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EMBRYONIC STEM CELLS/INDUCED PLURIPOTENT STEM CELLS

Soluble Flt-1 Regulates Flk-1 Activation to Control Hematopoietic and Endothelial Development in an Oxygen-Responsive Manner

^aDepartment of Chemical Engineering and Applied Chemistry,
^bInstitute of Biomaterials and Biomedical Engineering, and
^cDepartment of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, Canada;
^dSamuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada;
^eDepartment of Pathology and Immunology and
^fDevelopmental Biology Program, Washington University School of Medicine, St. Louis, Missouri, USA;
^gTerrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada;
^hHeart & Stroke/Richard Lewar Centre of Excellence, McEwen Centre for Regenerative Medicine, University Health Network, Toronto Medical Discovery Tower, Toronto, Ontario, Canada

Key Words. Hematopoiesis • Vasculogenesis • Vascular endothelial growth factor • Hypoxia • Embryonic development

Correspondence: Correspondence: Peter W. Zandstra, Ph.D., Terrence Donnelly Centre for Cellular and Biomolecular Research, 160 College Street, Office 1116, Toronto, Ontario, Canada M5S 3G9. Telephone: 416-978-0553; Fax: 416-978-2666; e-mail: peter.zandstra{at}utoronto.ca

Received on March 12, 2008; accepted for publication on August 27, 2008.

First published online in STEM CELLS EXPRESS  September 4, 2008.

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.

Disclosure of potential conflicts of interest is found at the end of this article.