title: Angiogenic factors reconstitute hematopoiesis by recruiting stem cells from bone marrow microenvironment.
abstract: The mechanism by which angiogenic factors recruit bone marrow (BM)-derived quiescent endothelial and hematopoietic stem cells (HSCs) is not known. Here, we report that functional vascular endothelial growth factor receptor-1 (VEGFR1, Flt-1) is expressed on a subpopulation of human CD34(+) and mouse Lin-Sca-1(+)c-Kit(+) BM-repopulating stem cells, conveying signals for recruitment of HSCs and reconstitution of hematopoiesis. Inhibition of VEGFR1 signaling, but not VEGFR2 (Flk-1, KDR), blocked HSC cell cycling, differentiation and hematopoietic recovery after BM suppression, resulting in the demise of the treated mice. Plasma elevation of placental growth factor (PlGF), which signals through VEGFR1, but not VEGFR2, restored hematopoiesis during the early and late phases following BM suppression. The mechanism whereby PlGF enhanced early phases of BM recovery was mediated directly through rapid chemotaxis of readily available VEGFR1(+) BM-repopulating and progenitor cells. The late phase of hematopoietic recovery was driven by PlGF-induced upregulation of matrix metalloproteinase-9 (MMP-9) in the BM, mediating the release of soluble Kit-ligand (sKitL). sKitL increased proliferation and motility of HSCs and progenitor cells, thereby augmenting hematopoietic recovery. PlGF promotes recruitment of VEGFR1(+) HSCs from a quiescent to a proliferative microenvironment within the BM, favoring differentiation, mobilization, and reconstitution of hematopoiesis.
authors.affiliation: Cornell University Medical College, New York, New York 10021, USA. sraffi@med.cornell.edu
authors.forename: Shahin
authors.initials: S
authors.lastname: Rafii
authors.forename: Scott
authors.initials: S
authors.lastname: Avecilla
authors.forename: Sergey
authors.initials: S
authors.lastname: Shmelkov
authors.forename: Koji
authors.initials: K
authors.lastname: Shido
authors.forename: Rafael
authors.initials: R
authors.lastname: Tejada
authors.forename: Malcolm A S
authors.initials: MA
authors.lastname: Moore
authors.forename: Beate
authors.initials: B
authors.lastname: Heissig
authors.forename: Koichi
authors.initials: K
authors.lastname: Hattori
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism*; D002465:Cell Movement; D016228:Endothelial Growth Factors / Q000378:metabolism; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D018919:Neovascularization, Physiologic; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D016228:Endothelial Growth Factors; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D020780:Matrix Metalloproteinase 9