We recently developed a mouse model of retinal neovascularization that mimics many features of human disease. The retina represents a unique vascular bed associated with an avascular vitreous, known to contain a plethora of anti-angiogenic molecules arid to be resistant to new blood vessel growth. This series of experiments was designed to ask if resident adult HSC could contribute to endogenous neovascularization along with the development of blood, thus exhibiting "hemangioblast" activity. Bone marrow transplant recipients were durably reconstituted by donor HSC from congenic mice expressing gfp. Physiological localization of marrow-derived progeny to retina was detected by confocal microscopy of newly differentiated gfp+ endothelial cells around rhodamine tubes representing the perfused retinal vasculature. Both FACS and fluorescent microscopy confirmed full multilineage hematopoietic reconstitution of the transplant recipients. These studies demonstrate that adult HSC exhibit an efficient "hemangioblast" activity leading to the development of both blood cells and endothelial cells. Furthermore, serial transplants confirmed that "hemangioblast" activity co-enriches with the HSC, as defined by the concurrent ability to self renew and durably reconstitute multilineage hematopoiesis. In this R21 proposal we seek to extend this model to determine: Aim 1: Do human HSC exhibit hemangioblast activity in a NOD/SCID xenograft model? Human HSC will be enriched from both cord blood and bone marrow and transplanted into NOD/SCID mice. Successful hematopoietic xenografts will receive ischemic injury exactly as the murine model. Human specific antibodies will be used to detect xenograft contributions to neovascularization. Aim 2: In NOD/SCID xenografts can human HSC contribute to tumor vasculogenesis? If so, can treatments which block HSC homing impair neovascularization?