VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism.
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.
Gerber
Hans-Peter
HP
Department of Molecular Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. gerberhp@gene.com
Malik
Ajay K
AK
Solar
Gregg P
GP
Sherman
Daniel
D
Liang
Xiao Huan
XH
Meng
Gloria
G
Hong
Kyu
K
Marsters
James C
JC
Ferrara
Napoleone
N
D000818:Animals; D019898:Autocrine Communication / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002463:Cell Membrane Permeability; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002999:Clone Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005434:Flow Cytometry; D017353:Gene Deletion; D006410:Hematopoiesis / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008222:Lymphokines / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D019899:Paracrine Communication; D011518:Proto-Oncogene Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D017978:Receptors, Growth Factor / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012995:Solubility; D014161:Transduction, Genetic; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1