Blood Journal
Leading the way in experimental and clinical research in hematology

Hypoxic induction of vascular endothelial growth factor regulates murine hematopoietic stem cell function in the low-oxygenic niche

  1. Matilda Rehn1,
  2. André Olsson1,
  3. Kristian Reckzeh1,
  4. Eva Diffner2,
  5. Peter Carmeliet3,
  6. Göran Landberg2, and
  7. Jörg Cammenga1,*
  1. 1 Division of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund, Sweden;
  2. 2 Center for Molecular Pathology, Skane University Hospital, Malmo, Sweden;
  3. 3 Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center (VRC), VIB, Leuven, Belgium
  1. * Corresponding author; email: jorg.cammenga{at}


Hypoxia is emerging as an important characteristic of the hematopoietic stem cell (HSC) niche, but the molecular mechanisms contributing to quiescence, self-renewal, and survival remain elusive. Vascular endothelial growth factor A (VEGFA) is a key regulator of angiogenesis and hematopoiesis. Its expression is commonly regulated by hypoxia-inducible factors (HIF) that are functionally induced in low-oxygen conditions and that activate transcription by binding to hypoxia-response elements (HRE). Vegfa is indispensable for HSC survival, mediated by a cell-intrinsic, autocrine mechanism. We hypothesized that a hypoxic HSC microenvironment is required for maintenance or upregulation of Vegfa expression in HSCs and therefore crucial for HSC survival. We have tested this hypothesis in the mouse model Vegfaδ/δ, where the HRE in the Vegfa promoter is mutated, preventing HIF binding. Vegfa expression was reduced in highly purified HSCs from Vegfaδ/δ mice, showing that HSCs reside in hypoxic areas. Loss of hypoxia-regulated Vegfa expression increases the numbers of phenotypically defined hematopoietic stem and progenitor cells. However, HSC function was clearly impaired when assessed in competitive transplantation assays. Our data provide further evidence that HSCs reside in a hypoxic microenvironment and demonstrate a novel way in which the hypoxic niche affects HSC fate, via the hypoxia-Vegfa axis.

  • Submitted January 26, 2011.
  • Accepted May 31, 2011.