Adult Hemangioblast/HSC Recruitment and Maintenance

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DESCRIPTION (provided by applicant): We have proven that the adult hematopoietic stem cell (HSC) is able to function as a hemangioblast. Using a unique model of adult retinal neovascularization, we performed a series of experiments to ask if adult HSC exhibit hemangioblast activity by contributing to both blood and blood vessel repair in response to ischemic injury. Bone marrow transplant recipients were durably reconstituted with a single donor HSC from congenic mice expressing Gfp. Ischemia was induced in one retina per animal. Physiological localization of marrow-derived progeny to retina was detected by confocal microscopy of newly differentiated vascular tufts composed of Gfp+ endothelial cells. Both FACS and fluorescent microscopy confirmed full multilineage hematopoietic reconstitution of the transplant recipients. This study is the first to prove that an adult stem cell can exhibit functional plasticity in a transplant setting. In this proposal we seek to utilize this unique model to address the following hypotheses: Aim 1. Hypothesis: Remodeling of the endothelial niche by hemangioblast activity is the initial step in bone marrow remodeling following bone marrow transplant. Aim 2. Hypothesis: HSC hemangioblast activity produces a developmental hierarchy of cells with the potential to differentiate into endothelial cells. With our model we can define the lineage relationships and phenotypes of this new hematopoietic activity. Aim 3. Hypothesis: HSC are the source of circulating endothelial progenitors. Therefore, factors that affect HSC or leukocyte migration will affect EPC production and recruitment.