An in vivo characterization of trophic factor production following neural precursor cell or bone marrow stromal cell transplantation for spinal cord injury

Stem Cells and Development

Volumn 21, Issue 12, 2012, Pages 2222-2238

  Hawryluk, Gregory W J ^a,b,c   Mothe, Andrea ^a   Wang, Jian ^a   Wang, Shelly ^a   Tator, Charles ^a,b,c   Fehlings, Michael G ^a,b,c  

^a UNIVERSITY HEALTH NETWORK   (Canada)

^b UNIVERSITY OF TORONTO   (Canada)

^c UNIVERSITY OF TORONTO   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

BRAIN DERIVED NEUROTROPHIC FACTOR; CILIARY NEUROTROPHIC FACTOR; EPIDERMAL GROWTH FACTOR; GLIAL CELL LINE DERIVED NEUROTROPHIC FACTOR; GLIAL GROWTH FACTOR 2; GLYCERALDEHYDE 3 PHOSPHATE DEHYDROGENASE; LEUKEMIA INHIBITORY FACTOR; NERVE GROWTH FACTOR; NEURITE PROMOTING FACTOR; NEUROTROPHIN 3; NEUROTROPHIN 4; PLATELET DERIVED GROWTH FACTOR A; SOMATOMEDIN C; TRANSFORMING GROWTH FACTOR BETA1; UNCLASSIFIED DRUG; VASCULOTROPIN A;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BFGF GENE; BONE MARROW STROMAL CELL TRANSPLANTATION; CELL TRANSPLANTATION; CNTF GENE; CONTROLLED STUDY; EGF GENE; FEMALE; GAPDH GENE; GENE; GGF2 GENE; HOUSEKEEPING GENE; IGF 1 GENE; IN VIVO STUDY; LIF GENE; MALE; NEURAL STEM CELL; NGF GENE; NONHUMAN; PDGF A GENE; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN SECRETION; RAT; SPINAL CORD INJURY; TGF BETA1 GENE; UPREGULATION; VEGF A GENE;

ANIMALS; BONE MARROW CELLS; BONE MARROW TRANSPLANTATION; CELLS, CULTURED; CERVICAL VERTEBRAE; FEMALE; GENE EXPRESSION; GENE EXPRESSION REGULATION; GREEN FLUORESCENT PROTEINS; INFLAMMATION MEDIATORS; NERVE GROWTH FACTORS; NEURAL STEM CELLS; RATS; RATS, TRANSGENIC; RATS, WISTAR; SPINAL CORD; SPINAL CORD INJURIES; THORACIC VERTEBRAE; VASCULAR ENDOTHELIAL GROWTH FACTOR A;

RATTUS;

EID: 84863029363     PISSN: 15473287     EISSN: 15578534     Source Type: Journal    
DOI: 10.1089/scd.2011.0596     Document Type: Article

References (130)

1. Hawryluk GW and MG Fehlings. (2009). Cellular trans-plantation approaches for repair of the injured spinal cord: ongoing and pending clinical trials. Top SCI Rehabil 14: 47-61.
2. Pearse DD, FC Pereira, AE Marcillo, ML Bates, YA Berrocal, MT Filbin and MB Bunge. (2004). cAMP and Schwann cells promote axonal growth and functional re-covery after spinal cord injury. Nat Med 10:610-616.
3. Erceg S, M Ronaghi, M Oria, MG Rosello, MA Arago, MG Lopez, I Radojevic, V Moreno-Manzano, FJ Rodriguez-Jimenez, et al. (2010). Transplanted oligodendrocytes and motoneuron progenitors generated from human embryonic stem cells promote locomotor recovery after spinal cord transection. Stem Cells 28:1541-1549.
4. Tetzlaff W, EB Okon, S Karimi-Abdolrezaee, CE Hill, JS Sparling, JR Plemel, WT Plunet, EC Tsai, D Baptiste, et al. (2011). A systematic review of cellular transplantation ther-apies for spinal cord injury. J Neurotrauma 28:1611-1682.
5. Enzmann GU, RL Benton, JF Talbott, Q Cao and SR Whittemore. (2006). Functional considerations of stem cell transplantation therapy for spinal cord repair. J Neuro-trauma 23:479-495.
6. Hawryluk GW and MG Fehlings. (2008). The center of the spinal cord may be central to its repair. Cell Stem Cell 3:230-232.
7. Koshizuka S, S Okada, A Okawa, M Koda, M Murasawa, M Hashimoto, T Kamada, K Yoshinaga, M Murakami, H Moriya and M Yamazaki. (2004). Transplanted hemato-poietic stem cells from bone marrow differentiate into neural lineage cells and promote functional recovery after spinal cord injury in mice. J Neuropathol Exp Neurol 63:64-72.
8. Ohta M, Y Suzuki, T Noda, Y Ejiri, M Dezawa, K Kataoka, H Chou, N Ishikawa, N Matsumoto, et al. (2004). Bone marrow stromal cells infused into the cerebrospinal fluid promote functional recovery of the injured rat spinal cord with reduced cavity formation. Exp Neurol187:266-278.
9. Wu S, Y Suzuki, Y Ejiri, T Noda, H Bai, M Kitada, K Kataoka, M Ohta, H Chou and C Ide. (2003). Bone marrow stromal cells enhance differentiation of cocultured neuro-sphere cells and promote regeneration of injured spinal cord. J Neurosci Res 72:343-351.
10. Parr AM, CH Tator and A Keating. (2007). Bone marrow-derived mesenchymal stromal cells for the repair of cen-tral nervous system injury. Bone Marrow Transplant 40: 609-619.
11. Chen J, Y Li, M Katakowski, X Chen, L Wang, D Lu, M Lu, SC Gautam and M Chopp. (2003). Intravenous bone mar-row stromal cell therapy reduces apoptosis and promotes endogenous cell proliferation after stroke in female rat. J Neurosci Res 73:778-786.
12. Widenfalk J, K Lundströmer, M Jubran, S Brene and L Olson. (2001). Neurotrophic factors and receptors in the immature and adult spinal cord after mechanical injury or kainic acid. J Neurosci 21:3457-3475.
13. Mocchetti I and JR Wrathall. (1995). Neurotrophic factors in central nervous system trauma. J Neurotrauma 12:853-870.
14. Namiki J, A Kojima and CH Tator. (2000). Effect of brain-derived neurotrophic factor, nerve growth factor, and neurotrophin-3 on functional recovery and regeneration after spinal cord injury in adult rats. J Neurotrauma 17:1219-1231.
15. Koda M, M Murakami, H Ino, K Yoshinaga, O Ikeda, M Hashimoto, M Yamazaki, C Nakayama and H Moriya. (2002). Brain-derived neurotrophic factor suppresses de-layed apoptosis of oligodendrocytes after spinal cord injury in rats. J Neurotrauma 19:777-785.
16. Neuhuber B, B Timothy Himes, JS Shumsky, G Gallo and I Fischer. (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.
17. Tolwani RJ, JM Cosgaya, S Varma, R Jacob, LE Kuo and EM Shooter. (2004). BDNF overexpression produces a long-term increase in myelin formation in the peripheral nervous system. J Neurosci Res 77:662-669.
18. Hempstead BL and JL Salzer. (2002). A glial spin on neu-rotrophins. Science 298:1184-1186.
19. Nakamura M, H Okano, Y Toyama, HN Dai, TP Finn and BS Bregman. (2005). Transplantation of embryonic spinal cord-derived neurospheres support growth of supraspinal projections and functional recovery after spinal cord injury in the neonatal rat. J Neurosci Res 81:457-468.
20. Chen Q, L Zhou and HD Shine. (2006). Expression of neurotrophin-3 promotes axonal plasticity in the acute but not chronic injured spinal cord. J Neurotrauma 23:1254-1260.
21. Sharp J, J Frame, M Siegenthaler, G Nistor and HS Keirstead. (2010). Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants improve re-covery after cervical spinal cord injury. Stem Cells 28: 152-163.
22. Bambakidis NC and RH Miller. (2004). Transplantation of oligodendrocyte precursors and sonic hedgehog results in improved function and white matter sparing in the spinal cords of adult rats after contusion. Spine J 4:16-26.
23. Ankeny DP, DM McTigue and LB Jakeman. (2004). Bone marrow transplants provide tissue protection and direc-tional guidance for axons after contusive spinal cord injury in rats. Exp Neurol 190:17-31.
24. Chopp M, XH Zhang, Y Li, L Wang, J Chen, D Lu, M Lu and M Rosenblum. (2000). Spinal cord injury in rat: treat-ment with bone marrow stromal cell transplantation. Neuroreport 11:3001-3005.
25. Hawryluk GWJ, A Mothe, M Chamankhah, J Wang, C Tator and MG Fehlings. (2011). In vitro characterization of trophic factor expression in neural precursor cells. Epub ahead of print; DOI: 10.1089/scd.2011.0242.
26. Strauss S. (2010). Geron trial resumes, but standards for stem cell trials remain elusive. Nat Biotechnol 28:989-990.
27. Sykova E, A Homola, R Mazanec, H Lachmann, SL Konradova, P Kobylka, R Padr, J Neuwirth, V Komrska, et al. (2006). Autologous bone marrow transplantation in patients with subacute and chronic spinal cord injury. Cell Transplant 15:675-687.
28. Yoon SH, YS Shim, YH Park, JK Chung, JH Nam, MO Kim, HC Park, SR Park, BH Min, EY Kim, BH Choi, H Park and Y Ha. (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.
29. Hakamata Y, K Tahara, H Uchida, Y Sakuma, M Nakamura, A Kume, T Murakami, M Takahashi, R Taka-hashi, et al. (2001). Green fluorescent protein-transgenic rat: a tool for organ transplantation research. Biochem Biophys Res Commun 286:779-785.
30. Mothe AJ and CH Tator. (2008). Transplanted neural stem/progenitor cells generate myelinating oligodendrocytes and Schwann cells in spinal cord demyelination and dysmye-lination. Exp Neurol 213:176-190.
31. Karimi-Abdolrezaee S, E Eftekharpour, J Wang, CM Morshead and MG Fehlings. (2006). Delayed transplanta-tion of adult neural precursor cells promotes remyelination and functional neurological recovery after spinal cord in-jury. J Neurosci 26:3377-3389.
32. Parr AM, I Kulbatski, T Zahir, X Wang, C Yue, A Keating and CH Tator. (2008). Transplanted adult spinal cord-derived neural stem/progenitor cells promote early func-tional recovery after rat spinal cord injury. Neuroscience 155:760-770.
33. Clark BR, C Jamieson and A Keating. (1997). Human long-term bone marrow culture. Methods Mol Biol 75:249-256.
34. Dominici M, K Le Blanc, I Mueller, I Slaper-Cortenbach, F Marini, D Krause, R Deans, A Keating, D Prockop and E Horwitz. (2006). Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8:315-317.
35. Mothe AJ, G Bozkurt, J Catapano, J Zabojova, X Wang, A Keating and CH Tator. (2011). Intrathecal transplantation of stem cells by lumbar puncture for thoracic spinal cord injury in the rat. Spinal Cord 49:967-973.
36. Rivlin AS and CH Tator. (1978). Effect of duration of acute spinal cord compression in a new acute cord injury model in the rat. Surg Neurol 10:38-43.
37. Modo M, RP Stroemer, E Tang, S Patel and H Hodges. (2003). Effects of implantation site of dead stem cells in rats with stroke damage. Neuroreport 14:39-42.
38. Wilkins A, S Chandran and A Compston. (2001). A role for oligodendrocyte-derived IGF-1 in trophic support of corti-cal neurons. Glia 36:48-57.
39. Giehl KM, A Schutte, P Mestres and Q Yan. (1998). The survival-promoting effect of glial cell line-derived neuro-trophic factor on axotomized corticospinal neurons in vivo is mediated by an endogenous brain-derived neurotrophic factor mechanism. J Neurosci 18:7351-7360.
40. Deleyrolle L, S Marchal-Victorion, C Dromard, V Fritz, M Saunier, JC Sabourin, C Tran Van Ba, A Privat and JP Hugnot. (2006). Exogenous and fibroblast growth factor 2/epidermal growth factor-regulated endogenous cytokines regulate neural precursor cell growth and differentiation. Stem Cells 24:748-762.
41. Magy L, C Mertens, V Avellana-Adalid, M Keita, F Lachapelle, B Nait-Oumesmar, B Fontaine and A Baron-Van Evercooren. (2003). Inducible expression of FGF2 by a rat oligodendrocyte precursor cell line promotes CNS myelination in vitro. Exp Neurol 184:912-922.
42. Du Y and CF Dreyfus. (2002). Oligodendrocytes as pro-viders of growth factors. J Neurosci Res 68:647-654.
43. Albrecht PJ, JC Murtie, JK Ness, JM Redwine, JR Enterline, RC Armstrong and SW Levison. (2003). Astrocytes produce CNTF during the remyelination phase of viral-induced spinal cord demyelination to stimulate FGF-2 production. Neurobiol Dis 13:89-101.
44. Blesch A, HS Uy, RJ Grill, JG Cheng, PH Patterson and MH Tuszynski. (1999). Leukemia inhibitory factor augments neurotrophin expression and corticospinal axon growth after adult CNS injury. J Neurosci 19:3556-3566.
45. Zai LJ, S Yoo and JR Wrathall. (2005). Increased growth factor expression and cell proliferation after contusive spi-nal cord injury. Brain Res 1052:147-155.
46. Fressinaud C. (2005). Repeated injuries dramatically affect cells of the oligodendrocyte lineage: effects of PDGF and NT-3 in vitro. Glia 49:555-566.
47. Lu P, LL Jones, EY Snyder and MH Tuszynski. (2003). Neural stem cells constitutively secrete neurotrophic factors and promote extensive host axonal growth after spinal cord injury. Exp Neurol 181:115-129.
48. Nakamura M and BS Bregman. (2001). Differences in neu-rotrophic factor gene expression profiles between neonate and adult rat spinal cord after injury. Exp Neurol169:407-415.
49. Nakamura M, RA Houghtling, L MacArthur, BM Bayer and BS Bregman. (2003). Differences in cytokine gene ex-pression profile between acute and secondary injury in adult rat spinal cord. Exp Neurol 184:313-325.
50. Okragly AJ and M Haak-Frendscho. (1997). An acid-treatment method for the enhanced detection of GDNF in biological samples. Exp Neurol 145:592-596.
51. Dougherty KD, CF Dreyfus and IB Black. (2000). Brain-derived neurotrophic factor in astrocytes, oligodendro-cytes, and microglia/macrophages after spinal cord injury. Neurobiol Dis 7:574-585.
52. Follesa P, JR Wrathall and I Mocchetti. (1994). Induction of bFGF mRNA in spinal cord trauma. Mol Brain Res 22:1-8.
53. Dreyfus CF, X Dai, LD Lercher, BR Racey, WJ Friedman and IB Black. (1999). Expression of neurotrophins in the adult spinal cord in vivo. J Neurosci Res 56:1-7.
54. Nieto-Sampedro M, ER Lewis, CW Cotman, M Manthorpe, SD Skaper, G Barbin, FM Longo and S Varon. (1982). Brain injury causes a time-dependent increase in neuronotrophic activity at the lesion site. Science 217:860-861.
55. Finklestein SP, PJ Apostolides, CG Caday, J Prosser, MF Philips and M Klagsbrun. (1988). Increased basic fibroblast growth factor (bFGF) immunoreactivity at the site of focal brain wounds. Brain Res 460:253-259.
56. Zvarova K, E Murray and MA Vizzard. (2004). Changes in galanin immunoreactivity in rat lumbosacral spinal cord and dorsal root ganglia after spinal cord injury. J Comp Neurol 475:590-603.
57. Tokumine J, O Kakinohana, D Cizkova, DW Smith and M Marsala. (2003). Changes in spinal GDNF, BDNF, and NT-3 expression after transient spinal cord ischemia in the rat. J Neurosci Res 74:552-561.
58. Uchida K, H Baba, Y Maezawa, S Furukawa, M Omiya, Y Kokubo, C Kubota and H Nakajima. (2003). Increased expression of neurotrophins and their receptors in the mechanically compressed spinal cord of the spinal hyper-ostotic mouse (twy/twy). Acta Neuropathol 106:29-36.
59. Ikeda O, M Murakami, H Ino, M Yamazaki, T Nemoto, M Koda, C Nakayama and H Moriya. (2001). Acute up-regulation of brain-derived neurotrophic factor expression resulting from experimentally induced injury in the rat spinal cord. Acta Neuropathol 102:239-245.
60. Li XL, W Zhang, X Zhou, XY Wang, HT Zhang, DX Qin, H Zhang, Q Li, M Li and TH Wang. (2007). Temporal changes in the expression of some neurotrophins in spinal cord transected adult rats. Neuropeptides 41:135-143.
61. Zhang HT, ZY Gao, YZ Chen and TH Wang. (2008). Temporal changes in the level of neurotrophins in the spinal cord and associated precentral gyrus following spinal hemisection in adult Rhesus monkeys. J Chem Neuroanat 36:138-143.
62. Johnson RA, AJ Okragly, M Haak-Frendscho and GS Mitchell. (2000). Cervical dorsal rhizotomy increases brain-derived neurotrophic factor and neurotrophin-3 expression in the ventral spinal cord. J Neurosci 20:RC77.
63. Brown A, MJ Ricci and LC Weaver. (2004). NGF message and protein distribution in the injured rat spinal cord. Exp Neurol 188:115-127.
64. Gulino R, SA Lombardo, A Casabona, G Leanza and V Perciavalle. (2004). Levels of brain-derived neurotrophic factor and neurotrophin-4 in lumbar motoneurons after low-thoracic spinal cord hemisection. Brain Res 1013:174-181.
65. Qin DX, XL Zou, W Luo, W Zhang, HT Zhang, XL Li, H Zhang, XY Wang and TH Wang. (2006). Expression of some neurotrophins in the spinal motoneurons after cord hemisection in adult rats. Neurosci Lett 410: 222-227.
66. Hajebrahimi Z, SJ Mowla, M Movahedin and M Tavallaei. (2008). Gene expression alterations of neurotrophins, their receptors and prohormone convertases in a rat model of spinal cord contusion. Neurosci Lett 441:261-266.
67. Hayashi M, T Ueyama, K Nemoto, T Tamaki and E Senba. (2000). Sequential mRNA expression for immediate early genes, cytokines, and neurotrophins in spinal cord injury. J Neurotrauma 17:203-218.
68. Kerr BJ and PH Patterson. (2004). Potent pro-inflammatory actions of leukemia inhibitory factor in the spinal cord of the adult mouse. Exp Neurol188:391-407.
69. Bandtlow CE, M Meyer, D Lindholm, M Spranger, R Heumann and H Thoenen. (1990). Regional and cellular codistribution of interleukin 1 beta and nerve growth factor mRNA in the adult rat brain: possible relationship to the regulation of nerve growth factor synthesis. J Cell Biol 111:1701-1711.
70. Saporito MS, HM Wilcox, KC Hartpence, ME Lewis, JL Vaught and S Carswell. (1993). Pharmacological induction of nerve growth factor mRNA in adult rat brain. Exp Neurol 123:295-302.
71. Spranger M, D Lindholm, C Bandtlow, R Heumann, H Gnahn, M Naher-Noe and H Thoenen. (1990). Regulation of nerve growth factor (NGF) synthesis in the rat central nervous system: comparison between the effects of inter-leukin-1 and various growth factors in astrocyte cultures and in vivo. Eur J Neurosci 2:69-76.
72. Beattie MS, AW Harrington, R Lee, JY Kim, SL Boyce, FM Longo, JC Bresnahan, BL Hempstead and SO Yoon. (2002). ProNGF induces p75-mediated death of oligodendrocytes following spinal cord injury. Neuron 36:375-386.
73. Kurek JB, TM Bennett, JJ Bower, CM Muldoon and L Austin. (1998). Leukaemia inhibitory factor (LIF) produc-tion in a mouse model of spinal trauma. Neurosci Lett 249:1-4.
74. Sendtner M, R Gotz, B Holtmann, JL Escary, Y Masu, P Carroll, E Wolf, G Brem, P Brulet and H Thoenen. (1996). Cryptic physiological trophic support of motoneurons by LIF revealed by double gene targeting of CNTF and LIF. Curr Biol 6:686-694.
75. Hughes RA, M Sendtner and H Thoenen. (1993). Mem-bers of several gene families influence survival of rat motoneurons in vitro and in vivo. J Neurosci Res 36: 663-671.
76. Vartanian T, Y Li, M Zhao and K Stefansson. (1995). In-terferon-gamma- induced oligodendrocyte cell death: im-plications for the pathogenesis of multiple sclerosis. Mol Med 1:732-743.
77. Azari MF, C Profyris, T Karnezis, CC Bernard, DH Small, SS Cheema, E Ozturk, I Hatzinisiriou and S Petratos. (2006). Leukemia inhibitory factor arrests oligodendrocyte death and demyelination in spinal cord injury. J Neuro-pathol Exp Neurol 65:914-929.
78. Kerr BJ and PH Patterson. (2005). Leukemia inhibitory factor promotes oligodendrocyte survival after spinal cord injury. Glia 51:73-79.
79. Bugga L, RA Gadient, K Kwan, CL Stewart and PH Pat-terson. (1998). Analysis of neuronal and glial phenotypes in brains of mice deficient in leukemia inhibitory factor. J Neurobiol 36:509-524.
80. Kahn MA and J De Vellis. (1994). Regulation of an oligo-dendrocyte progenitor cell line by the interleukin-6 family of cytokines. Glia 12:87-98.
81. Mayer M, K Bhakoo and M Noble. (1994). Ciliary neuro-trophic factor and leukemia inhibitory factor promote the generation, maturation and survival of oligodendrocytes in vitro. Development 120:143-153.
82. Richards LJ, TJ Kilpatrick, R Dutton, SS Tan, DP Gearing, PF Bartlett and M Murphy. (1996). Leukaemia inhibi-tory factor or related factors promote the differentiation of neuronal and astrocytic precursors within the developing murine spinal cord. Eur J Neurosci 8:291-299.
83. Hollis ER, 2nd, P Lu, A Blesch and MH Tuszynski. (2009). IGF-I gene delivery promotes corticospinal neuronal sur-vival but not regeneration after adult CNS injury. Exp Neurol 215:53-59.
84. Nakao Y, H Otani, T Yamamura, R Hattori, M Osako and H Imamura. (2001). Insulin-like growth factor 1 prevents neuronal cell death and paraplegia in the rabbit model of spinal cord ischemia. J Thorac Cardiovasc Surg 122:136-143.
85. Ozdinler PH and JD Macklis. (2006). IGF-I specifically en-hances axon outgrowth of corticospinal motor neurons. Nat Neurosci 9:1371-1381.
86. Hamada Y, T Ikata, S Katoh, K Katoh, M Niwa, Y Tsutsumishita and K Fukuzawa. (1996). Effects of exoge-nous transforming growth factor-beta 1 on spinal cord injury in rats. Neurosci Lett 203:97-100.
87. Prehn JH, C Backhauss and J Krieglstein. (1993). Trans-forming growth factor-beta 1 prevents glutamate neuro-toxicity in rat neocortical cultures and protects mouse neocortex from ischemic injury in vivo. J Cereb Blood Flow Metab 13:521-525.
88. Krady JK, HW Lin, CM Liberto, A Basu, SG Kremlev and SW Levison. (2008). Ciliary neurotrophic factor and inter-leukin-6 differentially activate microglia. J Neurosci Res 86:1538-1547.
89. Liu Y, S Figley, SK Spratt, G Lee, D Ando, R Surosky and MG Fehlings. (2010). An engineered transcription factor which activates VEGF-A enhances recovery after spinal cord injury. Neurobiol Dis 37:384-393.
90. Rossi SL, G Nistor, T Wyatt, HZ Yin, AJ Poole, JH Weiss, MJ Gardener, S Dijkstra, DF Fischer and HS Keirstead. (2010). Histological and functional benefit following trans-plantation of motor neuron progenitors to the injured rat spinal cord. PLoS One 5:e11852.
91. Rossi SL and HS Keirstead. (2009). Stem cells and spinal cord regeneration. Curr Opin Biotechnol 20:552-562.
92. Sykova E, P Jendelova, L Urdzikova, P Lesny and A Hejcl. (2006). Bone marrow stem cells and polymer hydrogels\two strategies for spinal cord injury repair. Cell Mol Neu-robiol 26:1113-1129.
93. Pearse DD and MB Bunge. (2006). Designing cell-and gene-based regeneration strategies to repair the injured spinal cord. J Neurotrauma 23:438-452.
94. Yan J, AM Welsh, SH Bora, EY Snyder and VE Koliatsos. (2004). Differentiation and tropic/trophic effects of exoge-nous neural precursors in the adult spinal cord. J Comp Neurol 480:101-114.
95. Clatterbuck RE, DL Price and VE Koliatsos. (1994). Further characterization of the effects of brain-derived neurotrophic factor and ciliary neurotrophic factor on axotomized neo-natal and adult mammalian motor neurons. J Comp Neurol 342:45-56.
96. Dittrich F, G Ochs, A Grosse-Wilde, U Berweiler, Q Yan, JA Miller, KV Toyka and M Sendtner. (1996). Pharmacoki-netics of intrathecally applied BDNF and effects on spinal motoneurons. Exp Neurol 141:225-239.
97. Friedman B, D Kleinfeld, NY Ip, VM Verge, R Moulton, P Boland, E Zlotchenko, RM Lindsay and L Liu. (1995). BDNF and NT-4/5 exert neurotrophic influences on injured adult spinal motor neurons. J Neurosci 15:1044-1056.
98. Kishino A, Y Ishige, T Tatsuno, C Nakayama and H No-guchi. (1997). BDNF prevents and reverses adult rat motor neuron degeneration and induces axonal outgrowth. Exp Neurol 144:273-286.
99. Novikov L, L Novikova and JO Kellerth. (1995). Brain-derived neurotrophic factor promotes survival and blocks nitric oxide synthase expression in adult rat spinal moto-neurons after ventral root avulsion. Neurosci Lett 200:45-48.
100. Nakahara Y, FH Gage and MH Tuszynski. (1996). Grafts of fibroblasts genetically modified to secrete NGF, BDNF, NT-3, or basic FGF elicit differential responses in the adult spinal cord. Cell Transplant 5:191-204.
101. Yan Q, J Elliott and WD Snider. (1992). Brain-derived neurotrophic factor rescues spinal motor neurons from axotomy-induced cell death. Nature 360:753-755.
102. Kobayashi NR, DP Fan, KM Giehl, AM Bedard, SJ Wiegand and W Tetzlaff. (1997). BDNF and NT-4/5 prevent atrophy of rat rubrospinal neurons after cervical axotomy, stimulate GAP-43 and Talpha1-tubulin mRNA expression, and pro-mote axonal regeneration. J Neurosci 17:9583-9595.
103. Grill R, K Murai, A Blesch, FH Gage and MH Tuszynski. (1997). Cellular delivery of neurotrophin-3 promotes corti-cospinal axonal growth and partial functional recovery after spinal cord injury. J Neurosci 17:5560-5572.
104. Giehl KM and W Tetzlaff. (1996). BDNF and NT-3, but not NGF, prevent axotomy-induced death of rat corticospinal neurons in vivo. Eur J Neurosci 8:1167-1175.
105. Kraemer R and BL Hempstead. (2003). Neurotrophins: novel mediators of angiogenesis. Front Biosci 8:s1181-s1186.
106. Yamauchi J, JR Chan and EM Shooter. (2004). Neuro-trophins regulate Schwann cell migration by activating divergent signaling pathways dependent on Rho GTPases. Proc Natl Acad Sci USA 101:8774-8779.
107. Chan JR, JM Cosgaya, YJ Wu and EM Shooter. (2001). Neurotrophins are key mediators of the myelination pro-gram in the peripheral nervous system Proc Natl Acad Sci USA 98:14661-14668.
108. Lin LF, DH Doherty, JD Lile, S Bektesh and F Collins. (1993). GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science 260:1130-1132.
109. Ramer MS, JV Priestley and SB McMahon. (2000). Func-tional regeneration of sensory axons into the adult spinal cord. Nature 403:312-316.
110. Teng YD, I Mocchetti and JR Wrathall. (1998). Basic and acidic fibroblast growth factors protect spinal motor neu-rones in vivo after experimental spinal cord injury. Eur J Neurosci 10:798-802.
111. Yasuda T, J Grinspan, J Stern, B Franceschini, P Bannerman and D Pleasure. (1995). Apoptosis occurs in the oligoden-droglial lineage, and is prevented by basic fibroblast growth factor. J Neurosci Res 40:306-317.
112. Yamada M, T Ikeuchi and H Hatanaka. (1997). The neu-rotrophic action and signalling of epidermal growth factor. Prog Neurobiol 51:19-37
113. Wright KT, W El Masri, A Osman, J Chowdhury and WE Johnson. (2010). Bone marrow for the treatment of spinal cord injury: mechanisms and clinical application. Stem Cells 29:169-178.
114. Kamada T, M Koda, M Dezawa, K Yoshinaga, M Hashimoto, S Koshizuka, Y Nishio, H Moriya and M Yamazaki. (2005). Transplantation of bone marrow stro-mal cell-derived Schwann cells promotes axonal regen-eration and functional recovery after complete transection of adult rat spinal cord. J Neuropathol Exp Neurol 64
115. Lu P, LL Jones and MH Tuszynski. (2005). BDNF-expressing marrow stromal cells support extensive axonal growth at sites of spinal cord injury. Exp Neurol 191: 344-360.
116. Nandoe Tewarie RD, A Hurtado, GJ Ritfeld, ST Rahiem, DF Wendell, MM Barroso, JA Grotenhuis and M Oudega. (2009). Bone marrow stromal cells elicit tissue sparing after acute but not delayed transplantation into the con-tused adult rat thoracic spinal cord. J Neurotrauma 26: 2313-2322.
117. Someya Y, M Koda, M Dezawa, T Kadota, M Hashimoto, T Kamada, Y Nishio, R Kadota, C Mannoji, et al. (2008). Reduction of cystic cavity, promotion of axonal regenera-tion and sparing, and functional recovery with trans-planted bone marrow stromal cell-derived Schwann cells after contusion injury to the adult rat spinal cord. J Neu-rosurg Spine 9:600-610.
118. Teng YD, EB Lavik, X Qu, KI Park, J Ourednik, D Zur-akowski, R Langer and EY Snyder. (2002). Functional re-covery following traumatic spinal cord injury mediated by a unique polymer scaffold seeded with neural stem cells. Proc Natl Acad Sci USA 99:3024-3029.
119. Sykova E and P Jendelova. (2005). Magnetic resonance tracking of implanted adult and embryonic stem cells in injured brain and spinal cord. Ann N Y Acad Sci 1049:146-160.
120. Zurita M and J Vaquero. (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.
121. Bakshi A, AL Barshinger, SA Swanger, V Madhavani, JS Shumsky, B Neuhuber and I Fischer. (2006). Lumbar puncture delivery of bone marrow stromal cells in spinal cord contusion: a novel method for minimally invasive cell transplantation. J Neurotrauma 23:55-65.
122. Crigler L, RC Robey, A Asawachaicharn, D Gaupp and DG Phinney. (2006). Human mesenchymal stem cell subpopu-lations express a variety of neuro-regulatory molecules and promote neuronal cell survival and neuritogenesis. Exp Neurol 198:54-64.
123. Bjorklund A and O Lindvall. (2000). Cell replacement therapies for central nervous system disorders. Nat Neu-rosci 3:537-544.
124. Alexander JK and PG Popovich. (2009). Neuroinflamma-tion in spinal cord injury: therapeutic targets for neuro-protection and regeneration. Prog Brain Res 175:125-137.
125. Bartholdi D and ME Schwab. (1997). Expression of pro-inflammatory cytokine and chemokine mRNA upon experimental spinal cord injury in mouse: an in situ hy-bridization study. Eur J Neurosci 9:1422-1438.
126. Streit WJ, SL Semple-Rowland, SD Hurley, RC Miller, PG Popovich and BT Stokes. (1998). Cytokine mRNA profiles in contused spinal cord and axotomized facial nucleus suggest a beneficial role for inflammation and gliosis. Exp Neurol 152:74-87.
127. Pierce GF, TA Mustoe, BW Altrock, TF Deuel and A Tho-mason. (1991). Role of platelet-derived growth factor in wound healing. J Cell Biochem 45:319-326.
128. Zhang SX, F Huang, M Gates, J White and EG Holmberg. (2010). Extensive scarring induced by chronic intrathecal tubing augmented cord tissue damage and worsened functional recovery after rat spinal cord injury. J Neurosci Methods 191:201-207.
129. Jones LL and MH Tuszynski. (2001). Chronic intrathecal infusions after spinal cord injury cause scarring and com-pression. Microsc Res Tech 54:317-324.
130. Rabchevsky AG and WJ Streit. (1998). Role of microglia in post injury repair and regeneration of the CNS. MRRD Res Rev 4:187-192.