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

Hans-Peter Gerber (), Ajay K. Malik, Gregg P. Solar, Daniel Sherman, Xiao Huan Liang, Gloria Meng, Kyu Hong, James C. Marsters and Napoleone Ferrara
Additional contact information
Hans-Peter Gerber: Genentech, Inc.
Ajay K. Malik: Genentech, Inc.
Gregg P. Solar: Genentech, Inc.
Daniel Sherman: Genentech, Inc.
Xiao Huan Liang: Genentech, Inc.
Gloria Meng: Genentech, Inc.
Kyu Hong: Genentech, Inc.
James C. Marsters: Genentech, Inc.
Napoleone Ferrara: Genentech, Inc.

Nature, 2002, vol. 417, issue 6892, 954-958

Abstract: 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.

Date: 2002
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DOI: 10.1038/nature00821

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