Abstract 10172: Cerebral Ischemia-Induced Progenitor Cell Proliferation Requires Ribosomal S6 (RSK) Activation in Neural Stem Cells
Cerebral ischemia induces a complex interplay of events that contribute to both the pathophysiology and partial recovery of the affected tissue. Within hours of an ischemic event, a convergence of neuroinflammation, oxidative stress, and high levels of excitatory neuortransmission lead to cell injury and ultimately cell death. Concurrently, cerebral ischemia induces neural stem cell (NSC) proliferation and neurogenesis in the hippocampal subgranular zone (SGZ) as well as the subventricular zone of the lateral ventricles. Recent work indicates that a large number of neurons born into this pathophysiological environment are able to functionally integrate into existing neural networks, thus indicating a reparative purpose of ischemia-induced neurogenesis. In order to better understand and exploit the cell signaling mechanisms that regulate ischemia-induced proliferation, we examined the role of the p42/44 mitogen-activated protein kinase (MAPK) cascade effector, ribosomal S6 kinase (RSK), in this process. Using a transient ischemia model (intrahippocampal endothelin-1 infusion) in C57Bl/6 mice, we show that ischemia induces robust RSK activation in SGZ progenitor cells (analyzed 2 days post-ischemia). Further, pharmacological inhibition of RSK prior to endothelin-1 infusion led to a significant reduction of SGZ progenitor cell proliferation. Further, the cell-autonomous nature of these effects was validated using in vitro assays of adult-derived NSCs. In these experiments, the pharmacological inhibition of RSK led to a significant reduction in NSC proliferative capacity. Together, these data suggest that the MAPK-RSK pathway is a key conduit by which ischemia drives progenitor cell proliferation. Overall, a clearer understanding of the cellular/molecular mechanisms that regulate inducible proliferation may reveal novel therapeutic strategies designed to enhance post-ischemic neuronal recovery.
- © 2013 by American Heart Association, Inc.