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(Hypertension. 2006;48:112.)
© 2006 American Heart Association, Inc.

Original Articles

Model of Vasculogenesis from Embryonic Stem Cells for Vascular Research and Regenerative Medicine

Hironori Nakagami; Namika Nakagawa; Yasushi Takeya; Katsunobu Kashiwagi; Chisato Ishida; Shin-ichiro Hayashi; Motokuni Aoki; Kunio Matsumoto; Toshikazu Nakamura; Toshio Ogihara; Ryuichi Morishita

From the Divisions of Gene Therapy Science (H.N., K.K., C.I.), Clinical Gene Therapy (N.N., Y.T., S.H., R.M.), and Molecular Regenerative Medicine (K.M., T.N.), and the Department of Geriatric Medicine (N.N., Y.T., S.H., M.A., T.O.), Graduate School of Medicine, Osaka University, Japan.

Correspondence to Ryuichi Morishita, MD, PhD, Professor, Clinical Gene Therapy, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871 Japan. E-mail morishit{at}cgt.med.osaka-u.ac.jp

Embryonic stem (ES) cells are highlighted as promising cell sources for regenerative medicine. Here, we focused on providing the platform that forced ES cells to reproduce the vascular organization process, leading to efficiency and safety evaluation as preclinical testing of biological agents. Murine ES cell–derived embryoid bodies on matrigel, but not collagen or gelatin, could be differentiated into sprouting blood vessels without the addition of growth factors. The expression of endothelial cell marker CD31 and smooth muscle marker -smooth muscle actin was partially colocalized and started to increase 7 days after culture on matrigel, accompanied by the induction of a number of growth factors, such as vascular endothelial growth factor, fibroblast growth factor-2, hepatocyte growth factor, transforming growth factor-ß, and angiopoietin-1. Moreover, notch-related genes, such as Del1 or Del4 (-like 1/4) and hey1 or hey2 (hairy/enhancer of split related TRPW motif 1/2), were upregulated in a similar time course. The treatment of neutralizing antibodies against these growth factors failed to inhibit the differentiation into the sprouting blood vessels, whereas arginine-glycine-aspartic peptide, a selective inhibitor for the vß3-integrins, did inhibit differentiation. An anticancer drug to inhibit angiogenesis, TNP-470, also blocked the vascular formation in this model. ES cells could reproduce the vascular organization process on the biosynthetic scaffolds, such as matrigel, without the addition of growth factors. In the future, a human ES-based tissue model would be an optional tool for the screening of pharmaceutical drugs for vascular disease.

Key Words: vasculature • endothelial growth factors • endothelium

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