We have isolated and characterized a glial restricted precursor cell (GRP cell) that is present at embryonic age 13.5 (E13.5) in the rat spinal cord and can give rise to oligodendrocytes and astrocytes in vitro and in vivo. We have shown that GRP cells are generated as a direct progeny from the multipotent neuroepithelial stem cells (NEP cells) of the E10.5 spinal cord. At a later time point, the glial precursor population that gives rise to oligodendrocytes, the O-2A/OPC, is formed in the ventral half of the spinal cord. GRP cells, which are not restricted to the ventral half of the spinal cord, can give rise to O-2A/OPC cells in vitro. We now test the hypothesis that the generation of O-2A/OPCs from GRP cells is dependent on factors present in the ventral half of the spinal cord and can be inhibited by dorsally derived signals. In addition, we propose to determine the role of GRP cells in the dorsal region of the spinal cord, and in particular their potential role as an ancestor of astrocytes. ? ? In the spinal cord, there appears to be a direct lineal relationship, involving sequential lineage restrictions, between NEP cells, GRP cells and O-2A/OPCs. We will now test the hypothesis that a similar process occurs in the embryonic brain. In addition to the characterization of putative brain derived GRP cells in vitro, we will determine whether the properties we can identify in tissue culture are retained in vivo by transplanting the cells into the neonatal CNS. ? ? Finally we will test the hypothesis that the lineage restrictions and cell types that are involved during gliogenesis in the embryo are conserved during gliogenesis in the neonatal and adult CNS. We propose to generate GRP cells from adult spinal cord- derived stem cells and from primary adult tissue.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Kleitman, Naomi
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University of Rochester
Schools of Dentistry
United States
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Davies, Stephen J A; Shih, Chung-Hsuan; Noble, Mark et al. (2011) Transplantation of specific human astrocytes promotes functional recovery after spinal cord injury. PLoS One 6:e17328
Noble, Mark; Davies, Jeannette E; Mayer-Proschel, Margot et al. (2011) Precursor cell biology and the development of astrocyte transplantation therapies: lessons from spinal cord injury. Neurotherapeutics 8:677-93
Noble, Mark; Mayer-Proschel, Margot; Davies, Jeannette E et al. (2011) Cell therapies for the central nervous system: how do we identify the best candidates? Curr Opin Neurol 24:570-6
Davies, Jeannette E; Proschel, Christoph; Zhang, Ningzhe et al. (2008) Transplanted astrocytes derived from BMP- or CNTF-treated glial-restricted precursors have opposite effects on recovery and allodynia after spinal cord injury. J Biol 7:24
Davies, Jeannette E; Huang, Carol; Proschel, Christoph et al. (2006) Astrocytes derived from glial-restricted precursors promote spinal cord repair. J Biol 5:7
Dietrich, Jorg; Lacagnina, Michelle; Gass, David et al. (2005) EIF2B5 mutations compromise GFAP+ astrocyte generation in vanishing white matter leukodystrophy. Nat Med 11:277-83
Hill, Caitlin E; Proschel, Christoph; Noble, Mark et al. (2004) Acute transplantation of glial-restricted precursor cells into spinal cord contusion injuries: survival, differentiation, and effects on lesion environment and axonal regeneration. Exp Neurol 190:289-310