Ng2+progenitors derived from embryonic stem cells penetrate glial scar and promote axonal outgrowth into white matter after spinal cord injury

Stem Cells Translational Medicine

Volumn 4, Issue 4, 2015, Pages 401-411

  Vadivelu, Sudhakar ^a   Stewart, Todd J ^b   Qu, Yun ^a   Horn, Kevin ^c   Liu, Su ^a   Li, Qun ^a   Silver, Jerry ^c   McDonald, John W ^a,d  

^a KENNEDY KRIEGER INSTITUTE   (United States)

^b WASHINGTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

^c CASE WESTERN RESERVE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^d JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Axonal regeneration; Central nervous; Differentiation; Glia; Glial scar; Matrix metalloproteinase; Neural progenitor; Plasticity; Spinal cord injury

Indexed keywords

AGGRECAN; CHOLINE ACETYLTRANSFERASE; GELATINASE B; GLIAL FIBRILLARY ACIDIC PROTEIN; MICROTUBULE ASSOCIATED PROTEIN 2; NERVE GLIAL ANTIGEN 2; NERVE PROTEIN; NESTIN; PROTEOCHONDROITIN SULFATE; UNCLASSIFIED DRUG; ANTIGEN; CHONDROITIN SULFATE PROTEOGLYCAN 4; MMP9 PROTEIN, HUMAN; PROTEOGLYCAN;

ADULT; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CELL CULTURE; CELL DIFFERENTIATION; CELL LABELING; CELL LINEAGE; CELL MIGRATION; CONFOCAL MICROSCOPY; CONTROLLED STUDY; EMBRYONIC STEM CELL; FEMALE; GRAY MATTER; IMMUNOHISTOCHEMISTRY; IN VIVO STUDY; MICROENVIRONMENT; NERVE CELL PLASTICITY; NERVE FIBER GROWTH; NERVE REGENERATION; NEURAL STEM CELL; NONHUMAN; OLIGODENDROCYTE PRECURSOR CELL; PROTEIN DEGRADATION; PROTEIN EXPRESSION; RAT; SCAR; SPINAL CORD INJURY; STEM CELL NICHE; STEM CELL TRANSPLANTATION; WHITE MATTER; CYTOLOGY; GLIA; GROWTH, DEVELOPMENT AND AGING; HUMAN; METABOLISM; NERVE CELL; NERVE FIBER; PATHOLOGY; SPINAL CORD INJURIES; TRANSPLANTATION;

ANTIGENS; AXONS; CHONDROITIN SULFATE PROTEOGLYCANS; CICATRIX; EMBRYONIC STEM CELLS; HUMANS; MATRIX METALLOPROTEINASE 9; NERVE REGENERATION; NEUROGLIA; NEURONS; PROTEOGLYCANS; SPINAL CORD INJURIES; WHITE MATTER;

EID: 84929939097     PISSN: 21576564     EISSN: 21576580     Source Type: Journal    
DOI: 10.5966/sctm.2014-0107     Document Type: Article

References (68)

1. Sellers DL, Maris DO, Horner PJ. Postinjury niches induce temporal shifts in progenitor fates to direct lesion repair after spinal cord injury. J Neurosci 2009;29:6722–6733.
2. Busch SA, Horn KP, Cuascut FX et al. Adult NG2+ cells are permissive to neurite outgrowth and stabilize sensory axons during macrophageinduced axonal dieback after spinal cord injury. J Neurosci 2010;30:255–265.
3. Dou CL, Levine JM. Inhibition of neurite growth by the NG2 chondroitin sulfate proteoglycan. J Neurosci 1994;14:7616–7628.
4. Jones LL, Sajed D, Tuszynski MH. Axonal regeneration through regions of chondroitin sulfate proteoglycan deposition after spinal cord injury: A balance of permissiveness and inhibition. J Neurosci 2003;23:9276–9288.
5. GrandPré T, Nakamura F, Vartanian T et al. Identification of the Nogo inhibitor of axon regeneration as a Reticulon protein. Nature 2000;403:439–444.
6. Davies SJ, Fitch MT, Memberg SP et al. Regeneration of adult axons in white matter tracts of the central nervous system. Nature 1997;390: 680–683.
7. Davies SJ, Field PM, Raisman G. Embryonic tissue induces growth of adult axons frommyelinated fiber tracts. Exp Neurol 1997;145:471–476.
8. Fouad K, Dietz V, Schwab ME. Improving axonal growth and functional recovery after experimental spinal cord injury by neutralizing myelin associated inhibitors. Brain Res Brain Res Rev 2001;36:204–212.
9. Bradbury EJ, Moon LD, Popat RJ et al. Chondroitinase ABC promotes functional recovery after spinal cord injury. Nature 2002;416:636–640.
10. Cafferty WB, Yang SH, Duffy PJ et al. Functional axonal regeneration through astrocytic scar genetically modified to digest chondroitin sulfate proteoglycans. J Neurosci 2007; 27:2176–2185.
11. Houle JD, Tom VJ, Mayes D et al. Combining an autologous peripheral nervous system “bridge” and matrix modification by chondroitinase allows robust, functional regeneration beyond a hemisection lesion of the adult rat spinal cord. J Neurosci 2006;26:7405–7415.
12. Fouad K, Schnell L, Bunge MB et al. Combining Schwann cell bridges and olfactoryensheathing glia grafts with chondroitinase promotes locomotor recovery after complete transection of the spinal cord. J Neurosci 2005;25:1169–1178.
13. Sabelström H, Stenudd M, Réu P et al. Resident neural stem cells restrict tissue damage and neuronal loss after spinal cord injury in mice. Science 2013;342:637–640.
14. Ankeny DP, McTigue DM, Jakeman LB. Bone marrow transplants provide tissue protection and directional guidance for axons after contusive spinal cord injury in rats. Exp Neurol 2004;190:17–31.
15. Nikulina E, Tidwell JL, Dai HN et al. The phosphodiesterase inhibitor rolipram delivered after a spinal cord lesion promotes axonal regeneration and functional recovery. Proc Natl Acad Sci USA 2004;101:8786–8790.
16. Ellezam B, Dubreuil C, WintonMet al. Inactivation of intracellular Rho to stimulate axon growth and regeneration. Prog Brain Res 2002; 137:371–380.
17. Jin Y, Fischer I, Tessler A et al. Transplants of fibroblasts genetically modified to express BDNFpromote axonal regeneration from supraspinal neurons following chronic spinal cord injury. Exp Neurol 2002;177:265–275.
18. Dergham P, Ellezam B, Essagian C et al. Rho signaling pathway targeted to promote spinal cord repair. J Neurosci 2002;22:6570–6577.
19. Qiu J, Cai D, Dai H et al. Spinal axon regeneration induced by elevation of cyclic AMP. Neuron 2002;34:895–903.
20. Wictorin K, Björklund A. Axon outgrowth from grafts of human embryonic spinal cord in the lesioned adult rat spinal cord. Neuroreport 1992;3:1045–1048.
21. Neumann S, Bradke F, Tessier-Lavigne M et al. Regeneration of sensory axons within the injured spinal cord induced by intraganglionic cAMP elevation. Neuron 2002;34:885–893.
22. Harper JM, Krishnan C, Darman JS et al. Axonal growth of embryonic stem cell-derived motoneurons in vitro and in motoneuron-injured adult rats. Proc Natl Acad Sci USA 2004;101: 7123–7128.
23. Hill CE, Proschel C, Noble M et al. Acute transplantation of glial-restricted precursor cells into spinal cord contusion injuries: Survival, differentiation, and effects on lesion environment and axonal regeneration. Exp Neurol 2004;190:289–310.
24. Friedman JA, Windebank AJ, Moore MJ et al. Biodegradable polymer grafts for surgical repair of the injured spinal cord. Neurosurgery 2002;51:742–751.
25. McTigue DM, Horner PJ, Stokes BT et al. Neurotrophin-3 and brain-derived neurotrophic factor induce oligodendrocyte proliferation and myelination of regenerating axons in the contused adult rat spinal cord. J Neurosci 1998;18:5354–5365.
26. Koprivica V, Cho KS, Park JB et al. EGFRactivation mediates inhibition of axon regeneration by myelin and chondroitin sulfate proteoglycans. Science 2005;310:106–110.
27. Nothias JM, Mitsui T, Shumsky JS et al. Combined effects of neurotrophin secreting transplants, exercise, and serotonergic drug challenge improve function in spinal rats. Neurorehabil Neural Repair 2005;19:296–312.
28. Lu P, Yang H, Jones LL et al. Combinatorial therapy with neurotrophins and cAMP promotes axonal regeneration beyond sites of spinal cord injury. J Neurosci 2004;24:6402–6409.
29. Pearse DD, Pereira FC, Marcillo AE et al. cAMP and Schwann cells promote axonal growth and functional recovery after spinal cord injury. Nat Med 2004;10:610–616.
30. Chau CH, Shum DK, Li H et al. Chondroitinase ABC enhances axonal regrowth through Schwann cell-seeded guidance channels after spinal cord injury. FASEB J 2004;18:194–196.
31. Steinmetz MP, Horn KP, Tom VJ et al. Chronic enhancement of the intrinsic growth capacity of sensory neurons combined with the degradation of inhibitory proteoglycans allows functional regeneration of sensory axons through thedorsal rootentryzoneinthemammalian spinal cord. J Neurosci 2005;25:8066–8076.
32. Vadivelu S, Platik MM, Choi L et al. Multigerm layer lineage central nervous system repair: Nerve and vascular cell generation by embryonic stem cells transplanted in the injured brain. J Neurosurg 2005;103:124–135.
33. Houle JD, Tessler A. Repairof chronic spinal cord injury. Exp Neurol 2003;182:247–260.
34. Reier PJ, Houle JD, Jakeman L et al. Transplantation of fetal spinal cord tissue into acute and chronic hemisection and contusion lesions of the adult rat spinal cord. Prog Brain Res 1988; 78:173–179.
35. Coumans JV, Lin TT, Dai HN et al. Axonal regeneration and functional recovery after complete spinal cord transection in rats by delayed treatment with transplants and neurotrophins. J Neurosci 2001;21:9334–9344.
36. Jin Y, Tessler A, Fischer I et al. Fibroblasts genetically modified to produce BDNF support regrowth of chronically injured serotonergic axons. Neurorehabil Neural Repair 2000;14:311–317.
37. Barakat DJ, Gaglani SM, Neravetla SR et al. Survival, integration, and axon growth support of glia transplanted into the chronically contused spinal cord. Cell Transplant 2005;14: 225–240.
38. Lu P, Jones LL, Tuszynski MH. Axon regeneration through scars and into sites of chronic spinal cord injury. Exp Neurol 2007;203:8–21.
39. Lu P, Wang Y, Graham L et al. Longdistance growth and connectivity of neural stem cells after severe spinal cord injury. Cell 2012;150:1264–1273.
40. Liu S, Qu Y, Stewart TJ et al. Embryonic stem cells differentiate into oligodendrocytes and myelinate in culture and after spinal cord transplantation. Proc Natl Acad Sci USA 2000; 97:6126–6131.
41. Keirstead HS, Nistor G, Bernal G et al. Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury. J Neurosci 2005;25:4694–4705.
42. Hadjantonakis AK, Gertsenstein M, Ikawa M et al. Generating green fluorescent mice by germline transmission of green fluorescent ES cells. Mech Dev 1998;76:79–90.
43. McDonald JW, Liu XZ, Qu Y et al. Transplanted embryonic stem cells survive, differentiate and promote recovery in injured rat spinal cord. Nat Med 1999;5:1410–1412.
44. Bain G, Kitchens D, Yao M et al. Embryonic stem cells express neuronal properties in vitro. Dev Biol 1995;168:342–357.
45. Tom VJ, Steinmetz MP, Miller JH et al. Studies on the development and behavior of the dystrophic growth cone, the hallmark of regeneration failure, in an in vitro model of the glial scar and after spinal cord injury. J Neurosci 2004;24:6531–6539.
46. Dong H, Fazzaro A, Xiang C et al. Enhanced oligodendrocyte survival after spinal cord injury in Bax-deficient mice and mice with delayed Wallerian degeneration. J Neurosci 2003;23:8682–8691.
47. Qu Y, Vadivelu S, Choi L et al. Neurons derived from embryonic stem (ES) cells resemble normal neurons in their vulnerability to excitotoxic death. Exp Neurol 2003;184:326–336.
48. Tom VJ, Doller CM, Malouf AT et al. Astrocyte-associated fibronectin is critical for axonal regeneration in adult white matter. J Neurosci 2004;24:9282–9290.
49. Tan AM, Zhang W, Levine JM. NG2: A component of the glial scar that inhibits axon growth. J Anat 2005;207:717–725.
50. Pasterkamp RJ, Verhaagen J. Emerging roles for semaphorins in neural regeneration. Brain Res Brain Res Rev 2001;35:36–54.
51. Houlé JD, Reier PJ. Transplantation of fetal spinal cordtissueinto thechronically injuredadult rat spinal cord. JCompNeurol 1988;269:535–547.
52. Yang Z, Suzuki R, Daniels SB et al. NG2 glial cells provide a favorable substrate for growing axons. J Neurosci 2006;26:3829–3839.
53. Busch SA, Hamilton JA, Horn KP et al. Multipotent adult progenitor cells prevent macrophage-mediated axonal dieback and promote regrowth after spinal cord injury. J Neurosci 2011;31:944–953.
54. Ketschek AR, Haas C, Gallo G et al. The roles of neuronal and glial precursors in overcoming chondroitin sulfate proteoglycan inhibition. Exp Neurol 2012;235:627–637.
55. Noble LJ, Donovan F, Igarashi T et al. Matrix metalloproteinases limit functional recovery after spinal cord injury by modulation of early vascular events. J Neurosci 2002;22: 7526–7535.
56. Goussev S, Hsu JY, Lin Y et al. Differential temporal expression of matrix metalloproteinases after spinal cord injury: Relationship to revascularization and wound healing. J Neurosurg 2003;99 (suppl):188–197.
57. Larsen PH, Wells JE, Stallcup WB et al. Matrix metalloproteinase-9 facilitates 7remyelination in part by processing the inhibitory NG2 proteoglycan. JNeurosci2003;23:11127–11135.
58. Oh LY, Larsen PH, Krekoski CA et al. Matrix metalloproteinase-9/gelatinase B is required for process outgrowth by oligodendrocytes. J Neurosci 1999;19:8464–8475.
59. Uhm JH, Dooley NP, Oh LY et al. Oligodendrocytes utilize a matrix metalloproteinase, MMP-9, to extend processes along an astrocyte extracellular matrix. Glia 1998;22:53–63.
60. Pendleton JC, Shamblott MJ, Gary DS et al. Chondroitin sulfate proteoglycans inhibit oligodendrocyte myelination through PTPs Exp Neurol 2013;247:113–121.
61. Filous AR, Tran A, Howell CJ et al. Entrapment via synaptic-like connections between NG2 proteoglycan+ cells and dystrophic axons in the lesion plays a role in regeneration failure after spinal cord injury. J Neurosci 2014;34: 16369–16384.
62. Sellers DL, Horner PJ. Instructive niches: Environmental instructions that confound NG2 proteoglycan expression and the faterestriction of CNS progenitors. J Anat 2005; 207:727–734.
63. Horner PJ, Thallmair M, Gage FH. Defining the NG2-expressing cell of the adult CNS. J Neurocytol 2002;31:469–480.
64. McTigue DM, Wei P, Stokes BT. Proliferation of NG2-positive cells and altered oligodendrocyte numbers in the contused rat spinal cord. J Neurosci 2001;21:3392–3400.
65. McTigue DM, Tripathi R, Wei P. NG2 colocalizes with axons and is expressed by a mixed cell population in spinal cord lesions. J Neuropathol Exp Neurol 2006;65:406–420.
66. Zuo J, Ferguson TA, Hernandez YJ et al. Neuronal matrix metalloproteinase-2 degrades and inactivates a neurite-inhibiting chondroitin sulfate proteoglycan. J Neurosci 1998;18:5203–5211.
67. Duchossoy Y, Horvat JC, Stettler O. MMPrelated gelatinase activity is strongly induced in scar tissue of injured adult spinal cord and forms pathways for ingrowing neurites. Mol Cell Neurosci 2001;17:945–956.
68. Lakka SS, Rajan M, Gondi C et al. Adenovirus-mediated expression of antisense MMP-9 in glioma cells inhibits tumor growth and invasion. Oncogene 2002;21:8011–8019.