Cytokine-mediated deployment of SDF-1 induces revascularization through recruitment of CXCR4+ hemangiocytes.
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.
Jin
David K
DK
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
K
Kopp
Hans-Georg
HG
Petit
Isabelle
I
Shmelkov
Sergey V
SV
Young
Lauren M
LM
Hooper
Andrea T
AT
Amano
Hideki
H
Avecilla
Scott T
ST
Heissig
Beate
B
Hattori
Koichi
K
Zhang
Fan
F
Hicklin
Daniel J
DJ
Wu
Yan
Y
Zhu
Zhenping
Z
Dunn
Ashley
A
Salari
Hassan
H
Werb
Zena
Z
Hackett
Neil R
NR
Crystal
Ronald G
RG
Lyden
David
D
Rafii
Shahin
S
D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000097:blood*; D006801:Humans; D007511:Ischemia / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D012038:Regeneration; D019089:Stem Cell Factor / Q000378:metabolism; D013234:Stem Cells / Q000502:physiology*; D013921:Thrombocytopenia / Q000378:metabolism; D013926:Thrombopoietin / Q000097:blood / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D016207:Cytokines; D019718:Receptors, CXCR4; D019089:Stem Cell Factor; D042461:Vascular Endothelial Growth Factor A; D013926:Thrombopoietin; D040281:Vascular Endothelial Growth Factor Receptor-1; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse