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.
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NOTE: In the version of this article initially published, one of the micrographs in Figure 4d was incorrect. In Figure 4d, the micrograph showing CD31 staining of AdNull-treated adductor muscle is overlapping with the micrograph showing CD31 staining of the AdNull-treated gastrocnemius muscle. The authors of the article have indicated that the micrograph shown for the adductor muscle was incorrectly included due to an inadvertent error during manuscript preparation, and that the error does not affect the quantitative results shown in Figure 4d or any of the conclusions of the article. The error has been corrected in the HTML and PDF versions of the article.
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We wish to acknowledge the technical assistance of P. Lau, M. Choy, G. Kanhai, R. Tejada, G. Lam and A. Intrator. We would also like to thank F. de Sauvage from Genentech for providing the Thpo−/− and Mpl−/− mice. S.R. is an investigator of Howard Hughes Medical Institute and is supported by the American Cancer Society, the Lymphoma and Leukemia Society and the National Institutes of Health (RO1-HL075234, HL59312, HL66592 and HL67839). D.K.J. is supported by the Hermione Foundation. D.L. is supported by the Doris Duke Charitable Foundation, the Children's Blood Foundation and a grant from the National Cancer Institute.
Daniel Hicklin, Yan Wu and Zhenping Zhu are employees of ImClone Systems, Inc. Hassan Salari is an employee of Chemokine Therapeutics Corporation.
TPO and SDF-1 accelerate ischemic revascularization. (PDF 1101 kb)
TPO promotes tumor neoangiogenesis. (PDF 4864 kb)
VEGFR1 modulates proangiogenic activity of hemangiocytes and cytokine-mediated release of SDF-1 is impaired in Mmp9−/− platelets. (PDF 1273 kb)
Phenotypic characterization of hemangiocytes. (PDF 277 kb)
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Jin, D., Shido, K., Kopp, HG. et al. Cytokine-mediated deployment of SDF-1 induces revascularization through recruitment of CXCR4+ hemangiocytes. Nat Med 12, 557–567 (2006). https://doi.org/10.1038/nm1400
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