Demyelination in the setting of oligodendrocytic loss is a significant contributor to neurological dysfunction in a variety of subcortical pathologies, including posthypoxic leukoencephalopathy, capsular stroke, and head trauma, as well as in the inflammatory, hereditary and degenerative leukoencephalopathies. We have found that a distinct and separate pool of mitotically-competent oligodendrocyte (oligo) progenitor cells resides in the adult human capsular white matter. This glial progenitor does not appear to be uncommon; it may comprise as many as 4 percent of the cells of the mature white matter. Although the existence of an analogous cell-type has been postulated in rats, its presence in humans had remained controversial, in part because of the difficulty in specifically identifying or obtaining these cells. We therefore developed a means of isolating these cells from adult human patients, by transfecting dissociates of resected white matter with plasmids that selectively identify oligo progenitors, by their expression of fluorescent transgenes controlled by early oligodendrocyte promoters. Specifically, we use the early promoter (P2) for cyclic nucleotide phosphodiesterase (CNP), which is preferentially active in mitotic oligo progenitors, to direct expression of green fluorescence protein (GFP) to these cells. This approach has allowed us not only to identify live oligo progenitors in vitro, but to enrich them by fluorescence-activated cell sorting (FACS). As a result, we can use FACS based upon CNP2:hGFP expression to purify oligodendrocyte progenitor cells from the adult human white matter, in high-yield, and with retained mitotic potential, differentiation competence and in vitro survival. In this application, I will capitalize upon our acquisition of these purified adult human oligodendrocyte progenitor cells, with experiments designed to assess their capacity for structural remyelination. To this end, I plan to define several therapeutically-relevant aspects of the biology of these cells, including 1) their lineage potential and capacity for myelination, and the humoral control thereof, and 2) the humoral regulation of their clonal expansion, and 3) their capacity for oligodendrocytic maturation and myelination upon engraftment. To these ends, I plan to transplant P/CNP2:hGFP-defined, FACS-purified populations of adult human oligo progenitors into a rodent model of focal demyelination. These latter studies would serve as a prelude to preclinical analysis of this cell type's response to implantation in nonhuman primates, in models of both chemical and radiation-induced demyelination. This application is intended to develop oligodendrocyte precursor implants, as well as induced oligoneogenesis from endogenous progenitors, as feasible therapeutic options for the structural repair of demyelinated brain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS039559-04
Application #
6625472
Study Section
Special Emphasis Panel (ZRG1-MDCN-2 (01))
Program Officer
Chiu, Arlene Y
Project Start
1999-12-01
Project End
2004-08-31
Budget Start
2002-12-01
Budget End
2004-08-31
Support Year
4
Fiscal Year
2003
Total Cost
$319,687
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Neurology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Osorio, M Joana; Rowitch, David H; Tesar, Paul et al. (2017) Concise Review: Stem Cell-Based Treatment of Pelizaeus-Merzbacher Disease. Stem Cells 35:311-315
Goldman, Steven A (2016) Stem and Progenitor Cell-Based Therapy of the Central Nervous System: Hopes, Hype, and Wishful Thinking. Cell Stem Cell 18:174-88
Nedergaard, Maiken; Goldman, Steven A (2016) BRAIN DRAIN. Sci Am 314:44-9
Wang, Su; Bates, Janna; Li, Xiaojie et al. (2013) Human iPSC-derived oligodendrocyte progenitor cells can myelinate and rescue a mouse model of congenital hypomyelination. Cell Stem Cell 12:252-64
Auvergne, Romane M; Sim, Fraser J; Wang, Su et al. (2013) Transcriptional differences between normal and glioma-derived glial progenitor cells identify a core set of dysregulated genes. Cell Rep 3:2127-41
Guo, Huang; Zhao, Zhen; Yang, Qi et al. (2013) An activated protein C analog stimulates neuronal production by human neural progenitor cells via a PAR1-PAR3-S1PR1-Akt pathway. J Neurosci 33:6181-90
McClain, Crystal R; Sim, Fraser J; Goldman, Steven A (2012) Pleiotrophin suppression of receptor protein tyrosine phosphatase-?/? maintains the self-renewal competence of fetal human oligodendrocyte progenitor cells. J Neurosci 32:15066-75
Goldman, Steven A; Nedergaard, Maiken; Windrem, Martha S (2012) Glial progenitor cell-based treatment and modeling of neurological disease. Science 338:491-5
Oberheim, Nancy Ann; Goldman, Steven A; Nedergaard, Maiken (2012) Heterogeneity of astrocytic form and function. Methods Mol Biol 814:23-45
Goldman, Steven A; Chen, Zhuoxun (2011) Perivascular instruction of cell genesis and fate in the adult brain. Nat Neurosci 14:1382-9

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