Cytokine-mediated deployment of SDF-1 induces revascularization through recruitment of CXCR4+ hemangiocytes

Abstract

The mechanisms through which hematopoietic cytokines accelerate revascularization are unknown. Here, we show that the magnitude of cytokine-mediated release of SDF-1 from platelets and the recruitment of nonendothelial CXCR4⁺VEGFR1⁺ hematopoietic progenitors, 'hemangiocytes,' constitute the major determinant of revascularization. Soluble Kit-ligand (sKitL), thrombopoietin (TPO, encoded by Thpo) and, to a lesser extent, erythropoietin (EPO) and granulocyte-macrophage colony-stimulating factor (GM-CSF) induced the release of SDF-1 from platelets, enhancing neovascularization through mobilization of CXCR4⁺VEGFR1⁺ hemangiocytes. Although revascularization of ischemic hindlimbs was partially diminished in mice deficient in both GM-CSF and G-CSF (Csf2^−/−Csf3^−/−), profound impairment in neovascularization was detected in sKitL-deficient Mmp9^−/− as well as thrombocytopenic Thpo^−/− and TPO receptor–deficient (Mpl^−/−) mice. SDF-1–mediated mobilization and incorporation of hemangiocytes into ischemic limbs were impaired in Thpo^−/−, Mpl^−/− and Mmp9^−/− mice. Transplantation of CXCR4⁺VEGFR1⁺ hemangiocytes into Mmp9^−/− mice restored revascularization, whereas inhibition of CXCR4 abrogated cytokine- and VEGF-A–mediated mobilization of CXCR4⁺VEGFR1⁺ cells and suppressed angiogenesis. In conclusion, hematopoietic cytokines, through graded deployment of SDF-1 from platelets, support mobilization and recruitment of CXCR4⁺VEGFR1⁺ hemangiocytes, whereas VEGFR1 is essential for their angiogenic competency for augmenting revascularization. Delivery of SDF-1 may be effective in restoring angiogenesis in individuals with vasculopathies.