Nature Medicine
- 12, 557 - 567 (2006)
Published online: 30 April 2006; | doi:10.1038/nm1400
There is a Corrigendum (August 2006) associated with this Article.
Cytokine-mediated deployment of SDF-1 induces revascularization through recruitment of CXCR4+ hemangiocytesDavid K Jin1, 2, Koji Shido1, 9, Hans-Georg Kopp1, 9, Isabelle Petit1, Sergey V Shmelkov1, Lauren M Young1, Andrea T Hooper1, Hideki Amano1, Scott T Avecilla1, Beate Heissig1, Koichi Hattori1, Fan Zhang1, Daniel J Hicklin3, Yan Wu3, Zhenping Zhu3, Ashley Dunn4, Hassan Salari5, Zena Werb6, Neil R Hackett1, Ronald G Crystal1, David Lyden7 & Shahin Rafii1, 2, 81
Department of Genetic Medicine, Division of Hematology-Medical Oncology, Weill Medical College of Cornell University, 1300 York Avenue, New York, New York 10021, USA. 2
Department of Medicine, Division of Hematology-Medical Oncology, Weill Medical College of Cornell University, 1300 York Avenue, New York, New York 10021, USA. 3
ImClone Systems, Inc., 180 Varick Street, New York, New York 10014, USA. 4
Ludwig Institute for Cancer Research, Melbourne Tumor Biology Branch, Royal Melbourne Hospital, Parkville 3050, Victoria, Australia. 5
Chemokine Therapeutics Corp., 6190 Agronomy Road, Suite 405, Vancouver, British Columbia V6T 1Z3, Canada. 6
Department of Anatomy, University of California, 513 Parnassus Avenue, HSW-1321, Box 0452, San Francisco, California 94143-0452, USA. 7
Department of Pediatrics and Children's Blood Foundation Laboratories, 1300 York Avenue, New York, New York 10021, USA. 8
Howard Hughes Medical Institute, Weill Medical College of Cornell University, 1300 York Avenue, New York, New York 10021, USA. 9
These authors contributed equally to this work.
Correspondence should be addressed to Shahin Rafii srafii@med.cornell.edu 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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