The Role of HIF-1 alpha in Vasculotrophic Influence of Neural Stem Cells

University Of New Mexico Health Scis Ctr, Albuquerque NM

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Abstract

DESCRIPTION (provided by applicant): Neural stem/progenitor cells (NSPCs) have been proposed as an endogenous cellular source for the neuronal replacement and treatment of stroke. However, there is little evidence of a causal link between the formation of new neurons and symptomatic recovery from stroke, suggesting that the neurogenic response to stroke may be important in repair processes apart from replacement of lost neurons. We had demonstrated that NSPCs exhibit a strong ability to support endothelial cell survival, morphogenesis and angiogenesis following ischemia. These findings lead to our central hypothesis that neural stem cells provide protection for brain endothelial cells leading to the functional remodeling of brain vasculature following ischemia. NSPCs reside within a specialized stem cell niche, in close proximity to blood vessels, suggesting a functional interaction between neural progenitors and endothelial cells, which may be critical in revascularization and repair following stroke. In our preliminary studies, the vasculotrophic effect of NSPCs was mediated via vascular endothelial growth factor VEGF and governed by hypoxia-inducible factor HIF-1a, both constitutively expressed in NSPCs in vitro and in vivo. The goal of the proposed study is to further explore the role of HIF-1a in vasculotrophic properties of NSPCs, using a conditional HIF-1a knockout mouse model. We will test whether NSPC-specific HIF-1a gene deletion will result in impaired revascularization in response to in vitro and in vivo ischemia. The second goal is to determine whether NSPC stimulate post-ischemic revascularization and thus, improve brain tissue reperfusion following hypoxia. Dynamic changes in vasculogenesis following experimental focal ischemia will be assessed in wild type and HIF-1a conditional knockout adult mice using histological analyses, immunocytochemistry and in vivo fluorescent dextran injections. The overarching hypothesis of our proposal is that the vasculotrophic effects of NSPCs are governed by transcription factor HIF-11, both under normal conditions and following hypoxia. To address this hypothesis, the following Specific Aims are proposed: Specific Aim 1: To determine the role of HIF-1a in NSPC-mediated support of endothelial cells under conditions of in vitro ischemia. Specific Aim 2: To determine the effects of NSPC-specific HIF-1a gene deletion on stroke-induced angiogenesis in vivo. The results of the proposed project will expose a functional link between neurogenic and angiogenic responses to cerebral ischemia, which may have important implications for the therapeutic use of stem cells to support revascularization following stroke injury. PUBLIC HEALTH RELEVANCE: Our main hypothesis is that neural stem cells protect brain blood vessels and induce new vessel formation following stroke. The goal of our study is to identify the molecules and mechanisms responsible for the neural stem cell-induced protection. Our findings may have important implications for the therapeutic use of stem cells in the treatment and prevention of stroke.