Biomedical Sciences ETDs

Publication Date

12-1-2010

Abstract

Stroke can be caused by focal ischemia due to cerebral artery occlusion or by global ischemia that occurs when global blood supply to the brain is interrupted. The acute phase of ischemic brain injury is followed by a more prolonged period of revascularization and repair that can last for several months. One hallmark of this repair phase includes an endogenous neural stem/progenitor cell (NSPC) regenerative response that occurs concomitant with angiogenesis. Several studies suggest that the cytogenic response is beneficial for recovery following stroke, however, more studies need to be done to determine whether the beneficial effects are due to functional replacement of lost neurons and/or due to nutritive functions of the NSPCs for penumbral tissue. Therapeutic targeting of regeneration and repair phases of stroke will require an understanding of NSPC function, particularly under conditions of hypoxia/ischemia. This dissertation is focused on elucidating the metabolic properties of NSPCs that allow them to withstand sudden onset and prolonged hypoxia, and the mechanisms by which NSPCs may provide neuroprotection against ischemic damage. We found that NSPCs express stabilized hypoxia-inducible factor-1 alpha (HIF-1 alpha) under normoxic conditions, a transcription factor that has been shown to regulate a variety of genes including those involved in angiogenesis, neuroprotection, and glycolytic metabolism. In this dissertation, we show that, in vitro, HIF-1 alpha expression in NSPCs mediates the ability of NSPCs to provide protection to neurons that undergo oxygen-glucose deprivation through regulation of vascular endothelial growth factor. We also show that HIF-1 alpha is required for NSPCs to survive 24 h anoxia in culture. We determined that NSPCs appear to produce most of their ATP via glycolysis, although the metabolic phenotype of NSPCs under normoxic conditions does not appear to be regulated by HIF-1 alpha. To determine whether NSPCs display similar properties in vivo, we created a nestin-CreERT2/R26R-YFP/Hif1afl/fl mouse that could simultaneously express yellow fluorescent protein and delete Hif1a specifically in nestin-positive NSPCs following tamoxifen administration. The results of these experiments increase our understanding of endogenous NSPC properties under hypoxic conditions and form the basis for future studies that aim to therapeutically manipulate NSPC function for facilitating brain repair.

Keywords

neurogenesis, hypoxia, cerebral ischemia, stem cell, stroke, metabolism

Sponsors

American Heart Association, National Institutes of Health, University of New Mexico Graduate and Professional Student Association, University of New Mexico School of Medicine Dedicated Health Research Funds

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Advisor

Cunningham, Lee Anna

First Committee Member (Chair)

McGuire, Paul

Second Committee Member

Rosenberg, Gary A.

Third Committee Member

Wilson, Michael C.

Fourth Committee Member

Shuttleworth, C. William

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