VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism |
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Authors: | Gerber Hans-Peter Malik Ajay K Solar Gregg P Sherman Daniel Liang Xiao Huan Meng Gloria Hong Kyu Marsters James C Ferrara Napoleone |
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Affiliation: | Department of Molecular Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. gerberhp@gene.com |
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Abstract: | Vascular endothelial growth factor (VEGF) is a principal regulator of blood vessel formation and haematopoiesis, 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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