Soluble Flt-1 regulates Flk-1 activation to control hematopoietic and endothelial development in an oxygen-responsive manner

Kelly A. Purpura, Sophia H.L. George, Stephen M. Dang, Kyunghee Choi, Andras Nagy, Peter W. Zandstra

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

Vascular endothelial growth factor (VEGF) and the vascular endothelial growth factor receptors (VEGFRs) regulate the development of hemogenic mesoderm. Oxygen concentration-mediated activation of hypoxia-inducible factor targets such as VEGF may serve as the molecular link between the microenvironment and mesoderm-derived blood and endothelial cell specification. We used controlled-oxygen microenvironments to manipulate the generation of hemogenic mesoderm and its derivatives from embryonic stem cells. Our studies revealed a novel role for soluble VEGFR1 (sFlt-1) in modulating hemogenic mesoderm fate between hematopoietic and endothelial cells. Parallel measurements of VEGF and VEGFRs demonstrated that sFlt-1 regulates VEGFR2 (Flk-1) activation in both a developmental-stage-dependent and oxygen-dependent manner. Early transient Flk-1 signaling occurred in hypoxia because of low levels of sFlt-1 and high levels of VEGF, yielding VEGF-dependent generation of hemogenic mesoderm. Sustained (or delayed) Flk-1 activation preferentially yielded hemogenic mesoderm-derived endothelial cells. In contrast, delayed (sFlt-1-mediated) inhibition of Flk-1 signaling resulted in hemogenic mesoderm-derived blood progenitor cells. Ex vivo analyses of primary mouse embryo-derived cells and analysis of transgenic mice secreting a Flt-1-Fc fusion protein (Fc, the region of an antibody which is constant and binds to receptors) support a hypothesis whereby microenvironmentally regulated blood and endothelial tissue specification is enabled by the temporally variant control of the levels of Flk-1 activation.

Original languageEnglish (US)
Pages (from-to)2832-2842
Number of pages11
JournalSTEM CELLS
Volume26
Issue number11
DOIs
StatePublished - Nov 2008
Externally publishedYes

Keywords

  • Embryonic development
  • Hematopoiesis
  • Hypoxia
  • Vascular endothelial growth factor
  • Vasculogenesis

ASJC Scopus subject areas

  • Molecular Medicine
  • Developmental Biology
  • Cell Biology

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