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VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism

Nature volume 417, pages 954–958 (2002)Cite this article

Abstract

Vascular endothelial growth factor (VEGF) is a principal regulator of blood vessel formation and haematopoiesis1,2, but the mechanisms by which VEGF differentially regulates these processes have been elusive. Here we describe a regulatory loop by which VEGF controls survival of haematopoietic stem cells (HSCs). We observed a reduction in survival, colony formation and in vivo repopulation rates of HSCs after ablation of the VEGF gene in mice. Intracellularly acting small-molecule inhibitors of VEGF receptor (VEGFR) tyrosine kinase dramatically reduced colony formation of HSCs, thus mimicking deletion of the VEGF gene. However, blocking VEGF by administering a soluble VEGFR-1, which acts extracellularly, induced only minor effects. These findings support the involvement in HSC survival of a VEGF-dependent internal autocrine loop mechanism (that is, the mechanism is resistant to inhibitors that fail to penetrate the intracellular compartment). Not only ligands selective for VEGF and VEGFR-2 but also VEGFR-1 agonists rescued survival and repopulation of VEGF-deficient HSCs, revealing a function for VEGFR-1 signalling during haematopoiesis.

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Figure 1: Real-time RT–PCR analysis of BMMNCs and HSCs and competitive repopulation frequencies of VEGF-deficient HSCs.
Figure 2: Comparison between the competitive repopulation of CD45.2-positive Sca+ Kit+ Linlo bone marrow cells deleted in both VEGF alleles (VEGFflox/flox) or control (VEGFlox/lox) cells 8 weeks after transplantation into lethally irradiated CD45.1-positive recipient mice.
Figure 3: VEGF inactivation by Flt–IgG interferes with the paracrine but not autocrine mechanism and small-molecule inhibitors targeting VEGFR-1 and -2 block both functions.

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Acknowledgements

We thank E. Humke and F. Radtke for discussions and advice; and L. Lasky, F. de Sauvage and D. Eaton for critical review of the manuscript and comments. We also thank M. Kelly, K. Broderik and the Genentech animal facility for animal care and breeding; L. Thom for tail DNA isolation and genotype analysis; and B. Li and B. Moffat for VEGF mutants. We also thank P. Schow and C. Grimmer for FACS analysis; G. Hatami, L. Leong and L. Cabote for blood cell analysis; and M. Van Hoy, E. Pegg, D. Eberhard and K. Hillan for pathology support.

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Authors and Affiliations

  1. Departments of Molecular Oncology, Genentech, Inc., 1 DNA Way, South, California, 94080, San Francisco, USA

    Hans-Peter Gerber, Ajay K. Malik, Daniel Sherman, Xiao Huan Liang & Napoleone Ferrara

  2. Departments of Protein Chemistry, Genentech, Inc., 1 DNA Way, South, California, 94080, San Francisco, USA

    Gregg P. Solar

  3. Departments of Assay Development, Genentech, Inc., 1 DNA Way, South, California, 94080, San Francisco, USA

    Gloria Meng & Kyu Hong

  4. Departments of Organic Chemistry, Genentech, Inc., 1 DNA Way, South, California, 94080, San Francisco, USA

    James C. Marsters

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  1. Hans-Peter Gerber
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Correspondence to Hans-Peter Gerber.

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Gerber, HP., Malik, A., Solar, G. et al. VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism. Nature 417, 954–958 (2002). https://doi.org/10.1038/nature00821

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