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.
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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 120:3255–3266
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 167:27–39
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 1:47–55
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 190:17–31
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 3:54–59
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 170:48–62
Barnabe-Heider F, Frisen J (2008) Stem cells for spinal cord repair. Cell Stem Cell 3:16–24
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 139:244–256
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 123:118–132
Bernstein-Goral H, Bregman BS (1997) Axotomized rubrospinal neurons rescued by fetal spinal cord transplants maintain axon collaterals to rostral CNS targets. Exp Neurol 148:13–25
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 70:207–223
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 88:1182–1192
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 31:4675–4686
Bregman BS (1987a) Development of serotonin immunoreactivity in the rat spinal cord and its plasticity after neonatal spinal cord lesions. Brain Res 431:245–263
Bregman BS (1987b) Spinal cord transplants permit the growth of serotonergic axons across the site of neonatal spinal cord transection. Brain Res 431:265–279
Bregman BS, Reier PJ (1986) Neural tissue transplants rescue axotomized rubrospinal cells from retrograde death. J Comp Neurol 244:86–95
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 123:3–16
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 72:257–275
Busch SA, Silver J (2007) The role of extracellular matrix in CNS regeneration. Curr Opin Neurobiol 17:120–127
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 34:130–131
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 167:48–58
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 177:349–359
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 25:6947–6957
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 30:2989–3001
Caplan AI (2007) Adult mesenchymal stem cells for tissue engineering versus regenerative medicine. J Cell Physiol 213:341–347
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 297:1299
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 143:543–547
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 454:43–48
Collins WF (1983) A review and update of experiment and clinical studies of spinal cord injury. Paraplegia 21:204–219
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 102:14069–14074
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 28:474–481
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 5:7
Dawson MR, Levine JM, Reynolds R (2000) NG2-expressing cells in the central nervous system: are they oligodendroglial progenitors? J Neurosci Res 61:471–479
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 10:565–574
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 18:763–778
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 8:315–317
Erceg S, Ronaghi M, Stojkovic M (2009) Human embryonic stem cell differentiation toward regional specific neural precursors. Stem Cells 27:78–87
Evans MJ, Kaufman MH (1981) Establishment in culture of pluripotential cells from mouse embryos. Nature 292:154–156
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 45:190–205
Field P, Li Y, Raisman G (2003) Ensheathment of the olfactory nerves in the adult rat. J Neurocytol 32:317–324
Franklin RJ (2002) Remyelination of the demyelinated CNS: the case for and against transplantation of central, peripheral and olfactory glia. Brain Res Bull 57:827–832
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 92:11879–11883
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 10:1294–1299
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 17:1277–1293
Giger RJ, Hollis ER 2nd, Tuszynski MH (2010) Guidance molecules in axon regeneration. Cold Spring Harb Perspect Biol 2:a001867
Gledhill RF, Harrison BM, McDonald WI (1973) Demyelination and remyelination after acute spinal cord compression. Exp Neurol 38:472–487
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 22:248–256
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 17:5560–5572
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 16:1091–1100
Groopman J (2003) The Reeve effect. The New Yorker, Nov 10:82-93
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 362:453–455
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 45:1–16
Harris DT (2008) Cord blood stem cells: a review of potential neurological applications. Stem Cell Rev 4:269–274
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 99:2199–2204
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 8:346–353
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 16:3199–3208
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:e5871
Houle JD, Reier PJ (1988) Transplantation of fetal spinal cord tissue into the chronically injured adult rat spinal cord. J Comp Neurol 269:535–547
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 6:186–198
Hulsebosch CE (2002) Recent advances in pathophysiology and treatment of spinal cord injury. Adv Physiol Educ 26:238–255
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 854:70–78
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 84:1669–1681
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 80:182–190
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 177:265–275
Johansson CB, Svensson M, Wallstedt L, Janson AM, Frisen J (1999) Neural stem cells in the adult human brain. Exp Cell Res 253:733–736
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 10:3129–3140
Kakulas BA (1999) A review of the neuropathology of human spinal cord injury with emphasis on special features. J Spinal Cord Med 22:119–124
Kalyani AJ, Rao MS (1998) Cell lineage in the developing neural tube. Biochem Cell Biol 76:1051–1068
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 26:3377–3389
Keating A (2006) Mesenchymal stromal cells. Curr Opin Hematol 13:419–425
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 25:4694–4705
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 65:1275–1278
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 21:944–950
Krabbe C, Zimmer J, Meyer M (2005) Neural transdifferentiation of mesenchymal stem cells—a critical review. APMIS 113:831–844
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 7:241–248
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 116:40–51
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 45:232–242
Levine JM, Reynolds R (1999) Activation and proliferation of endogenous oligodendrocyte precursor cells during ethidium bromide-induced demyelination. Exp Neurol 160:333–347
Levine JM, Stincone F, Lee YS (1993) Development and differentiation of glial precursor cells in the rat cerebellum. Glia 7:307–321
Levine JM, Reynolds R, Fawcett JW (2001) The oligodendrocyte precursor cell in health and disease. Trends Neurosci 24:39–47
Li Y, Field PM, Raisman G (1997) Repair of adult rat corticospinal tract by transplants of olfactory ensheathing cells. Science 277:2000–2002
Lu J, Feron F, Mackay-Sim A, Waite PM (2002) Olfactory ensheathing cells promote locomotor recovery after delayed transplantation into transected spinal cord. Brain 125:14–21
Lu P, Tuszynski MH (2008) Growth factors and combinatorial therapies for CNS regeneration. Exp Neurol 209:313–320
Lu P, Blesch A, Tuszynski MH (2004a) Induction of bone marrow stromal cells to neurons: differentiation, transdifferentiation, or artifact? J Neurosci Res 77:174–191
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 24:6402–6409
Lu P, Jones LL, Tuszynski MH (2005) BDNF-expressing marrow stromal cells support extensive axonal growth at sites of spinal cord injury. Exp Neurol 191:344–360
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 26:11120–11130
Lu P, Jones LL, Tuszynski MH (2007) Axon regeneration through scars and into sites of chronic spinal cord injury. Exp Neurol 203:8–21
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 Diego
Maherali N, Hochedlinger K (2008) Guidelines and techniques for the generation of induced pluripotent stem cells. Cell Stem Cell 3:595–605
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 1:55–70
Marcus AJ, Woodbury D (2008) Fetal stem cells from extra-embryonic tissues: do not discard. J Cell Mol Med 12:730–742
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 78:7634–7638
Mayer-Proschel M, Kalyani AJ, Mujtaba T, Rao MS (1997) Isolation of lineage-restricted neuronal precursors from multipotent neuroepithelial stem cells. Neuron 19:773–785
Mayor S (2010) First patient enters trial to test safety of stem cells in spinal injury. BMJ 341:c5724
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 5:1410–1412
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 25:3499–3508
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 25:9624–9636
Mothe AJ, Tator CH (2008) Transplanted neural stem/progenitor cells generate myelinating oligodendrocytes and Schwann cells in spinal cord demyelination and dysmyelination. Exp Neurol 213:176–190
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 214:113–127
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 26:101–106
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 1035:73–85
Newman MB, Davis CD, Kuzmin-Nichols N, Sanberg PR (2003) Human umbilical cord blood (HUCB) cells for central nervous system repair. Neurotox Res 5:355–368
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 49:385–396
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 21:1345–1357
O'Donoghue K, Fisk NM (2004) Fetal stem cells. Best Pract Res Clin Obstet Gynaecol 18:853–875
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 69:925–933
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 19:1839–1841
Okita K, Yamanaka S (2011) Induced pluripotent stem cells: opportunities and challenges. Philos Trans R Soc Lond B Biol Sci 366:2198–2207
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 11:897–911
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 6:474–486
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 19:8487–8497
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 7:181–194
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 11:913–922
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 451:141–146
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 20:1695–1704
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 1:255–266
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 25:2896–2902
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 284:143–147
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 43:209–212
Polito A, Reynolds R (2005) NG2-expressing cells as oligodendrocyte progenitors in the normal and demyelinated adult central nervous system. J Anat 207:707–716
Ramon-Cueto A, Avila J (1998) Olfactory ensheathing glia: properties and function. Brain Res Bull 46:175–187
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 25:425–435
Rao MS (1999) Multipotent and restricted precursors in the central nervous system. Anat Rec 257:137–148
Rao MS, Mayer-Proschel M (1997) Glial-restricted precursors are derived from multipotent neuroepithelial stem cells. Dev Biol 188:48–63
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 95:3996–4001
Reubinoff BE, Pera MF, Fong CY, Trounson A, Bongso A (2000) Embryonic stem cell lines from human blastocysts: somatic differentiation in vitro. Nat Biotechnol 18:399–404
Reynolds BA, Weiss S (1992) Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 255:1707–1710
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 313:1839–1852
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 6:271–277
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 64:53–59
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:e12272
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 222:515–521
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 164:247–256
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 24:8485–8493
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 28:152–163
Sherwood AM, Dimitrijevic MR, McKay WB (1992) Evidence of subclinical brain influence in clinically complete spinal cord injury: discomplete SCI. J Neurol Sci 110:90–98
Shihabuddin LS, Ray J, Gage FH (1997) FGF-2 is sufficient to isolate progenitors found in the adult mammalian spinal cord. Exp Neurol 148:577–586
Sieber-Blum M, Grim M (2004) The adult hair follicle: cradle for pluripotent neural crest stem cells. Birth Defects Res Part C Embryo Today 72:162–172
Sieber-Blum M, Hu Y (2008) Epidermal neural crest stem cells (EPI-NCSC) and pluripotency. Stem Cell Rev 4:256–260
Sieber-Blum M, Grim M, Hu YF, Szeder V (2004) Pluripotent neural crest stem cells in the adult hair follicle. Dev Dyn 231:258–269
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 45:206–221
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 198:483–499
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 15:675–687
Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676
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 131:861–872
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 22:6670–6681
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 282:1145–1147
Thuret S, Moon LD, Gage FH (2006) Therapeutic interventions after spinal cord injury. Nat Rev Neurosci 7:628–643
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 72:319–326
Tse W, Laughlin MJ (2005) Umbilical cord blood transplantation: a new alternative option. Hematology Am Soc Hematol Educ Program 2005:377-383
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 181:47–56
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 45:222–231
Uccelli A, Moretta L, Pistoia V (2008) Mesenchymal stem cells in health and disease. Nat Rev Immunol 8:726–736
Uccelli A, Benvenuto F, Laroni A, Giunti D (2011) Neuroprotective features of mesenchymal stem cells. Best Pract Res Clin Haematol 24:59–64
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 97:14720–14725
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 98:346–350
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 18:743–751
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 83:949–962
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 19:1325–1337
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 32:7454–7468
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 34:1–13
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 2:929–945
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 413:495–506
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 16:7599–7609
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 448:318–324
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 10:93–97
Woodbury D, Schwarz EJ, Prockop DJ, Black IB (2000) Adult rat and human bone marrow stromal cells differentiate into neurons. J Neurosci Res 61:364–370
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 69:908–917
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 46:811–817
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 5:1271–1278
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 38:65–79
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 172:115–127
Yamanaka S (2009) A fresh look at iPS cells. Cell 137:13–17
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:e39
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 29:1983–1994
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 25:2066–2073
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 318:1917–1920
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 96:4089–4094
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 24:1863–1877
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 402:51–56
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This work was supported by Wings for Life, Spinal Cord Research Foundation (to B.S.), the International Foundation for Research in Paraplegia (P119 to A.B. and N.W.) and the EU (IRG268282 to A.B.).
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Sandner, B., Prang, P., Rivera, F.J. et al. Neural stem cells for spinal cord repair. Cell Tissue Res 349, 349–362 (2012). https://doi.org/10.1007/s00441-012-1363-2
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DOI: https://doi.org/10.1007/s00441-012-1363-2