4.7 Article

Signaling Hierarchy Regulating Human Endothelial Cell Development

Journal

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 29, Issue 5, Pages 718-U209

Publisher

LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.109.184200

Keywords

human embryonic stem cells; endothelial cells; Indian hedgehog; BMP signaling; vascular development

Funding

  1. NIH [EB-005173, EB-007076 R01, DK-075355, T32 DK-064717]

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Objective-Our present knowledge of the regulation of mammalian endothelial cell differentiation has been largely derived from studies of mouse embryonic development. However, unique mechanisms and hierarchy of signals that govern human endothelial cell development are unknown and, thus, explored in these studies. Methods and Results-Using human embryonic stem cells as a model system, we were able to reproducibly and robustly generate differentiated endothelial cells via coculture on OP9 marrow stromal cells. We found that, in contrast to studies in the mouse, bFGF and VEGF had no specific effects on the initiation of human vasculogenesis. However, exogenous Ihh promoted endothelial cell differentiation, as evidenced by increased production of cells with cobblestone morphology that coexpress multiple endothelial-specific genes and proteins, form lumens, and exhibit DiI-AcLDL uptake. Inhibition of BMP signaling using Noggin or BMP4, specifically, using neutralizing antibodies suppressed endothelial cell formation; whereas, addition of rhBMP4 to cells treated with the hedgehog inhibitor cyclopamine rescued endothelial cell development. Conclusions-Our studies revealed that Ihh promoted human endothelial cell differentiation from pluripotent hES cells via BMP signaling, providing novel insights applicable to modulating human endothelial cell formation and vascular regeneration for human clinical therapies. (Arterioscler Thromb Vasc Biol. 2009; 29: 718-724.)

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