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(Circulation. 2008;118:498-506.)
© 2008 American Heart Association, Inc.

Molecular Cardiology

Directed and Systematic Differentiation of Cardiovascular Cells From Mouse Induced Pluripotent Stem Cells

Genta Narazaki, MS; Hideki Uosaki, MD; Mizue Teranishi, BS; Keisuke Okita, PhD; Bongju Kim, PhD; Satoshi Matsuoka, MD, PhD; Shinya Yamanaka, MD, PhD; Jun K. Yamashita, MD, PhD

From the Laboratory of Stem Cell Differentiation, Stem Cell Research Center, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan (G.N., H.U., M.T., J.K.Y.); Department of Stem Cell Biology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan (K.O., S.Y.); Center for iPS Cell Research and Application, Institute for Integrated Cell-Material Sciences, Kyoto University, Kyoto, Japan (K.O., S.Y., J.K.Y.); Department of Physiology and Biophysics, Kyoto University Graduate School of Medicine, Kyoto, Japan (B.K., S.M.); Gladstone Institute of Cardiovascular Disease, San Francisco, Calif (S.Y.); and CREST, Japan Science and Technology Agency, Kawaguchi, Japan (S.Y.).

Correspondence to Jun K. Yamashita, MD, PhD, Laboratory of Stem Cell Differentiation, Stem Cell Research Center, Institute for Frontier Medical Sciences, Kyoto University, 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. E-mail juny{at}frontier.kyoto-u.ac.jp

Received January 28, 2008; accepted May 6, 2008.

Background— Induced pluripotent stem (iPS) cells are a novel stem cell population induced from mouse and human adult somatic cells through reprogramming by transduction of defined transcription factors. However, detailed differentiation properties and the directional differentiation system of iPS cells have not been demonstrated.

Methods and Results— Previously, we established a novel mouse embryonic stem (ES) cell differentiation system that can reproduce the early differentiation processes of cardiovascular cells. We applied our ES cell system to iPS cells and examined directional differentiation of mouse iPS cells to cardiovascular cells. Flk1 (also designated as vascular endothelial growth factor receptor-2)-expressing mesoderm cells were induced from iPS cells after 4-day culture for differentiation. Purified Flk1⁺ cells gave rise to endothelial cells and mural cells by addition of vascular endothelial growth factor and serum. Arterial, venous, and lymphatic endothelial cells were also successfully induced. Self-beating cardiomyocytes could be induced from Flk1⁺ cells by culture on OP9 stroma cells. Time course and efficiency of the differentiation were comparable to those of mouse ES cells. Occasionally, reexpression of transgene mRNAs, including c-myc, was observed in long-term differentiation cultures.

Conclusions— Various cardiovascular cells can be systematically induced from iPS cells. The differentiation properties of iPS cells are almost completely identical to those of ES cells. This system would greatly contribute to a novel understanding of iPS cell biology and the development of novel cardiovascular regenerative medicine.

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