Nature Medicine
8, 841 - 849 (2002)
Published online: 1 July 2002; | doi:10.1038/nm740
Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1+ stem cells from bone-marrow microenvironmentKoichi Hattori1, 6, Beate Heissig1, 6, Yan Wu3, Sergio Dias1, Rafael Tejada1, Barbara Ferris1, Daniel J. Hicklin3, Zhenping Zhu3, Peter Bohlen3, Larry Witte3, Jan Hendrikx4, Neil R. Hackett1, Ronald G. Crystal1, Malcolm A.S. Moore2, Zena Werb5, David Lyden1, 2
& Shahin Rafii11
Department of Medicine, Cornell University Medical College, New York, New York, USA
2
Sloan−Kettering Institute, New York, New York, USA
3
ImClone Systems Inc., New York, New York, USA
4
New York Blood Center, New York, New York, USA
5
Department of Anatomy, University of California, San Francisco, California, USA
6
K.H. and B.H. contributed equally to this study.
Correspondence should be addressed to Shahin Rafii srafii@med.cornell.eduThe 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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