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Nature Medicine 12, 557–567 (1 May 2006) | doi:10.1038/nm1400

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

David K Jin , Koji Shido , Hans-Georg Kopp , Isabelle Petit , Sergey V Shmelkov , Lauren M Young , Andrea T Hooper , Hideki Amano , Scott T Avecilla , Beate Heissig , Koichi Hattori , Fan Zhang , Daniel J Hicklin , Yan Wu , Zhenping Zhu , Ashley Dunn , Hassan Salari , Zena Werb , Neil R Hackett , Ronald G Crystal , David Lyden & Shahin Rafii

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|[minus]|/|[minus]|Csf3|[minus]|/|[minus]|), profound impairment in neovascularization was detected in sKitL-deficient Mmp9|[minus]|/|[minus]| as well as thrombocytopenic Thpo|[minus]|/|[minus]| and TPO receptor–deficient (Mpl|[minus]|/|[minus]|) mice. SDF-1–mediated mobilization and incorporation of hemangiocytes into ischemic limbs were impaired in Thpo|[minus]|/|[minus]|, Mpl|[minus]|/|[minus]| and Mmp9|[minus]|/|[minus]| mice. Transplantation of CXCR4+VEGFR1+ hemangiocytes into Mmp9|[minus]|/|[minus]| 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.