In the first 4 years of this grant, we assessed the cell biology and transplantation characteristics of adult human oligodendrocyte progenitor cells. We established means for their specific isolation, using CNP2:GFP and A2B5 based fluorescence-activated cell sorting (FACS), and then assessed their lineage potential. We discovered that when removed to low density culture, the progenitors were multipotential, and gave rise to neurons as well as to gila. Thus, absent autocrine and paracrine influences on their differentiation, adult WMPCs were not restricted to oligodendrocytic fate. To assess the role of the tissue environment in regulating progenitor fate, we then investigated gene expression by adult human WMPCs. We focused on identifying those transcripts that are differentially expressed by the WMPC, relative to its local tissue environment. This process enabled us to predict ligand-receptor interactions that maintain the progenitor state, as well as those that determine whether a given cell develops into an astrocyte, oligodendrocyte, or neuron. This analysis identified a set of parallel pathways that together appear to regulate the maintenance, mobilization and differentiated fate of parenchymal progenitor cells. In particular, we noted a complex interaction of: 1) receptor tyrosine phosphatase beta/zeta signaling, as regulated by its ligands pleiotrophin and NrCAM; 2) a parallel avenue of syndecan3 regulated signaling through CASK and tbr1; 3) FGFR3-dependent signaling, likely mediated through syndecan3 proteolysis and release of CASK; and 4) a neuralin and BAMBI-suppression of BMP signals. It appears that the net output of these pathways biases adult progenitors to either self-renewal or differentiation. In this application, we propose to use a combination of protein delivery, adenoviral overexpression and lentiviral RNAi knock-down to evaluate the individual elements of these candidate systems. By this means, we intend to better define the niche for gliogenesis in the adult human white matter, and by so doing to establish both necessary and sufficient genetic targets for directing the phenotypes generated by resident progenitor cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS039559-05
Application #
6871626
Study Section
Neurodegeneration and Biology of Glia Study Section (NDBG)
Program Officer
Owens, David F
Project Start
1999-12-01
Project End
2009-05-31
Budget Start
2004-09-15
Budget End
2005-05-31
Support Year
5
Fiscal Year
2004
Total Cost
$324,675
Indirect Cost
Name
University of Rochester
Department
Neurology
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
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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