Regulation of Hemangiogenesis by Hypoxia-Inducible Factor 1 and microRNAs

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DESCRIPTION (provided by applicant): The existence of hematopoietic stem-progenitor cells, which are present in the adult marrow and capable of self-renewal and differentiation into the progenitors that give rise to all types of mature blood cells, has been known for over half a century. More recently, endothelial stem-progenitor cells have also been identified. There remain several major obstacles to a more complete understanding of the molecular mechanisms underlying the self-renewal and differentiation of these stem-progenitor cells. First, these cells are present in low abundance and are difficult to purify from their more differentiated progeny. Techniques are needed to expand these cells, while maintaining their capacity for subsequent differentiation, in order that they might be better studied and utilized therapeutically. Second, in the case of endothelial stem-progenitors, thus far it has not been possible to establish a hierarchical lineage similar to what has been described for hematopoietic cells. Third, it is not clear whether the hematopoietic and endothelial stem-progenitors in adult marrow are themselves the descendants of a common stem cell, the hemangioblast. The molecular basis for development is the elaboration of discrete programs of gene expression in each cell type. Two central mechanisms for regulating gene expression are transcription factors, which determine the rate at which DNA sequences are transcribed into mRNA, and microRNAs, which determine the rate at which mRNAs are transcribed into protein. We hypothesize that there are key transcription factors and microRNAs which play critical roles in regulating the self-renewal and differentiation of hematopoietic and endothelial stem-progenitor cells. These cells are essential for hemangiogenesis, the formation of blood and blood vessels, respectively, which in turn are essential for the continuous delivery of O2 to all cells of the body. Within the marrow, undifferentiated cells are located along the endosteum, whereas more differentiated cells are located in proximity to the highly vascularized marrow cavity, from whence they enter the peripheral blood. The endosteal niche is hypoxic and may promote stem cell maintenance, whereas increased O2 levels in the vascular niche may promote proliferation and differentiation. We hypothesize that O2 functions as a developmental regulator for hemangiogenic cells, such that stem vs progenitor cell populations may require different O2 concentrations. The transcriptional regulator hypoxia-inducible factor 1 (HIF-1) mediates adaptive developmental and physiological responses to hypoxia and plays an essential, but only partially defined role, in hemangiogenesis. In this grant application, we propose to delineate the molecular mechanisms whereby HIF-1 and microRNAs regulate hemangiogenesis. By doing so, we hope to: better identify and characterize hemangiogenic progenitor cell lineages; direct the differentiation of stem and progenitor cells to desired cell fates; and develop new strategies for therapeutic utilization of these cells for in vivo hematopoiesis and vascularization.