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

Abstract

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.

Cathepsin K-mediated notch1 activation contributes to neovascularization in response to hypoxia

“…Moreover, ELISA showed that CatK deficiency significantly reduced plasma VEGF levels at day 7 after ischaemia in CatK À / À mice compared with CatK þ / þ mice. VEGF has been shown to modulate EPC mobilization from BM to the circulation and to support vasculogenesis 32,33 . More importantly, our observations here show that the reception of CatK þ / þ BM-derived EPC-like MNCs, but not that of CatK À / À BM-derived EPC-like MNCs, rescued blood flow impairment after hindlimb ischaemia in CatK À / À mice.…”

Impact of serum vascular endothelial growth factor on prognosis in patients with unresectable hepatocellular carcinoma after transarterial chemoembolization

“…A study has demonstrated that increased levels of bone marrow-derived endothelial progenitor cells in the peripheral circulation of patients with advanced HCC, and a high correlation between serum VEGF levels and levels of circulating endothelial progenitor cells were observed [31] . It has been suggested that platelets aggregate at metastatic sites, due to factors released from metastatic cells and vascular invasion, resulting in microthrombosis, tumor adhesion, and may release VEGF to the circulation [32,33] . Therefore, we considered that in metastatic HCC patient platelet activation was a part of the sources of serum VEGF.…”

Chemokine-mobilized adult stem cells; defining a better hematopoietic graft

“…104 Adenoviral delivered hSDF-1a can mobilize bone marrow-derived endothelial stem cells. 105 The ability of chemokines to mobilize endothelial stem cells and the rapidity of mobilization observed via the chemokine axis, suggest that this axis may have utility in mobilizing stem cells for vascular repair. Further characterization studies on the adult stem cell content of mobilized blood may identify other therapeutic potentials for these cells.…”