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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS064185-02
Application #
8015248
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Owens, David F
Project Start
2010-01-19
Project End
2011-12-31
Budget Start
2011-01-01
Budget End
2011-12-31
Support Year
2
Fiscal Year
2011
Total Cost
$221,603
Indirect Cost
Name
University of New Mexico Health Sciences Center
Department
Neurosciences
Type
Schools of Medicine
DUNS #
829868723
City
Albuquerque
State
NM
Country
United States
Zip Code
87131
Caballero-Garrido, Ernesto; Pena-Philippides, Juan Carlos; Lordkipanidze, Tamar et al. (2015) In Vivo Inhibition of miR-155 Promotes Recovery after Experimental Mouse Stroke. J Neurosci 35:12446-64
Cunningham, Lee Anna; Candelario, Kate; Li, Lu (2012) Roles for HIF-1α in neural stem cell function and the regenerative response to stroke. Behav Brain Res 227:410-7
Roitbak, Tamara; Surviladze, Zurab; Cunningham, Lee Anna (2011) Continuous expression of HIF-1α in neural stem/progenitor cells. Cell Mol Neurobiol 31:119-33
Roitbak, Tamara; Li, Lu; Cunningham, Lee Anna (2008) Neural stem/progenitor cells promote endothelial cell morphogenesis and protect endothelial cells against ischemia via HIF-1alpha-regulated VEGF signaling. J Cereb Blood Flow Metab 28:1530-42