This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.During embryogenesis, hematopoiesis is highly coordinated with angiogenesis. Recent studies suggest that hematopoietic and endothelial precursors may originate from a common ancestor, the hemangioblast. Key molecular players determining the fate of hemangioblasts towards hematopoietic and endothelial lineages are not fully determined. The receptor tyrosine kinase, EphB4, and its ligand, ephrinB2, are critical for angiogenesis. Loss of either EphB4 or ephrinB2 causes fatal abnormalities of capillary formation in null mice. We originally identified EphB4 in human bone marrow CD34+ cells, and found that its forced expression influences the function and phenotype of primitive human hematopoietic cells. We are testing the hypothesis that EphB4/ephrinB2 signaling may function in the regulation of hemangioblast development, and hematopoietic and endothelial differentiation during early development. In vitro assays of embryonic stem (ES) cells (both mouse and human) and in vivo experiments (including knockout mice and bone marrow transplantation) are being conducted to assess the differentiation potential of EphB4 loss- and gain-of-function. Overall, studies will test roles for EphB4 signaling in distinctly regulating vascular and blood lineage commitment. Results may have significant implications for the future use of human ES cells in bone marrow transplantation, stem cell therapy of leukemia, and tissue regeneration. (NIH approved human ES cell lines are used in this project.)
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