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 CrystalDavid Lyden, Shahin Rafii

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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.

Original languageEnglish
Pages (from-to)557-567
Number of pages11
JournalNature Medicine
Volume12
Issue number5
DOIs
Publication statusPublished - 1 May 2006
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Jin, D. K., Shido, K., Kopp, H. G., Petit, I., Shmelkov, S. V., Young, L. M., Hooper, A. T., Amano, H., Avecilla, S. T., Heissig, B., Hattori, K., Zhang, F., Hicklin, D. J., Wu, Y., Zhu, Z., Dunn, A., Salari, H., Werb, Z., Hackett, N. R., ... Rafii, S. (2006). Cytokine-mediated deployment of SDF-1 induces revascularization through recruitment of CXCR4+ hemangiocytes. Nature Medicine, 12(5), 557-567. https://doi.org/10.1038/nm1400