ADHESION PATHWAYS OF BLOOD/ENDOTHELIAL PROGENITORS

The overall objective of the proposal is to evaluate the adhesive mechanisms mediating the in vivo trafficking of hematopoietic and endothelial progenitor cells. While the emigration of mature leukocytes to areas of inflammation is well characterized, little is known on the trafficking of hematopoietic progenitor cells (HPC). There is growing evidence suggesting that hematopoietic and endothelial progenitor cells have a common origin and that circulating endothelial progenitor cells (EPC) may contribute to neovascularization in vivo. Using a new technique of intravital examination of the bone marrow (BM) microvasculature, colony-forming unit assays, and competitive reconstitution experiments, we propose to investigate the adhesion pathways regulating the homing of HPCs to and their egress from the murine BM. We will also examine using intravital microscopy the differential adhesion mechanisms used by bone marrow, placental and mobilized CD34+ HPCs to interact with the bone marrow microvasculature of immunodeficient mice. Furthermore, we propose to assess the contribution of blood-borne EPCs in neovascularization during tumor development and wound healing, and to dissect the adhesion pathways regulating the recruitment of circulating EPCs in these neovessels using novel intravital murine models. These experiments should shed further light into the mechanisms mediating the trafficking of hematopoietic and endothelial progenitors in normal physiology and certain pathologic situations. A greater knowledge in these areas may lead to better ways to deliver HPCS modified by gene therapy to the bone marrow, to improve the collection of mobilized HPCs, and may impact diseases where new blood vessel formation is critical, such as cancer, wound healing and ischemic vascular illnesses.