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

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.

Vascular endothelial growth factor as a survival factor for human islets: effect of immunosuppressive drugs

“…More recently, VEGF 165 has been demonstrated to promote survival in an autocrine manner for a number of other cell types, including podocytes [10], renal tubular epithelial cells [11], haematopoietic stem cells [12] and tumour cells [13].…”

Enforced expression of KDR receptor promotes proliferation, survival and megakaryocytic differentiation of TF1 progenitor cell line

“…In fact, KDR promotes both cell growth and survival, thus implying that the growth increase may be caused by its antiapoptotic effect. 14,16,20 In the early phases of VEGF treatment in GM-CSF-supplemented cultures, we could uncouple the cell growth effect from the antiapoptotic action. In these conditions, KDR stimulation, while not exerting a survival effect, causes: (a) a slight, but significant increase of cell growth, and particularly (b) a sharp rise of mitotic figures.…”

“…19 In line with these findings, adult murine VEGF (À/À) cells show a sharp depletion of the HSC pool: importantly, treatment with VEGF mutants revealed that activation of KDR is sufficient to rescue the HSC activity. 20 Specifically, KDR favors self-renewal and survival of primitive hematopoietic cells. 8,20,21 The functional role of KDR at more advanced stages of hematopoiesis is under investigation.…”

“…20 Specifically, KDR favors self-renewal and survival of primitive hematopoietic cells. 8,20,21 The functional role of KDR at more advanced stages of hematopoiesis is under investigation. KDR and VEGF are significantly expressed in megakaryocytic (MK) cells, suggesting that KDR may play a role in megakaryopoiesis.…”

“…22 The co-expression of Flt1 and KDR in hematopoietic precursors renders difficult the investigation of the specific functional role, as compared to that of Flt1. 8,10,11,20 Noteworthily, KDR also co-operates with Flt1 to promote not only HSC survival 20 but also endothelial cell proliferation. 25 The human TF1 cell line may represent a suitable model to study the specific effects of KDR on hematopoietic progenitors, without any interference by other VEGF receptors.…”