Neural stem cells are resistant to apoptosis

Hypoxic-ischemic (H/I) brain injury as a result of asphyxia at term remains a major cause of neurologic disability. Unlike adult stroke, perinatal insults occur when the brain's stem cells (NSCs) are actively proliferating, migrating, and differentiating. If NSCs are eliminated from the brain following H/I, then the endogenous repair capacity of the brain would be severely limited. Alternatively, if NSCs resist H/I injury, these cells could be manipulated to repair damaged regions of the brain. We show here that in the immature mouse brain, cells in the lateral aspect of the subventricular zone (SVZ) undergo apoptosis following H/I, while cells in the medial SVZ resist death. Since NSCs reside in the medial region of the SVZ, we hypothesized that NSCs are resistant to apoptosis. The experiments in this thesis investigate the responses of neural stem/progenitor cells (NSPs) to multiple death effectors, and identify several properties that endow them with resistance to injury. These studies reveal that NSPs resist death by glutamate—one of the major death effectors of neurons and oligodendrocyte progenitor cells (OPCs) following perinatal H/I—and proliferate in response to high levels of extracellular glutamate. Additionally, cell viability is increased when the kainate or the mGluR3 receptor is agonized. Thus, glutamate can act as a pro-regenerative signal for early progenitors in the SVZ. Additionally, we investigated the effect of inhibiting key survival pathways in NSPs and late OPCs. While phosphatidyl-inositol-3 ′-OH kinase and extracellular-regulated kinase1/2 signaling are essential for late OPC survival and proliferation, respectively, inhibition of these pathways in early NSP cultures enriches for NSCs by eliminating lineage-restricted progenitors. RNase protection assays, Western blot analyses, and gene-arrays reveal higher levels of the antiapoptotic protein bcl-xL and lower levels of mRNAs for pro-apoptotic proteins in NSPs as compared to late OPCs, which is consistent with the resistance of NSPs to death following perinatal H/I. Taken together, these data demonstrate that NSPs resist death effectors and that they may initiate a compensatory proliferative response to potent injury signals. If this regenerative response can be appropriately harnessed and extended, it could provide the means to replace brain cells after perinatal injury.