, Komrska V, Vavra V, Stulik J, Bojar M (2006) Autologous bone marrow transplantation in patients with subacute and chronic spinal cord injury. Cell Transplant 15:675–687PubMedGoogle Scholar
  145. Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676PubMedGoogle Scholar
  146. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872PubMedGoogle Scholar
  147. Takami T, Oudega M, Bates ML, Wood PM, Kleitman N, Bunge MB (2002) Schwann cell but not olfactory ensheathing glia transplants improve hindlimb locomotor performance in the moderately contused adult rat thoracic spinal cord. J Neurosci 22:6670–6681PubMedGoogle Scholar
  148. Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM (1998) Embryonic stem cell lines derived from human blastocysts. Science 282:1145–1147PubMedGoogle Scholar
  149. Thuret S, Moon LD, Gage FH (2006) Therapeutic interventions after spinal cord injury. Nat Rev Neurosci 7:628–643PubMedGoogle Scholar
  150. Tondreau T, Lagneaux L, Dejeneffe M, Massy M, Mortier C, Delforge A, Bron D (2004) Bone marrow-derived mesenchymal stem cells already express specific neural proteins before any differentiation. Differentiation 72:319–326PubMedGoogle Scholar
  151. Tse W, Laughlin MJ (2005) Umbilical cord blood transplantation: a new alternative option. Hematology Am Soc Hematol Educ Program 2005:377-383Google Scholar
  152. Tuszynski MH, Grill R, Jones LL, Brant A, Blesch A, Low K, Lacroix S, Lu P (2003) NT-3 gene delivery elicits growth of chronically injured corticospinal axons and modestly improves functional deficits after chronic scar resection. Exp Neurol 181:47–56PubMedGoogle Scholar
  153. Tuszynski MH, Steeves JD, Fawcett JW, Lammertse D, Kalichman M, Rask C, Curt A, Ditunno JF, Fehlings MG, Guest JD, Ellaway PH, Kleitman N, Bartlett PF, Blight AR, Dietz V, Dobkin BH, Grossman R, Privat A (2007) 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 45:222–231PubMedGoogle Scholar
  154. Uccelli A, Moretta L, Pistoia V (2008) Mesenchymal stem cells in health and disease. Nat Rev Immunol 8:726–736PubMedGoogle Scholar
  155. Uccelli A, Benvenuto F, Laroni A, Giunti D (2011) Neuroprotective features of mesenchymal stem cells. Best Pract Res Clin Haematol 24:59–64PubMedGoogle Scholar
  156. Uchida N, Buck DW, He D, Reitsma MJ, Masek M, Phan TV, Tsukamoto AS, Gage FH, Weissman IL (2000) Direct isolation of human central nervous system stem cells. Proc Natl Acad Sci USA 97:14720–14725PubMedGoogle Scholar
  157. Vats A, Tolley NS, Bishop AE, Polak JM (2005) Embryonic stem cells and tissue engineering: delivering stem cells to the clinic. J R Soc Med 98:346–350PubMedGoogle Scholar
  158. Vroemen M, Aigner L, Winkler J, Weidner N (2003) Adult neural progenitor cell grafts survive after acute spinal cord injury and integrate along axonal pathways. Eur J Neurosci 18:743–751PubMedGoogle Scholar
  159. Wachs FP, Couillard-Despres S, Engelhardt M, Wilhelm D, Ploetz S, Vroemen M, Kaesbauer J, Uyanik G, Klucken J, Karl C, Tebbing J, Svendsen C, Weidner N, Kuhn HG, Winkler J, Aigner L (2003) High efficacy of clonal growth and expansion of adult neural stem cells. Lab Invest 83:949–962PubMedGoogle Scholar
  160. Wang G, Ao Q, Gong K, Zuo H, Gong Y, Zhang X (2010) Synergistic effect of neural stem cells and olfactory ensheathing cells on repair of adult rat spinal cord injury. Cell Transplant 19:1325–1337PubMedGoogle Scholar
  161. Wang JM, Zeng YS, Wu JL, Li Y, Teng YD (2011) Cograft of neural stem cells and schwann cells overexpressing TrkC and neurotrophin-3 respectively after rat spinal cord transection. Biomaterials 32:7454–7468PubMedGoogle Scholar
  162. Warrington AE, Barbarese E, Pfeiffer SE (1993) Differential myelinogenic capacity of specific developmental stages of the oligodendrocyte lineage upon transplantation into hypomyelinating hosts. J Neurosci Res 34:1–13PubMedGoogle Scholar
  163. Webber DJ, Bradbury EJ, McMahon SB, Minger SL (2007) Transplanted neural progenitor cells survive and differentiate but achieve limited functional recovery in the lesioned adult rat spinal cord. Regen Med 2:929–945PubMedGoogle Scholar
  164. Weidner N, Blesch A, Grill RJ, Tuszynski MH (1999) Nerve growth factor-hypersecreting Schwann cell grafts augment and guide spinal cord axonal growth and remyelinate central nervous system axons in a phenotypically appropriate manner that correlates with expression of L1. J Comp Neurol 413:495–506PubMedGoogle Scholar
  165. Weiss S, Dunne C, Hewson J, Wohl C, Wheatley M, Peterson AC, Reynolds BA (1996) Multipotent CNS stem cells are present in the adult mammalian spinal cord and ventricular neuroaxis. J Neurosci 16:7599–7609PubMedGoogle Scholar
  166. Wernig M, Meissner A, Foreman R, Brambrink T, Ku M, Hochedlinger K, Bernstein BE, Jaenisch R (2007) In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 448:318–324PubMedGoogle Scholar
  167. Windrem MS, Nunes MC, Rashbaum WK, Schwartz TH, Goodman RA, McKhann G 2nd, Roy NS, Goldman SA (2004) Fetal and adult human oligodendrocyte progenitor cell isolates myelinate the congenitally dysmyelinated brain. Nat Med 10:93–97PubMedGoogle Scholar
  168. Woodbury D, Schwarz EJ, Prockop DJ, Black IB (2000) Adult rat and human bone marrow stromal cells differentiate into neurons. J Neurosci Res 61:364–370PubMedGoogle Scholar
  169. Woodbury D, Reynolds K, Black IB (2002) Adult bone marrow stromal stem cells express germline, ectodermal, endodermal, and mesodermal genes prior to neurogenesis. J Neurosci Res 69:908–917PubMedGoogle Scholar
  170. Wright KT, Masri WE, Osman A, Roberts S, Trivedi J, Ashton BA, Johnson WE (2008) The cell culture expansion of bone marrow stromal cells from humans with spinal cord injury: implications for future cell transplantation therapy. Spinal Cord 46:811–817PubMedGoogle Scholar
  171. Wu P, Tarasenko YI, Gu Y, Huang LY, Coggeshall RE, Yu Y (2002a) Region-specific generation of cholinergic neurons from fetal human neural stem cells grafted in adult rat. Nat Neurosci 5:1271–1278PubMedGoogle Scholar
  172. Wu YY, Mujtaba T, Han SS, Fischer I, Rao MS (2002b) Isolation of a glial-restricted tripotential cell line from embryonic spinal cord cultures. Glia 38:65–79PubMedGoogle Scholar
  173. Yamamoto S, Yamamoto N, Kitamura T, Nakamura K, Nakafuku M (2001) Proliferation of parenchymal neural progenitors in response to injury in the adult rat spinal cord. Exp Neurol 172:115–127PubMedGoogle Scholar
  174. Yamanaka S (2009) A fresh look at iPS cells. Cell 137:13–17PubMedGoogle Scholar
  175. Yan J, Xu L, Welsh AM, Hatfield G, Hazel T, Johe K, Koliatsos VE (2007) Extensive neuronal differentiation of human neural stem cell grafts in adult rat spinal cord. PLoS Med 4:e39PubMedGoogle Scholar
  176. Yasuda A, Tsuji O, Shibata S, Nori S, Takano M, Kobayashi Y, Takahashi Y, Fujiyoshi K, Hara CM, Miyawaki A, Okano HJ, Toyama Y, Nakamura M, Okano H (2011) Significance of remyelination by neural stem/progenitor cells transplanted into the injured spinal cord. Stem Cells 29:1983–1994PubMedGoogle Scholar
  177. Yoon SH, Shim YS, Park YH, Chung JK, Nam JH, Kim MO, Park HC, Park SR, Min BH, Kim EY, Choi BH, Park H, Ha Y (2007) 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 25:2066–2073PubMedGoogle Scholar
  178. Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir GA, Ruotti V, Stewart R, Slukvin II, Thomson JA (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318:1917–1920PubMedGoogle Scholar
  179. Zhang SC, Ge B, Duncan ID (1999) Adult brain retains the potential to generate oligodendroglial progenitors with extensive myelination capacity. Proc Natl Acad Sci USA 96:4089–4094PubMedGoogle Scholar
  180. Zhang X, Zeng Y, Zhang W, Wang J, Wu J, Li J (2007) Co-transplantation of neural stem cells and NT-3-overexpressing Schwann cells in transected spinal cord. J Neurotrauma 24:1863–1877PubMedGoogle Scholar
  181. Zurita M, Vaquero J (2006) Bone marrow stromal cells can achieve cure of chronic paraplegic rats: functional and morphological outcome one year after transplantation. Neurosci Lett 402:51–56PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Beatrice Sandner
    • 1
  • Peter Prang
    • 1
  • Francisco J. Rivera
    • 2
  • Ludwig Aigner
    • 2
  • Armin Blesch
    • 1
    • 3
  • Norbert Weidner
    • 1
  1. 1.Spinal Cord Injury CenterHeidelberg University HospitalHeidelbergGermany
  2. 2.Institute of Molecular Regenerative MedicineParacelsus Medical UniversitySalzburgAustria
  3. 3.Department of NeurosciencesUniversity of California, San DiegoLa JollaUSA

Personalised recommendations