The existence of neural stem cells in the adult central nervous system (CNS) of all mammals, including humans, raises the possibility to self-replace damaged or lost neurons by activation of endogenous neural stem cells or transplantation of in vitro expanded stem cells and their progeny derived from the same person. For the full potential of adult neural stem cells to be realized, we need to identify the origin and source of adult neural stem cells, to understand the mechanisms underlying their proliferation, fate determination, and importantly in the case of neuronal lineages, to characterize their functional properties. In the intact mammalian CNS, active neurogenesis only occurs in discrete regions with mostly gliogenesis in other regions. Multipotent neural progenitors, however, can be isolated from both neurogenic and non-neurogenic regions. Since neurological diseases and injury occur in diverse regions of the CNS, including non-neurogenic regions, it is important to determine whether endogenous adult neural progenitors only exist in neurogenic regions or they are widely distributed and their neurogenic potentials are limited by their local environment. It is also important to determine whether in vitro expanded neural progenitors derived from different regions of the adult CNS behavior exhibit similar properties. Specifically, we need to understand whether cell-intrinsic differences between neural progenitors from different regions of the adult CNS, especially from non-neurogenic regions, (1) will influence their response to extrinsic stimulations for differentiation and maturation, and (2) will limit their capacity to acquire full spectrum of functional properties of mature CNS neurons. We have established multipotent clonal lines of adult neural progenitors derived from different regions of the adult CNS and developed methods to investigate their fate determination and measure their functional and electrophysiological properties. In this project, we propose to use adult neural progenitors from hippocampus (neurogenic region) and spinal cord (non-neurogenic region) as examples to examine the fate specification and maturation of in vitro expanded neural progenitors and the underlying molecular mechanisms. In particular, we will characterize the functional properties of neuronal progeny of different adult neural progenitors with immunocytochemistry, electron microscopy, FM imaging and electrophysiology. Finally, we will determine the intrinsic neurogenic potentials of endogenous progenitors of adult spinal cord by a set of transplantation studies
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