Increasing evidence suggests that both normal and cancerous stem cells depend upon their microenvironments or “niches” for signals which regulate survival, proliferation and self-renewal. My research focuses on characterizing the function of endothelial cells and the bone marrow vascular niche in regulating hematopoietic stem cell self-renewal and regeneration in vivo. To this end, we have demonstrated that transplantation of autologous and allogeneic endothelial progenitor cells can accelerate hematopoietic reconstitution following myelosuppression. We have also shown that primary human endothelial cells produce soluble proteins which induce the expansion of human hematopoietic stem cells in vitro. This research yielded the discovery of pleiotrophin, a novel heparin binding growth factor, which induces the expansion of HSCs in vitro and the regeneration of the hematopoietic stem cell pool in vivo following myelosuppression. Currently, we are studying the effects of constitutive deletion of pleiotrophin and its receptor, RPTP beta-zeta, on hematopoietic stem cell content and hematopoietic function in mice. Concurrently, we are utilizing transgenic mouse models to conditionally delete target genes in bone marrow endothelial cells to determine the function of bone marrow endothelial cells in regulating hematopoietic stem cell homeostasis and regeneration following injury in vivo. Our long term objective is to define the mechanisms through which bone marrow endothelial cells regulate the homeostasis and regeneration of normal and leukemic stem cells.