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Published online 15 December 2003. doi:10.1083/jcb.200305147
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© The Rockefeller University Press, 0021-9525/2003/12/1303 $8.00
The Journal of Cell Biology, Volume 163, Number 6, 1303-1311

Article

 TGF-ß receptor kinase inhibitor enhances growth and integrity of embryonic stem cell–derived endothelial cells

Tetsuro Watabe1, Ayako Nishihara1, Koichi Mishima1, Jun Yamashita2, Kiyoshi Shimizu3, Keiji Miyazawa1, Shin-Ichi Nishikawa4 and Kohei Miyazono1,5

1 Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
2 Laboratory of Stem Cell Differentiation, Stem Cell Research Center, Institute for Frontier Medical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8509, Japan
3 Pharmaceutical Division, KIRIN Brewery Co. Ltd., Takasaki, Gunma 370-1295, Japan
4 Laboratory for Stem Cell Biology, RIKEN Center for Developmental Biology, Chuo-ku, Kobe, Hyogo 650-0047, Japan
5 Department of Biochemistry, The Cancer Institute of the Japanese Foundation for Cancer Research, Toshima-ku, Tokyo 170-8455, Japan

Address correspondence to Kohei Miyazono, Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Tel.: 81-3-5841-3345. Fax: 81-3-5841-3354. email: miyazono-ind{at}umin.ac.jp

Recent findings have shown that embryonic vascular progenitor cells are capable of differentiating into mural and endothelial cells. However, the molecular mechanisms that regulate their differentiation, proliferation, and endothelial sheet formation remain to be elucidated. Here, we show that members of the transforming growth factor (TGF)-ß superfamily play important roles during differentiation of vascular progenitor cells derived from mouse embryonic stem cells (ESCs) and from 8.5–days postcoitum embryos. TGF-ß and activin inhibited proliferation and sheet formation of endothelial cells. Interestingly, SB-431542, a synthetic molecule that inhibits the kinases of receptors for TGF-ß and activin, facilitated proliferation and sheet formation of ESC-derived endothelial cells. Moreover, SB-431542 up-regulated the expression of claudin-5, an endothelial specific component of tight junctions. These results suggest that endogenous TGF-ß/activin signals play important roles in regulating vascular growth and permeability.

Key Words: vascular progenitor cells; endothelial development; tight junction; claudin-5; SB-431542

T. Watabe, A. Nishihara, and K. Mishima contributed equally to this work.

The online version of this article contains supplemental material.

Abbreviations used in this paper: ALK, activin receptor-like kinase; BBB, blood-brain barrier; BMP, bone morphogenetic protein; dpc, days postcoitum; ESC, embryonic stem cell; PECAM1, platelet-endothelial cell adhesion molecule 1; R-Smad, receptor-regulated Smad; SMA, {alpha}-smooth muscle actin; TJ, tight junction.


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