Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1+ stem cells from bone-marrow microenvironment

Koichi Hattori, Beate Heissig, Yan Wu, Sergio Dias, Rafael Tejada, Barbara Ferris, Daniel J. Hicklin, Zhenping Zhu, Peter Bohlen, Larry Witte, Jan Hendrikx, Neil R. Hackett, Ronald Crystal, Malcolm A.S. Moore, Zena Werb, David Lyden, Shahin Rafii

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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.

Original languageEnglish
Pages (from-to)841-849
Number of pages9
JournalNature Medicine
Volume8
Issue number8
DOIs
Publication statusPublished - 1 Jan 2002
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Hattori, K., Heissig, B., Wu, Y., Dias, S., Tejada, R., Ferris, B., Hicklin, D. J., Zhu, Z., Bohlen, P., Witte, L., Hendrikx, J., Hackett, N. R., Crystal, R., Moore, M. A. S., Werb, Z., Lyden, D., & Rafii, S. (2002). Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1+ stem cells from bone-marrow microenvironment. Nature Medicine, 8(8), 841-849. https://doi.org/10.1038/nm740