Mobilization of Endothelial and Hematopoietic Stem and Progenitor Cells by Adenovector‐Mediated Elevation of Serum Levels of SDF‐1, VEGF, and Angiopoietin‐1

Abstract

A bstract : The chemokine stroma‐derived factor‐1 (SDF‐1) is produced within the bone marrow and mediates chemokinesis and chemotaxis on a variety of cell types that express the CXCR4 receptor. SDF‐1‐responsive cell types include monocytes and macrophages, B and T lymphocytes, platelets and megakaryocytes, and CD34 + cells, including both hematopoietic progenitors and stem cells. We have used intravenous injection of a replication‐incompetent adenovector expressing the SDF‐1 gene to elevate serum levels of SDF‐1 in Balb/c and SCID mice. Within 3 to 5 days there was a marked leukocytosis, predominantly involving monocytes, and a three‐fold increase in platelets. In addition, AdSDF‐1 mobilized CFU‐GM, CFU‐s, and cells with long‐term repopulating potential. We have identified a bone marrow‐derived, circulating endothelial stem cell characterized by expression of the VEGFR2 (Flk‐1/KDR). This cell exhibits a chemotactic and chemokinetic response to SDF‐1 and VEGF. We have elevated serum levels of VEGF 165 using intravenous adenovector gene delivery and compared this to an adenovector expressing angiopoietin‐1 alone or in combination with VEGF. VEGF elevation was associated with rapid mobilization of hematopoietic stem and progenitor cells and a population of Flk‐1‐positive endothelial progenitors. In contrast angiopoietin induced a delayed mobilization of endothelial and hematopoietic progenitors. The combination of VEGF and angiopoietin produced a more prolonged elevation of these progenitors in the circulation with increased proliferation of capillaries and expansion of sinusoidal spaces in the marrow.