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Letters to Nature
Nature 417, 954-958 (27 June 2002) | doi:10.1038/nature00821; Received 13 February 2002; Accepted 11 April 2002
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- Beth Israel Deaconess Medical Center
- Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215
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- Detroit, Michigan, USA
VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism
Hans-Peter Gerber1, Ajay K. Malik1, Gregg P. Solar2, Daniel Sherman1, Xiao Huan Liang1, Gloria Meng3, Kyu Hong3, James C. Marsters4 & Napoleone Ferrara1
- Departments of
- Molecular Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA
- Protein Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA
- Assay Development, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA
- Organic Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA
Correspondence to: Hans-Peter Gerber1 Correspondence and requests for materials should be addressed to H.-P.G. (e-mail: Email: gerberhp@gene.com).
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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