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

Kenji Miki, Kohei Deguchi, Misato Nakanishi-Koakutsu, Antonio Lucena-Cacace, Shigeru Kondo, Yuya Fujiwara, Takeshi Hatani, Masako Sasaki, Yuki Naka, Chikako Okubo, Megumi Narita, Ikue Takei, Stephanie C. Napier, Tsukasa Sugo, Sachiko Imaichi, Taku Monjo, Tatsuya Ando, Norihisa Tamura, Kenichi Imahashi, Tomoyuki Nishimoto () and Yoshinori Yoshida ()
Additional contact information
Kenji Miki: Kyoto University
Kohei Deguchi: Takeda-CiRA Joint program (T-CiRA)
Misato Nakanishi-Koakutsu: Kyoto University
Antonio Lucena-Cacace: Kyoto University
Shigeru Kondo: Takeda-CiRA Joint program (T-CiRA)
Yuya Fujiwara: Kyoto University
Takeshi Hatani: Kyoto University
Masako Sasaki: Kyoto University
Yuki Naka: Kyoto University
Chikako Okubo: Kyoto University
Megumi Narita: Kyoto University
Ikue Takei: Kyoto University
Stephanie C. Napier: Takeda-CiRA Joint program (T-CiRA)
Tsukasa Sugo: GenAhead Bio Inc.
Sachiko Imaichi: Takeda Pharmaceutical Company Limited
Taku Monjo: Takeda Pharmaceutical Company Limited
Tatsuya Ando: Takeda Pharmaceutical Company Limited
Norihisa Tamura: Takeda-CiRA Joint program (T-CiRA)
Kenichi Imahashi: Takeda-CiRA Joint program (T-CiRA)
Tomoyuki Nishimoto: Takeda-CiRA Joint program (T-CiRA)
Yoshinori Yoshida: Kyoto University

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract 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 TNNI1EmGFP and TNNI3mCherry 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23816-3

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DOI: 10.1038/s41467-021-23816-3

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