Journal
NATURE MEDICINE
Volume 8, Issue 8, Pages 841-849Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm740
Keywords
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Funding
- NCI NIH HHS [CA 72006, P01 CA072006, R01 CA075072-03, CA 75072, P01 CA072006-07] Funding Source: Medline
- NHLBI NIH HHS [R01 HL61849, R01 HL061849, R01 HL-58707, P01 HL067839, R01 HL-66592, R01 HL61401, R01 HL-67839] Funding Source: Medline
- NIAMS NIH HHS [AR46238, R01 AR046238, R01 AR046238-03] Funding Source: Medline
- NINDS NIH HHS [R01 NS039278-05A1, NS39278, R01 NS039278] Funding Source: Medline
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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.
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