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(Circulation Research. 2009;104:372.)
© 2009 American Heart Association, Inc.

Cellular Biology

Wnt5a Is Required for Endothelial Differentiation of Embryonic Stem Cells and Vascularization via Pathways Involving Both Wnt/β-Catenin and Protein Kinase C

Dong-Hwa Yang, Ju-Young Yoon, Soung-Hoon Lee, Vitezslav Bryja, Emma R. Andersson, Ernest Arenas, Young-Guen Kwon, Kang-Yell Choi

From the National Research Laboratory of Molecular Complex Control and Department of Biotechnology (D.-H.Y., J.-Y.Y., S.-H.L., K.-Y.C.) and Department of Biochemistry (Y.-G.K.), College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea; Academy of Sciences of the Czech Republic and Institute of Experimental Biology (V.B.), Faculty of Science, Masaryk University, Brno, Czech Republic; and Laboratory of Molecular Neurobiology (E.R.A., E.A.), Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.

Correspondence to Kang-Yell Choi, Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-752, Korea. E-mail kychoi{at}yonsei.ac.kr

In this study, we examined the signaling pathways activated by Wnt5a in endothelial differentiation of embryonic stem (ES) cells and the function of Wnt5a during vascular development. We first found that Wnt5a^–/– mouse embryonic stem (mES) cells exhibited a defect in endothelial differentiation, which was rescued by addition of Wnt5a, suggesting that Wnt5a is required for endothelial differentiation of ES cells. Involvement of both β-catenin and protein kinase (PK)C pathways in endothelial differentiation of mES cells requiring Wnt5a was indicated by activation of both β-catenin and PKC in Wnt5a^+/– but not in Wnt5a^–/– mES cells. We also found that β-catenin or PKC knockdowns inhibited the Wnt5a-induced endothelial differentiation of ES cells. Moreover, the lack of endothelial differentiation of Wnt5a^–/– mES cells was rescued only by transfection of both β-catenin and PKC, indicating that both genes are required for Wnt5a-mediated endothelial differentiation. Wnt5a was also found to be essential for the differentiation of mES cells into immature endothelial progenitor cells, which are known to play a role in repair of damaged endothelium. Furthermore, a defect in the vascularization of the neural tissue was detected at embryonic day 14.5 in Wnt5a^–/– mice, implicating Wnt5a in vascular development in vivo. Thus, we conclude that Wnt5a is involved in the endothelial differentiation of ES cells via both Wnt/β-catenin and PKC signaling pathways and regulates embryonic vascular development.

Key Words: Wnt5a • embryonic stem cells • β-catenin • PKC • endothelial differentiation

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