Efficient mobilization and recruitment of marrow-derived endothelial and hematopoietic stem cells by adenoviral vectors expressing angiogenic factors.

Adult bone marrow (BM) is a rich reservoir for endothelial and hematopoietic stem and progenitor cells that contribute to revascularization of injured and tumor tissue. Physiological stress results in the release of specific chemo-cytokines that promote mobilization of stem cells to the circulation and direct their incorporation into the target tissues. In order to dissect the mechanism and identify the cellular mediators that regulate stem cell recruitment, we have developed an in vivo murine model, in which the plasma levels of chemokines are elevated by introducing adenoviral vectors (Advectors) expressing such chemokines. Among the known stem cell-active chemokines, the angiogenic factor VEGF through interaction with its receptors, VEGFR2 and VEGFR1 expressed on endothelial and hematopoietic stem cells, promotes mobilization and recruitment of these cells into the neo-angiogenic sites, thereby accelerating the revascularization process. Based on these studies, it has become apparent that mobilization of stem cells is a dynamic process and requires sequential release of chemocytokines, expression of adhesion molecules and activation of proteases that facilitate egress of cells from the BM to the circulation. Chemokine-activation of metalloproteinases is essential for the release of bio-active cytokines, thereby enhancing stem cell mobilization potential. Advectors are ideal for delivery of chemocytokines since they allow for long-term robust expression facilitating in vivo proliferation and mobilization of large numbers of an otherwise rare population of stem cells. VEGF-mobilized endothelial and hematopoietic stem cells provide for an enriched source of adult pluripotent cells that can be used for revascularization, tissue regeneration or gene therapy.