NEURAL STEM-PROGENITOR CELL REPAIR POTENTIAL AT DISTINCT SITES OF TBI PATHOLOGY

The repair capacity of neural stem/progenitor (NS-P) cells, i.e. endogenous cycling cells, in the adult brain has been revealed by experimental manipulations to increase permissiveness of the tissue environment and by transplantation of neural stem cells that modulate the immune response and stimulate endogenous NS-P cell regenerative responses. Distinct populations of NS-P cell populations persist in the adult brain, including those in germinal zones, such as the subventricular zone (SVZ) of the forebrain and subgranular zone (SGZ) of the hippocampus, but NS-P cells are also found at low frequencies in the white matter and cerebral cortex. Reactive proliferation of neural stem cells (NSC) in the SVZ and SGZ has been reported following TBI but the extent to which these cells can or could, with experimental modifications, contribute to functional repair is not clear. Although cerebral cortex involvement in TBI has long been appreciated, the response of local endogenous cells has not been sufficiently characterized. In addition, in mild TBI white matter tracts are emerging as areas of pathology with high correlation to functional deficits. Interestingly, NS-P cells that populate white matter may share a common precursor with interneurons, which may implicate a shared role in certain neuropsychiatric diseases. Again, the response to TBI and repair potential of NSP cells in white matter is not yet clear. Importantly, mild TBI can result in extensive white matter involvement with axonal injury that does not progress to discontinuity so that denuded axons may be highly vulnerable and potentially protected by remyelination initiated from white matter progenitors. We hypothesize that endogenous NS-P cells at distinct CNS sites may respond differently to mild TBI pathology and possess different repair potential, which can be enhanced by modifications of the local tissue environment. We will use a combination of molecular approaches to monitor in vivo cellular responses in mouse models of TBI.