ERRγ agonist under mechanical stretching manifests hypertrophic cardiomyopathy phenotypes of engineered cardiac tissue through maturation
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- Fujiwara, Yuya
- Center for iPS Cells Research and Application, Kyoto University; Takeda-CiRA Joint Program
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- Miki, Kenji
- Center for iPS Cells Research and Application, Kyoto University; Center for Organ Engineering, Department of Surgery, Massachusetts General Hospital; Department of Surgery, Harvard Medical School; Present address: Premium Research Institute for Human Metaverse Medicine, Osaka University
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- Deguchi, Kohei
- Takeda-CiRA Joint Program; T-CiRA Discovery, Takeda Pharmaceutical Company Limited
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- Naka, Yuki
- Center for iPS Cells Research and Application, Kyoto University; Takeda-CiRA Joint Program
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- Sasaki, Masako
- Center for iPS Cells Research and Application, Kyoto University; Takeda-CiRA Joint Program
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- Sakoda, Ayaka
- Takeda-CiRA Joint Program; T-CiRA Discovery, Takeda Pharmaceutical Company Limited
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- Narita, Megumi
- Center for iPS Cells Research and Application, Kyoto University
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- Imaichi, Sachiko
- Pharmaceutical Science, Takeda Pharmaceutical Company Limited; Present address: Department of Molecular Biology, Massachusetts General Hospital
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- Sugo, Tsukasa
- GenAhead Bio Inc.
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- Funakoshi, Shunsuke
- Center for iPS Cells Research and Application, Kyoto University; Takeda-CiRA Joint Program
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- Nishimoto, Tomoyuki
- Orizuru therapeutic Inc.
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- Imahashi, Kenichi
- Takeda-CiRA Joint Program; T-CiRA Discovery, Takeda Pharmaceutical Company Limited
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- Yoshida, Yoshinori
- Center for iPS Cells Research and Application, Kyoto University; Takeda-CiRA Joint Program
Abstract
Engineered cardiac tissue (ECT) using human induced pluripotent stem cell-derived cardiomyocytes is a promising tool for modeling heart disease. However, tissue immaturity makes robust disease modeling difficult. Here, we established a method for modeling hypertrophic cardiomyopathy (HCM) malignant (MYH7 R719Q) and nonmalignant (MYBPC3 G115∗) pathogenic sarcomere gene mutations by accelerating ECT maturation using an ERRγ agonist, T112, and mechanical stretching. ECTs treated with T112 under 10% elongation stimulation exhibited more organized and mature characteristics. Whereas matured ECTs with the MYH7 R719Q mutation showed broad HCM phenotypes, including hypertrophy, hypercontraction, diastolic dysfunction, myofibril misalignment, fibrotic change, and glycolytic activation, matured MYBPC3 G115∗ ECTs displayed limited phenotypes, which were primarily observed only under our new maturation protocol (i.e., hypertrophy). Altogether, ERRγ activation combined with mechanical stimulation enhanced ECT maturation, leading to a more accurate manifestation of HCM phenotypes, including non-cardiomyocyte activation, consistent with clinical observations.
Stretching and stimulating engineered heart tissues to accurately portray hypertrophic cardiomyopathy. 京都大学プレスリリース. 2023-10-17.
Journal
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- Stem Cell Reports
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Stem Cell Reports 18 (11), 2108-2122, 2023-11-14
Elsevier BV
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Keywords
Details 詳細情報について
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- CRID
- 1050298201110998784
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- ISSN
- 22136711
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- HANDLE
- 2433/286048
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- Text Lang
- en
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- Article Type
- journal article
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- Data Source
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- IRDB