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February 28, 2011

The effect of cyclosporin A in causing cardiomyocyte differentiation of iPS cells

Scientists here have established a standard technique for obtaining functional cardiomyocytes from human induced pluripotent stem (iPS) cells. The team led by Jun K. Yamashita, an associate professor at the Center for iPS Cell Research and Application (CiRA) and the Institute for Frontier Medical Sciences, both at Kyoto University, found that cyclosporine-A dramatically promotes the induction of cardiac cells from mouse or human iPS cells.

iPS cells are generated from mouse and human tissues by reprogramming. Understanding the molecular mechanism that induces differentiation of cardiomyocytes from iPS cells and the development of an efficient induction method are essential for developing cardiac cell models as well as regenerative therapies. The research team previously reported that heart and blood vessels can be induced from mouse ES/iPS cells by using precursor cells that express Flk1+. They also found that cell groups of Flk1+/CXCR4+/VE-cadherin‾ (FCV cells) show a high differentiation ability as a cardiogenic precursor cells. In addition, their earlier study demonstrated that cyclosporin A (CSA) dramatically promotes the induction of FVC cells and myocardial cells from mouse ES cells. In this experiment, utilizing the findings obtained from the above research, the Yamashita lab investigated how CSA affects differentiation induction from mouse and human iPS cells into cardiac cells.

The study showed that when cultivating mouse iPS cell derived Flk1+ cells with OP9 stroma cells, cardiomyocytes and FCV cells dramatically increased with CSA added. Simultaneously beating colonies of cardiomyocytes derived from human iPS cells were obtained by co-culturing them with END-2 cells, which are endoderm-like supporting cells. Appearance of the beating colonies from human iPS cells was increased approximately 4.3 fold by adding CSA to the differentiation method.

Cardiomyocytes induced by human iPS cells using CSA showed various cardiac-specific marker expressions and also demonstrated synchronized calcium transients, cardiomyocyte-like action potentials, pharmacological response, and microscopic structures.

Application to toxicity tests in drug development and to the regenerative therapies of the myocardium is desired with cardiomyocytes produced from human iPS cells. There are still several issues to be improved regarding this cardiomyocyte induction method. The development of these techniques may significantly contribute to regenerative medicine such as cell transplantation therapy as well as the new drug development.

"Induction and enhancement of cardiac cell differentiation from mouse and human induced pluripotent stem cells with cyclosporin-A"
Masataka Fujiwara, Peishi Yan, Tomomi G. Otsuji, Genta Narazaki, Hideki Uosaki, Hiroyuki Fukushima, Hiroyuki Matsuda, Koichiro Kuwahara, Masaki Harada, Hiroyuki Matsuda, Satoshi Matsuoka Keisuke Okita, Kazutoshi Takahashi, Masato Nakagawa, Tadashi Ikeda, Ryuzo Sakata, Christine L. Mummery, Norio Nakatsuji, Shinya Yamanaka, Kazuwa Nakao, Jun K. Yamashita.
PLoS ONE. 2011 February Vol6 (2); e16734

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