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PMID: 16648859 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Nature medicine ·Vol. 12 ·No. 5 ·2006-05-00 ·Pages 557-67

Jin DK, Shido K, Kopp HG, Petit I, Shmelkov SV, Young LM, Hooper AT, Amano H, Avecilla ST, Heissig B, Hattori K, Zhang F, Hicklin DJ, Wu Y, Zhu Z, Dunn A, Salari H, Werb Z, Hackett NR, Crystal RG, Lyden D, Rafii S

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.

MeSH Terms
Animals Blood Platelets/metabolism Chemokine CXCL12 Chemokines, CXC/genetics,metabolism Cytokines/blood Humans Ischemia/metabolism Matrix Metalloproteinase 9/genetics,metabolism Mice Mice, Inbred C57BL Mice, Knockout Neovascularization, Physiologic Receptors, CXCR4/genetics,metabolism Regeneration Stem Cell Factor/metabolism Stem Cells/physiology Thrombocytopenia/metabolism Thrombopoietin/blood,genetics Vascular Endothelial Growth Factor A/metabolism Vascular Endothelial Growth Factor Receptor-1/genetics,metabolism
Chemicals
CXCL12 protein, human Chemokine CXCL12 Chemokines, CXC Cxcl12 protein, mouse Cytokines Receptors, CXCR4 Stem Cell Factor Vascular Endothelial Growth Factor A Thrombopoietin Vascular Endothelial Growth Factor Receptor-1 Matrix Metalloproteinase 9 Mmp9 protein, mouse
Authors & Affiliations
22 authors, click to expand affiliations / ORCID
Jin David K
Department of Genetic Medicine, Division of Hematology-Medical Oncology, Weill Medical College of Cornell University, 1300 York Avenue, New York, New York 10021, USA.
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
Rafii Shahin
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Article Info
Journal
Nature medicine
Abbr.
Nat Med
ISSN
1078-8956
DOI
10.1038/nm1400
Published
2006-05-00
Epub
2006-00-30
Pages
557-67
Language
English
Region
United States
NLM ID
9502015
PMCID
PMC2754288
Subset
IM
Grants
NHLBI NIH HHS · R01 HL061849-04 · United States
NHLBI NIH HHS · R01 HL058707-04 · United States
NHLBI NIH HHS · HL67839 · United States
NHLBI NIH HHS · P01 HL067839 · United States
NIA NIH HHS · R01 AG023218-03 · United States
NHLBI NIH HHS · R01 HL058707-03 · United States
NHLBI NIH HHS · R01 HL061849-03S1 · United States
Howard Hughes Medical Institute · United States
NHLBI NIH HHS · R01 HL061849-05 · United States
NHLBI NIH HHS · HL59312 · United States
NHLBI NIH HHS · P01 HL067839-010004 · United States
NHLBI NIH HHS · P01 HL067839-02 · United States
NHLBI NIH HHS · R01 HL061849-02 · United States
NIA NIH HHS · R01 AG023218 · United States
NCI NIH HHS · U01 CA105379 · United States
NHLBI NIH HHS · R01 HL075234-04 · United States
NHLBI NIH HHS · P01 HL067839-020004 · United States
NHLBI NIH HHS · P01 HL059312 · United States
NHLBI NIH HHS · R01 HL061849-03 · United States
NHLBI NIH HHS · R01 HL061849 · United States
NHLBI NIH HHS · P01 HL067839-050004 · United States
NHLBI NIH HHS · P01 HL067839-030004 · United States
NHLBI NIH HHS · HL66592 · United States
NHLBI NIH HHS · P01 HL059312-10 · United States
NHLBI NIH HHS · R01 HL075234 · United States
NCI NIH HHS · U01 CA105379-04 · United States
NHLBI NIH HHS · P01 HL067839-040004 · United States
NHLBI NIH HHS · R01-HL075234 · United States
Corrections
ErratumIn
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External Links
PubMed source DOI: 10.1038/nm1400 PMC Full Text View journal details
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