Conditioned Medium from Bone Marrow-Derived Mesenchymal Stem Cells Improves Recovery after Spinal Cord Injury in Rats: An Original Strategy to Avoid Cell Transplantation

PLoS ONE

Volumn 8, Issue 8, 2013, Pages

  Cantinieaux, Dorothée ^a   Quertainmont, Renaud ^a   Blacher, Silvia ^a   Rossi, Loïc ^a   Wanet, Thomas ^a   Noël, Agnès ^a   Brook, Gary ^b   Schoenen, Jean ^a   Franzen, Rachelle ^a  

^a UNIVERSITY OF LIÈGE   (Belgium)

^b UNIVERSITY HOSPITAL RWTH AACHEN   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

CYTOKINE;

ANIMAL EXPERIMENT; ANIMAL MODEL; APOPTOSIS; ARTICLE; B LYMPHOCYTE; CELL DIFFERENTIATION; CELL SURVIVAL; CELL TRANSPLANTATION; CONTROLLED STUDY; ENZYME LINKED IMMUNOSORBENT ASSAY; FEMALE; HISTOLOGY; IN VITRO STUDY; IN VIVO STUDY; MACROPHAGE CULTURE; MESENCHYMAL STEM CELL; NONHUMAN; PARACRINE SIGNALING; RAT; SPINAL CORD INJURY;

ANIMALS; APOPTOSIS; AXONS; CELLS, CULTURED; CULTURE MEDIA, CONDITIONED; CYTOKINES; FEMALE; INFLAMMATION MEDIATORS; MESENCHYMAL STROMAL CELLS; MOTOR SKILLS; NEOVASCULARIZATION, PHYSIOLOGIC; NERVE REGENERATION; RATS; RATS, WISTAR; RECOVERY OF FUNCTION; SPINAL CORD INJURIES; TISSUE CULTURE TECHNIQUES;

EID: 84883205797     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0069515     Document Type: Article

References (102)

1. Popovich PG, Wei P, Stokes BT, (1997) Cellular inflammatory response after spinal cord injury in Sprague-Dawley and Lewis rats. J Comp Neurol 377: 443-464.
2. Hausmann ON, (2003) Post-traumatic inflammation following spinal cord injury. Spinal Cord 41: 369-378.
3. Hall ED, (2011) Antioxidant Therapies for Acute Spinal Cord Injury. Neurotherapeutics 8: 152-167.
4. Park E, Velumian AA, Fehlings MG, (2004) The role of excitotoxicity in secondary mechanisms of spinal cord injury: a review with an emphasis on the implications for white matter degeneration. J Neurotrauma 21: 754-774.
5. Warden P, Bamber NI, Li H, Esposito A, Ahmad KA, et al. (2001) Delayed glial cell death following wallerian degeneration in white matter tracts after spinal cord dorsal column cordotomy in adult rats. Exp Neurol 168: 213-224.
6. Guest JD, Hiester ED, Bunge RP, (2005) Demyelination and Schwann cell responses adjacent to injury epicenter cavities following chronic human spinal cord injury. Exp Neurol 192: 384-393.
7. Kato H, Kanellopoulos GK, Matsuo S, Wu YJ, Jacquin MF, et al. (1997) Neuronal apoptosis and necrosis following spinal cord ischemia in the rat. Exp Neurol 148: 464-474.
8. Fujiki M, Kobayashi H, Inoue R, Goda M, (2004) Electrical preconditioning attenuates progressive necrosis and cavitation following spinal cord injury. J Neurotrauma 21: 459-470.
9. Wagner FC Jr, Van Gilder JC, Dohrmann GJ, (1977) The development of intramedullary cavitation following spinal cord injury: an experimental pathological study. Paraplegia 14: 245-250.
10. Wozniewicz B, Filipowicz K, Swiderska SK, Deraka K, (1983) Pathophysiological mechanism of traumatic cavitation of the spinal cord. Paraplegia 21: 312-317.
11. Nishio T, (2009) Axonal regeneration and neural network reconstruction in mammalian CNS. J Neurol 256 Suppl 3: 306-309.
12. Beattie MS, (2004) Inflammation and apoptosis: linked therapeutic targets in spinal cord injury. Trends Mol Med 10: 580-583.
13. Oatway MA, Chen Y, Bruce JC, Dekaban GA, Weaver LC, (2005) Anti-CD11d integrin antibody treatment restores normal serotonergic projections to the dorsal, intermediate, and ventral horns of the injured spinal cord. J Neurosci 25: 637-647.
14. Genovese T, Mazzon E, Muia C, Bramanti P, De Sarro A, et al. (2005) Attenuation in the evolution of experimental spinal cord trauma by treatment with melatonin. J Pineal Res 38: 198-208.
15. Song Y, Zeng Z, Jin C, Zhang J, Ding B, et al. (2012) Protective Effect of Ginkgolide B Against Acute Spinal Cord Injury in Rats and Its Correlation with the JAK/STAT Signaling Pathway. Neurochem Res.
16. van den Brand R, Heutschi J, Barraud Q, DiGiovanna J, Bartholdi K, et al. (2012) Restoring voluntary control of locomotion after paralyzing spinal cord injury. Science 336: 1182-1185.
17. Fan C, Zheng Y, Cheng X, Qi X, Bu P, et al. (2013) Transplantation of D15A-Expressing Glial-Restricted-Precursor-Derived Astrocytes Improves Anatomical and Locomotor Recovery after Spinal Cord Injury. Int J Biol Sci 9: 78-93.
18. Liu J, Chen J, Liu B, Yang C, Xie D, et al. (2013) Acellular spinal cord scaffold seeded with mesenchymal stem cells promotes long-distance axon regeneration and functional recovery in spinal cord injured rats. J Neurol Sci.
19. Dasari VR, Spomar DG, Gondi CS, Sloffer CA, Saving KL, et al. (2007) Axonal remyelination by cord blood stem cells after spinal cord injury. J Neurotrauma 24: 391-410.
20. Li X, Liu X, Cui L, Brunson C, Zhao W, et al. (2012) Engineering an in situ crosslinkable hydrogel for enhanced remyelination. FASEB J.
21. Quertainmont R, Cantinieaux D, Botman O, Sid S, Schoenen J, et al. (2012) Mesenchymal Stem Cell Graft Improves Recovery after Spinal Cord Injury in Adult Rats through Neurotrophic and Pro-Angiogenic Actions. PLoS One 7: e39500.
22. Choi JS, Leem JW, Lee KH, Kim SS, Suh-Kim H, et al. (2012) Effects of human mesenchymal stem cell transplantation combined with polymer on functional recovery following spinal cord hemisection in rats. Korean J Physiol Pharmacol 16: 405-411.
23. Boido M, Garbossa D, Fontanella M, Ducati A, Vercelli A, (2012) Mesenchymal Stem Cell Transplantation Reduces Glial Cyst and Improves Functional Outcome After Spinal Cord Compression. World Neurosurg.
24. Karaoz E, Kabatas S, Duruksu G, Okcu A, Subasi C, et al. (2012) Reduction of lesion in injured rat spinal cord and partial functional recovery of motility after bone marrow derived mesenchymal stem cell transplantation. Turk Neurosurg 22: 207-217.
25. Tharion G, Indirani K, Durai M, Meenakshi M, Devasahayam SR, et al. (2011) Motor recovery following olfactory ensheathing cell transplantation in rats with spinal cord injury. Neurol India 59: 566-572.
26. Franzen R, Schoenen J, Leprince P, Joosten E, Moonen G, et al. (1998) Effects of macrophage transplantation in the injured adult rat spinal cord: a combined immunocytochemical and biochemical study. J Neurosci Res 51: 316-327.
27. Assina R, Sankar T, Theodore N, Javedan SP, Gibson AR, et al. (2008) Activated autologous macrophage implantation in a large-animal model of spinal cord injury. Neurosurg Focus 25: E3.
28. Oudega M, Xu XM, (2006) Schwann cell transplantation for repair of the adult spinal cord. J Neurotrauma 23: 453-467.
29. Cusimano M, Biziato D, Brambilla E, Donega M, Alfaro-Cervello C, et al. (2012) Transplanted neural stem/precursor cells instruct phagocytes and reduce secondary tissue damage in the injured spinal cord. Brain 135: 447-460.
30. Nakajima H, Uchida K, Guerrero AR, Watanabe S, Sugita D, et al. (2012) Transplantation of mesenchymal stem cells promotes an alternative pathway of macrophage activation and functional recovery after spinal cord injury. J Neurotrauma 29: 1614-1625.
31. Uccelli A, Benvenuto F, Laroni A, Giunti D, (2011) Neuroprotective features of mesenchymal stem cells. Best Pract Res Clin Haematol 24: 59-64.
32. Dasari VR, Spomar DG, Cady C, Gujrati M, Rao JS, et al. (2007) Mesenchymal stem cells from rat bone marrow downregulate caspase-3-mediated apoptotic pathway after spinal cord injury in rats. Neurochem Res 32: 2080-2093.
33. Osaka M, Honmou O, Murakami T, Nonaka T, Houkin K, et al. (2010) Intravenous administration of mesenchymal stem cells derived from bone marrow after contusive spinal cord injury improves functional outcome. Brain Res 1343: 226-235.
34. Ide C, Nakai Y, Nakano N, Seo TB, Yamada Y, et al. (2010) Bone marrow stromal cell transplantation for treatment of sub-acute spinal cord injury in the rat. Brain Res 1332: 32-47.
35. Wu S, Suzuki Y, Ejiri Y, Noda T, Bai H, et al. (2003) Bone marrow stromal cells enhance differentiation of cocultured neurosphere cells and promote regeneration of injured spinal cord. J Neurosci Res 72: 343-351.
36. Himes BT, Neuhuber B, Coleman C, Kushner R, Swanger SA, et al. (2006) Recovery of function following grafting of human bone marrow-derived stromal cells into the injured spinal cord. Neurorehabil Neural Repair 20: 278-296.
37. Rooney GE, McMahon SS, Ritter T, Garcia Y, Moran C, et al. (2009) Neurotrophic factor-expressing mesenchymal stem cells survive transplantation into the contused spinal cord without differentiating into neural cells. Tissue Eng Part A 15: 3049-3059.
38. Cizkova D, Rosocha J, Vanicky I, Jergova S, Cizek M, (2006) Transplants of human mesenchymal stem cells improve functional recovery after spinal cord injury in the rat. Cell Mol Neurobiol 26: 1167-1180.
39. Wong RS, (2011) Mesenchymal stem cells: angels or demons? J Biomed Biotechnol 2011: 459510.
40. Breitbach M, Bostani T, Roell W, Xia Y, Dewald O, et al. (2007) Potential risks of bone marrow cell transplantation into infarcted hearts. Blood 110: 1362-1369.
41. Miura M, Miura Y, Padilla-Nash HM, Molinolo AA, Fu B, et al. (2006) Accumulated chromosomal instability in murine bone marrow mesenchymal stem cells leads to malignant transformation. Stem Cells 24: 1095-1103.
42. Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, et al. (2007) Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 449: 557-563.
43. Kunter U, Rong S, Boor P, Eitner F, Muller-Newen G, et al. (2007) Mesenchymal stem cells prevent progressive experimental renal failure but maldifferentiate into glomerular adipocytes. J Am Soc Nephrol 18: 1754-1764.
44. Jeong JO, Han JW, Kim JM, Cho HJ, Park C, et al. (2011) Malignant tumor formation after transplantation of short-term cultured bone marrow mesenchymal stem cells in experimental myocardial infarction and diabetic neuropathy. Circ Res 108: 1340-1347.
45. Timmers L, Lim SK, Hoefer IE, Arslan F, Lai RC, et al. (2011) Human mesenchymal stem cell-conditioned medium improves cardiac function following myocardial infarction. Stem Cell Res 6: 206-214.
46. Kinnaird T, Stabile E, Burnett MS, Shou M, Lee CW, et al. (2004) Local delivery of marrow-derived stromal cells augments collateral perfusion through paracrine mechanisms. Circulation 109: 1543-1549.
47. Togel F, Weiss K, Yang Y, Hu Z, Zhang P, et al. (2007) Vasculotropic, paracrine actions of infused mesenchymal stem cells are important to the recovery from acute kidney injury. Am J Physiol Renal Physiol 292: F1626-1635.
48. Kim HJ, Lee JH, Kim SH, (2010) Therapeutic effects of human mesenchymal stem cells on traumatic brain injury in rats: secretion of neurotrophic factors and inhibition of apoptosis. J Neurotrauma 27: 131-138.
49. Wagner W, Horn P, Castoldi M, Diehlmann A, Bork S, et al. (2008) Replicative senescence of mesenchymal stem cells: a continuous and organized process. PLoS One 3: e2213.
50. Urdzikova L, Jendelova P, Glogarova K, Burian M, Hajek M, et al. (2006) Transplantation of bone marrow stem cells as well as mobilization by granulocyte-colony stimulating factor promotes recovery after spinal cord injury in rats. J Neurotrauma 23: 1379-1391.
51. Chopp M, Zhang XH, Li Y, Wang L, Chen J, et al. (2000) Spinal cord injury in rat: treatment with bone marrow stromal cell transplantation. Neuroreport 11: 3001-3005.
52. Vaquero J, Zurita M, Oya S, Santos M, (2006) Cell therapy using bone marrow stromal cells in chronic paraplegic rats: systemic or local administration? Neurosci Lett 398: 129-134.
53. Park SI, Lim JY, Jeong CH, Kim SM, Jun JA, et al. (2012) Human umbilical cord blood-derived mesenchymal stem cell therapy promotes functional recovery of contused rat spinal cord through enhancement of endogenous cell proliferation and oligogenesis. J Biomed Biotechnol 2012: 362473.
54. Timmers L, Lim SK, Arslan F, Armstrong JS, Hoefer IE, et al. (2007) Reduction of myocardial infarct size by human mesenchymal stem cell conditioned medium. Stem Cell Res 1: 129-137.
55. You SW, Chen BY, Liu HL, Lang B, Xia JL, et al. (2003) Spontaneous recovery of locomotion induced by remaining fibers after spinal cord transection in adult rats. Restor Neurol Neurosci 21: 39-45.
56. Scheff SW, Rabchevsky AG, Fugaccia I, Main JA, Lumpp JE Jr, (2003) Experimental modeling of spinal cord injury: characterization of a force-defined injury device. J Neurotrauma 20: 179-193.
57. Simon CM, Sharif S, Tan RP, LaPlaca MC, (2009) Spinal cord contusion causes acute plasma membrane damage. J Neurotrauma 26: 563-574.
58. Namiki J, Kojima A, Tator CH, (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.
59. Hobson MI, Green CJ, Terenghi G, (2000) VEGF enhances intraneural angiogenesis and improves nerve regeneration after axotomy. J Anat 197 Pt 4: 591-605.
60. Dray C, Rougon G, Debarbieux F, (2009) Quantitative analysis by in vivo imaging of the dynamics of vascular and axonal networks in injured mouse spinal cord. Proc Natl Acad Sci U S A 106: 9459-9464.
61. Sun Y, Jin K, Xie L, Childs J, Mao XO, et al. (2003) VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia. J Clin Invest 111: 1843-1851.
62. Storkebaum E, Lambrechts D, Carmeliet P, (2004) VEGF: once regarded as a specific angiogenic factor, now implicated in neuroprotection. Bioessays 26: 943-954.
63. Sundberg LM, Herrera JJ, Narayana PA, (2011) Effect of vascular endothelial growth factor treatment in experimental traumatic spinal cord injury: in vivo longitudinal assessment. J Neurotrauma 28: 565-578.
64. Wang Y, Yan W, Lu X, Qian C, Zhang J, et al. (2011) Overexpression of osteopontin induces angiogenesis of endothelial progenitor cells via the avbeta3/PI3K/AKT/eNOS/NO signaling pathway in glioma cells. Eur J Cell Biol 90: 642-648.
65. Dai J, Peng L, Fan K, Wang H, Wei R, et al. (2009) Osteopontin induces angiogenesis through activation of PI3K/AKT and ERK1/2 in endothelial cells. Oncogene 28: 3412-3422.
66. Lederle W, Hartenstein B, Meides A, Kunzelmann H, Werb Z, et al. (2010) MMP13 as a stromal mediator in controlling persistent angiogenesis in skin carcinoma. Carcinogenesis 31: 1175-1184.
67. Li WM, Chen WB, (2004) Effect of FGF-BP on angiogenesis in squamous cell carcinoma. Chin Med J (Engl) 117: 621-623.
68. Harris VK, Coticchia CM, Kagan BL, Ahmad S, Wellstein A, et al. (2000) Induction of the angiogenic modulator fibroblast growth factor-binding protein by epidermal growth factor is mediated through both MEK/ERK and p38 signal transduction pathways. J Biol Chem 275: 10802-10811.
69. Geisbusch S, Schray D, Bischoff MS, Lin HM, Griepp RB, et al. (2012) Imaging of vascular remodeling after simulated thoracoabdominal aneurysm repair. J Thorac Cardiovasc Surg 144: 1471-1478.
70. Lu D, Mahmood A, Goussev A, Schallert T, Qu C, et al. (2004) Atorvastatin reduction of intravascular thrombosis, increase in cerebral microvascular patency and integrity, and enhancement of spatial learning in rats subjected to traumatic brain injury. J Neurosurg 101: 813-821.
71. Schucht P, Raineteau O, Schwab ME, Fouad K, (2002) Anatomical correlates of locomotor recovery following dorsal and ventral lesions of the rat spinal cord. Exp Neurol 176: 143-153.
72. Tejima E, Guo S, Murata Y, Arai K, Lok J, et al. (2009) Neuroprotective effects of overexpressing tissue inhibitor of metalloproteinase TIMP-1. J Neurotrauma 26: 1935-1941.
73. Wang Y, Luo W, Reiser G, (2007) Activation of protease-activated receptors in astrocytes evokes a novel neuroprotective pathway through release of chemokines of the growth-regulated oncogene/cytokine-induced neutrophil chemoattractant family. Eur J Neurosci 26: 3159-3168.
74. Uchida K, Nakajima H, Hirai T, Yayama T, Chen K, et al. (2012) The retrograde delivery of adenovirus vector carrying the gene for brain-derived neurotrophic factor protects neurons and oligodendrocytes from apoptosis in the chronically compressed spinal cord of twy/twy mice. Spine (Phila Pa 1976) 37: 2125-2135.
75. Jain A, McKeon RJ, Brady-Kalnay SM, Bellamkonda RV, (2011) Sustained delivery of activated Rho GTPases and BDNF promotes axon growth in CSPG-rich regions following spinal cord injury. PLoS One 6: e16135.
76. Nakano N, Nakai Y, Seo T-B, Yamada Y, Ohno T, et al. (2010) Characterization of conditioned medium of cultured bone marrow stromal cells. Neurosci Lett 483 (1) (): 57-61.
77. Hoch AI, Binder BY, Genetos DC, Leach JK, (2012) Differentiation-dependent secretion of proangiogenic factors by mesenchymal stem cells. PLoS One 7 (4) (): e35579.
78. Cirillo G, Bianco MR, Colangelo AM, Cavaliere C, Daniele de L, et al. (2011) Reactive astrocytosis-induced perturbation of synaptic homeostasis is restored by nerve growth factor. Neurobiol Dis 41: 630-639.
79. Paul C, Samdani AF, Betz RR, Fischer I, Neuhuber B, (2009) Grafting of human bone marrow stromal cells into spinal cord injury: a comparison of delivery methods. Spine (Phila Pa 1976) 34: 328-334.
80. Nandoe Tewarie RD, Hurtado A, Ritfeld GJ, Rahiem ST, Wendell DF, et al. (2009) Bone marrow stromal cells elicit tissue sparing after acute but not delayed transplantation into the contused adult rat thoracic spinal cord. J Neurotrauma 26: 2313-2322.
81. Samdani AF, Paul C, Betz RR, Fischer I, Neuhuber B, (2009) Transplantation of human marrow stromal cells and mono-nuclear bone marrow cells into the injured spinal cord: a comparative study. Spine (Phila Pa 1976) 34: 2605-2612.
82. Kang ES, Ha KY, Kim YH, (2012) Fate of transplanted bone marrow derived mesenchymal stem cells following spinal cord injury in rats by transplantation routes. J Korean Med Sci 27: 586-593.
83. Gabay C, (2006) Interleukin-6 and chronic inflammation. Arthritis Res Ther 8 Suppl 2: S3.
84. Pedroza M, Schneider DJ, Karmouty-Quintana H, Coote J, Shaw S, et al. (2011) Interleukin-6 contributes to inflammation and remodeling in a model of adenosine mediated lung injury. PLoS One 6: e22667.
85. Neumann J, Gunzer M, Gutzeit HO, Ullrich O, Reymann KG, et al. (2006) Microglia provide neuroprotection after ischemia. FASEB J 20: 714-716.
86. Weldon DT, Rogers SD, Ghilardi JR, Finke MP, Cleary JP, et al. (1998) Fibrillar beta-amyloid induces microglial phagocytosis, expression of inducible nitric oxide synthase, and loss of a select population of neurons in the rat CNS in vivo. J Neurosci 18: 2161-2173.
87. Fuller AD, Van Eldik LJ, (2008) MFG-E8 regulates microglial phagocytosis of apoptotic neurons. J Neuroimmune Pharmacol 3: 246-256.
88. Yang P, Wen H, Ou S, Cui J, Fan D, (2012) IL-6 promotes regeneration and functional recovery after cortical spinal tract injury by reactivating intrinsic growth program of neurons and enhancing synapse formation. Exp Neurol 236: 19-27.
89. Parish CL, Finkelstein DI, Tripanichkul W, Satoskar AR, Drago J, et al. (2002) The role of interleukin-1, interleukin-6, and glia in inducing growth of neuronal terminal arbors in mice. J Neurosci 22: 8034-8041.
90. Liu Z, Qiu YH, Li B, Ma SH, Peng YP, (2011) Neuroprotection of interleukin-6 against NMDA-induced apoptosis and its signal-transduction mechanisms. Neurotox Res 19: 484-495.
91. Li XZ, Bai LM, Yang YP, Luo WF, Hu WD, et al. (2009) Effects of IL-6 secreted from astrocytes on the survival of dopaminergic neurons in lipopolysaccharide-induced inflammation. Neurosci Res 65: 252-258.
92. Zeng X, Zeng YS, Ma YH, Lu LY, Du BL, et al. (2011) Bone marrow mesenchymal stem cells in a three-dimensional gelatin sponge scaffold attenuate inflammation, promote angiogenesis, and reduce cavity formation in experimental spinal cord injury. Cell Transplant 20: 1881-1899.
93. Keimpema E, Fokkens MR, Nagy Z, Agoston V, Luiten PG, et al. (2009) Early transient presence of implanted bone marrow stem cells reduces lesion size after cerebral ischaemia in adult rats. Neuropathol Appl Neurobiol 35: 89-102.
94. Figueiredo C, Pais TF, Gomes JR, Chatterjee S, (2008) Neuron-microglia crosstalk up-regulates neuronal FGF-2 expression which mediates neuroprotection against excitotoxicity via JNK1/2. J Neurochem 107: 73-85.
95. Bruce-Keller AJ, (1999) Microglial-neuronal interactions in synaptic damage and recovery. J Neurosci Res 58: 191-201.
96. Lalancette-Hebert M, Gowing G, Simard A, Weng YC, Kriz J, (2007) Selective ablation of proliferating microglial cells exacerbates ischemic injury in the brain. J Neurosci 27: 2596-2605.
97. Wislet-Gendebien S, Leprince P, Moonen G, Rogister B, (2003) Regulation of neural markers nestin and GFAP expression by cultivated bone marrow stromal cells. J Cell Sci 116: 3295-3302.
98. Hans G, Malgrange B, Lallemend F, Crommen J, Wislet-Gendebien S, et al. (2005) Beta-carbolines induce apoptosis in cultured cerebellar granule neurons via the mitochondrial pathway. Neuropharmacology 48: 105-117.
99. Sounni NE, Devy L, Hajitou A, Frankenne F, Munaut C, et al. (2002) MT1-MMP expression promotes tumor growth and angiogenesis through an up-regulation of vascular endothelial growth factor expression. FASEB J 16: 555-564.
100. Blacher S, Devy L, Burbridge MF, Roland G, Tucker G, et al. (2001) Improved quantification of angiogenesis in the rat aortic ring assay. Angiogenesis 4: 133-142.
101. Basso DM, Beattie MS, Bresnahan JC, (1995) A sensitive and reliable locomotor rating scale for open field testing in rats. J Neurotrauma 12: 1-21.
102. Perrin FE, Boniface G, Serguera C, Lonjon N, Serre A, et al. (2010) Grafted human embryonic progenitors expressing neurogenin-2 stimulate axonal sprouting and improve motor recovery after severe spinal cord injury. PLoS One 5: e15914.