Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Nature medicine, 2006-05, Vol.12 (5), p.557-567

Ort / Verlag

United States: Nature Publishing Group

Erscheinungsjahr

2006

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.