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大学・研究所にある論文を検索できる 「ERRγ enhances cardiac maturation with T-tubule formation in human iPSC-derived cardiomyocytes」の論文概要。リケラボ論文検索は、全国の大学リポジトリにある学位論文・教授論文を一括検索できる論文検索サービスです。

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ERRγ enhances cardiac maturation with T-tubule formation in human iPSC-derived cardiomyocytes

Miki, Kenji Deguchi, Kohei Nakanishi-Koakutsu, Misato Lucena-Cacace, Antonio Kondo, Shigeru Fujiwara, Yuya Hatani, Takeshi Sasaki, Masako Naka, Yuki Okubo, Chikako Narita, Megumi Takei, Ikue Napier, Stephanie C. Sugo, Tsukasa Imaichi, Sachiko Monjo, Taku Ando, Tatsuya Tamura, Norihisa Imahashi, Kenichi Nishimoto, Tomoyuki Yoshida, Yoshinori 京都大学 DOI:10.1038/s41467-021-23816-3

2021

概要

One of the earliest maturation steps in cardiomyocytes (CMs) is the sarcomere protein isoform switch between TNNI1 and TNNI3 (fetal and neonatal/adult troponin I). Here, we generate human induced pluripotent stem cells (hiPSCs) carrying a TNNI1[EmGFP] and TNNI3[mCherry] double reporter to monitor and isolate mature sub-populations during cardiac differentiation. Extensive drug screening identifies two compounds, an estrogen-related receptor gamma (ERRγ) agonist and an S-phase kinase-associated protein 2 inhibitor, that enhances cardiac maturation and a significant change to TNNI3 expression. Expression, morphological, functional, and molecular analyses indicate that hiPSC-CMs treated with the ERRγ agonist show a larger cell size, longer sarcomere length, the presence of transverse tubules, and enhanced metabolic function and contractile and electrical properties. Here, we show that ERRγ-treated hiPSC-CMs have a mature cellular property consistent with neonatal CMs and are useful for disease modeling and regenerative medicine.

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Acknowledgements

We thank Drs. Shinya Yamanaka and Seigo Izumo for supporting this project. We also

thank Takako Sono, Ayaka Sakoda, Miyuki Nomura, Yuko Ishikawa, and Haruka

Yamamoto (T-CiRA) for preparing some of the materials and technical assistance, and

Azusa Hama and Yoko Uematsu (CiRA), Shizuka Murakami, Yoshimitsu Nakashima,

Reiko Oikawa (Takeda Pharmaceutical Company Limited), Takanori Matsuo and Aya

Higashide (T-CiRA) for their administrative support. We also thank Peter Karagiannis

(CiRA) for reading the manuscript. We used development samples provided free from

Oji Holdings Corporation for the analysis. This research was supported by the

Takeda–CiRA collaboration program, a grant from Takeda Pharmaceutical Company

Limited, a grant from the Leducq Foundation (18CVD05), a grant from SECOM Science

and Technology Foundation, grants from the Research Center Network for Realization of

Regenerative Medicine (JP19bm0104001, JP19bm0204003, JP19bm0804008, and

JP20bm0804022), Research on Regulatory Science of Pharmaceuticals and Medical

Devices (JP19mk0104117), and Research Project for Practical Applications of Regenerative Medicine (JP19bk0104095) provided by the Japan Agency for Medical Research

and Development, JSPS KAKENHI Grants (JP18K15120, JP18KK0461, JP19K16041 and

JP17H04176) and the iPS Cell Research Fund. Kyoto University and Takeda Pharmaceutical Company Limited have filed a patent application broadly relevant to this work.

Author contributions

K.M., K.D., M.N.-K., N.T., K.I., T.N., and Y.Y. conceived and designed the project. K.M.,

K.D., M.N.-K., S.K., Y.F., M.S., Y.N., I.T. and S.C.N. performed the experimental work.

T.S. and S.I. performed the CRISPR constructions. M.S., A.L.-C., C.O., M.N., T.M., and

T.A. analyzed the RNA-seq data. T.H. and Y.F. performed the transmission electron

microscopy work. K.M., K.D., M.N.-K., A.L.-C., T.N., and Y.Y. wrote the manuscript.

All authors discussed the results.

Competing interests

Y.Y. received research expense from Takeda Pharmaceutical Company, Ltd, and K.D.,

S.K., S.C.N., S.I, T.M., T.A., N.T., K.I., T.N. are employees of Takeda Pharmaceutical

Company, Ltd. K.M., S.K., and Y.Y. are the inventors of the patent application

(WO2019/189554). The other authors declare no competing interests.

NATURE COMMUNICATIONS | (2021)12:3596 | https://doi.org/10.1038/s41467-021-23816-3 | www.nature.com/naturecommunications

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Additional information

Supplementary information The online version contains supplementary material

available at https://doi.org/10.1038/s41467-021-23816-3.

Correspondence and requests for materials should be addressed to T.N. or Y.Y.

Peer review information Nature Communications thanks the anonymous reviewer(s) for

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