An abundant population of glial progenitor cells resides in the adult human subcortical white matter. These cells give rise to myelinogenic oligodendrocytes upon transplantation, yet when removed from the tissue environment they behave as multipotential neurogenic progenitors. To identify genes that regulate their homeostasis and cell fate decisions of these adult progenitor cells, the transcriptional profile of A2B5+ white matter progenitor cells (WMPCs) sorted from human surgical resections. The profile of each progenitor isolate sorted cell population was then normalized against that of the tissue white matter from which it was derived to identify progenitor-enriched transcripts. WMPCs expressed high levels of PDGFaR, GD3 synthase and NG2 prototypic oligodendrocyte progenitor genes, yet they also expressed high levels of MASH1 and HES1, suggesting a more primitive phenotype. RNAs encoding the members of several parallel signaling pathways were differentially expressed by WPMCs relative to unsorted cells. These included receptor tyrosine phosphate (RTP)-β/ζ, its ligand pleiotrophin, and its modulators NrCAM, tenascin R, and the chondroitin sulfate proteoglycans (CSPG2-5); PDGFαR, which induces pleiotrophin; syndecan-3, its membrane partner FGFR3, and its intracellular partner CASK; the BMP inhibitors neuralin and BAMBI; and the notch intermediates HES1, musashi and FHL1B. When exposed to oxovanadate, an RTP inhibitor, WMPCs ceased expansion and differentiated as oligodendrocytes, validating the central role of RTP-β/ζ in progenitor self-maintenance. The co-activation of RTP-β/ζ with these interactive parallel pathways may provide the means by which adult progenitors are maintained in a multipotential and mitotically-competent state. As such, they may provide targets by which to perturb cell fate choices by progenitor cells of the adult human brain.
A population of nominally glial progenitor cells resides in the parenchyma of the adult human subcortical white matter. These cells may be defined by A2B5-immunoreactivity, and by their expression of fluorescent reporters placed under the control of the CNP2 promoter (Roy et al., “Identification, Isolation, and Promoter-defined Separation of Mitotic Oligodendrocyte Progenitor Cells From the Adult Human Subcortical White Matter.” J Neurosci 19: 9986-95 (1999); Nunes et al., “Identification and Isolation of Multipotential Neural Progenitor Cells from the Subcortical White Matter of the Adult Human Brain.” Nat Med 9: 439-447 (2003)). The cells typically act as oligodendrocyte progenitors, giving rise to myelinogenic oligodendrocytes upon transplantation. However, when removed from the tissue environment, they behave as multipotential and neurogenic progenitor cells. This observation suggested that the local tissue environment regulates both the self-renewal and phenotype of parenchymal glial progenitors, such that the latter actually represent a pool of multipotential progenitors whose fate is tonically restricted by their local tissue environment. As a result, the environmental cues presented to these cells, and their responsiveness to these signals, may determine not only their mitotic turnover, but also their undifferentiated self-renewal and post-mitotic lineage choices. Yet no studies to date have specifically examined the environment of the adult human white matter from the standpoint of steady-state cues and cell-specific responsiveness by resident progenitor cells.
The present invention is directed to overcoming this deficiency in the art.
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