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

Nature Medicine volume 8, pages 841–849 (2002)Cite this article

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.

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Figure 1: VEGFR1 is expressed on pluripotent murine HSCs with short-and long-term repopulating capacity.
Figure 2: Inhibition of VEGFR1, but not VEGFR2, after myelosuppression, results in delayed hematopoietic recovery and increased mortality of the treated mice.
Figure 3: Blocking VEGFR1 signaling after myeloablation inhibits cell-cycle progression, proliferation and differentiation of HSCs.
Figure 4: PlGF augments motogenic potential of VEGFR1+ BM-repopulating stem and progenitor cells.
Figure 5: PlGF-mediated upregulation of MMP-9 and release of sKitL is essential for recruitment and mobilization of BM-repopulating cells.
Figure 6: Administration of sKitL restores impaired hematopoiesis in mice treated with 5FU and neutralizing anti-VEGFR1.

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Acknowledgements

This work was supported by grants from the National Heart, Lung, and Blood Institute R01s, HL-58707, HL-61849, HL-66592, HL-67839 (to S.R.); the American Cancer Society (to S.R.); Leukemia and Lymphoma Foundation (to S.R.); the Doris Duke Charitable Foundation (to D.L.); National Institutes of Health, CA 72006, CA 75072, NS39278 and AR46238 (to Z.W.), and National Institutes of Health R01 HL61401 (to MASM).

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Author notes

  1. Koichi Hattori and Beate Heissig: K.H. and B.H. contributed equally to this study.

Authors and Affiliations

  1. Department of Medicine, Cornell University Medical College, New York, New York, USA

    Koichi Hattori, Beate Heissig, Sergio Dias, Rafael Tejada, Barbara Ferris, Neil R. Hackett, Ronald G. Crystal, David Lyden & Shahin Rafii

  2. Sloan–Kettering Institute, New York, New York, USA

    Malcolm A.S. Moore & David Lyden

  3. ImClone Systems Inc., New York, New York, USA

    Yan Wu, Daniel J. Hicklin, Zhenping Zhu, Peter Bohlen & Larry Witte

  4. New York Blood Center, New York, New York, USA

    Jan Hendrikx

  5. Department of Anatomy, University of California, San Francisco, California, USA

    Zena Werb

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Correspondence to Shahin Rafii.

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Competing interests

Monoclonal antibodies against VEGFR1 and VEGFR2 were generated by ImClone Systems Inc. D.H., Z.Z., P.B. and L.W. are employees of ImClone.

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Hattori, K., Heissig, B., Wu, Y. et al. Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1+ stem cells from bone-marrow microenvironment. Nat Med 8, 841–849 (2002). https://doi.org/10.1038/nm740

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