Stem cells continuously generate new neurons in restricted regions of the adult mammalian brain. The subventricular zone (SVZ) is the largest germinal region in the adult gives rise to neurons that migrate to the olfactory bulb as well as some oligodendrocytes. The in vivo stem cells are a subset of astrocytes, glial cells classically associated with support functions. These endogenous stem cells potentially represent a pool of cells that can be harnessed for brain repair. A balance between intrinsic and extrinsic signals mediates the activation of quiescent stem cells. However, the ability to distinguish between quiescent and activated stem cells has been hampered by a lack of markers. Here we identify a combination of markers that allow us to identify and isolate four populations of astrocytes from the SVZ directly from the in vivo niche. Based on cell cycle analysis, in vitro stem cell behavior and gene expression profiling, we hypothesize that they correspond to quiescent stem cell astrocytes, activated stem cell astrocytes and niche astrocytes. We propose to: 1) Define the cell cycle kinetics of the purified astrocyte populations, and their ability to act as stem cells in vitro, as well as how their numbers and functional properties change with aging, 2) perform lineage tracing of quiescent and activated stem cells under homeostasis and during regeneration and 3) define the role of PDGFRb in regulating adult neural stem cell quiescence. Together these studies will yield key insights into the regulation of stem cell quiescence in the adult brain.
Stem cells in the adult brain are a specialized kind of glial cell. Here we propose to define the progeny and molecular regulation of quiescent adult neural stems cells. These findings will inform strategies for brain repair.
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