Cytokine-mediated deployment of SDF-1 induces revascularization through recruitment of CXCR4+ hemangiocytes. Academic Article uri icon

Overview

MeSH

  • Animals
  • Blood Platelets
  • Chemokine CXCL12
  • Humans
  • Ischemia
  • Matrix Metalloproteinase 9
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Stem Cell Factor
  • Thrombocytopenia
  • Thrombopoietin
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factor Receptor-1

MeSH Major

  • Chemokines, CXC
  • Cytokines
  • Neovascularization, Physiologic
  • Receptors, CXCR4
  • Regeneration
  • Stem Cells

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.

publication date

  • May 2006

has subject area

  • Animals
  • Blood Platelets
  • Chemokine CXCL12
  • Chemokines, CXC
  • Cytokines
  • Humans
  • Ischemia
  • Matrix Metalloproteinase 9
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neovascularization, Physiologic
  • Receptors, CXCR4
  • Regeneration
  • Stem Cell Factor
  • Stem Cells
  • Thrombocytopenia
  • Thrombopoietin
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factor Receptor-1

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC2754288

Digital Object Identifier (DOI)

  • 10.1038/nm1400

PubMed ID

  • 16648859

Additional Document Info

start page

  • 557

end page

  • 567

volume

  • 12

number

  • 5