Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1(+) stem cells from bone-marrow microenvironment.
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.
Hattori
Koichi
K
Department of Medicine, Cornell University Medical College, New York, New York, USA.
Heissig
Beate
B
Wu
Yan
Y
Dias
Sergio
S
Tejada
Rafael
R
Ferris
Barbara
B
Hicklin
Daniel J
DJ
Zhu
Zhenping
Z
Bohlen
Peter
P
Witte
Larry
L
Hendrikx
Jan
J
Hackett
Neil R
NR
Crystal
Ronald G
RG
Moore
Malcolm A S
MA
Werb
Zena
Z
Lyden
David
D
Rafii
Shahin
S
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
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