title: Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1(+) 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) is expressed on 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, but not VEGFR2, blocked HSC cell cycling, differentiation and hematopoietic recovery after BM suppression, resulting in the demise of the treated mice. Placental growth factor (PlGF), which signals through VEGFR1, restored early and late phases of hematopoiesis following BM suppression. PlGF enhanced early phases of BM recovery directly through rapid chemotaxis of VEGFR1(+) BM-repopulating and progenitor cells. The late phase of hematopoietic recovery was driven by PlGF-induced upregulation of matrix metalloproteinase-9, mediating the release of soluble Kit ligand. Thus, PlGF promotes recruitment of VEGFR1(+) HSCs from a quiescent to a proliferative BM microenvironment, favoring differentiation, mobilization and reconstitution of hematopoiesis.
authors.affiliation: Department of Medicine, Cornell University Medical College, New York, New York, USA.
authors.forename: Koichi
authors.initials: K
authors.lastname: Hattori
authors.forename: Beate
authors.initials: B
authors.lastname: Heissig
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.forename: Sergio
authors.initials: S
authors.lastname: Dias
authors.forename: Rafael
authors.initials: R
authors.lastname: Tejada
authors.forename: Barbara
authors.initials: B
authors.lastname: Ferris
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Hicklin
authors.forename: Zhenping
authors.initials: Z
authors.lastname: Zhu
authors.forename: Peter
authors.initials: P
authors.lastname: Bohlen
authors.forename: Larry
authors.initials: L
authors.lastname: Witte
authors.forename: Jan
authors.initials: J
authors.lastname: Hendrikx
authors.forename: Neil R
authors.initials: NR
authors.lastname: Hackett
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Crystal
authors.forename: Malcolm A S
authors.initials: MA
authors.lastname: Moore
authors.forename: Zena
authors.initials: Z
authors.lastname: Werb
authors.forename: David
authors.initials: D
authors.lastname: Lyden
authors.forename: Shahin
authors.initials: S
authors.lastname: Rafii
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D002469:Cell Separation; D017690:Cell Transplantation; D002633:Chemotaxis; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D006410:Hematopoiesis / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D017978:Receptors, Growth Factor / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor; D018183:Transplantation Chimera; D014183:Transplantation, Heterologous; D040281:Vascular Endothelial Growth Factor Receptor-1
chemical_list: D000964:Antimetabolites, Antineoplastic; C000608036:PGF protein, human; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D000072483:Placenta Growth Factor; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1; D020780:Matrix Metalloproteinase 9; D005472:Fluorouracil