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

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 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.

SUBMITTER: Miki K

PROVIDER: S-EPMC8217550 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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

Miki Kenji K Deguchi Kohei K Nakanishi-Koakutsu Misato M Lucena-Cacace Antonio A Kondo Shigeru S Fujiwara Yuya Y Hatani Takeshi T Sasaki Masako M Naka Yuki Y Okubo Chikako C Narita Megumi M Takei Ikue I Napier Stephanie C SC Sugo Tsukasa T Imaichi Sachiko S Monjo Taku T Ando Tatsuya T Tamura Norihisa N Imahashi Kenichi K Nishimoto Tomoyuki T Yoshida Yoshinori Y

Nature communications 20210621 1

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<sup>EmGFP</sup> and TNNI3<sup>mCherry</sup> 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 k ...[more]

PMID: 34155205

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Project description:BackgroundInduced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have emerged as a powerful tool for disease modeling, though their immature nature currently limits translation into clinical practice. Maturation strategies increasingly pay attention to cardiac metabolism because of its pivotal role in cardiomyocyte development and function. Moreover, aberrances in cardiac metabolism are central to the pathogenesis of cardiac disease. Thus, proper modeling of human cardiac disease warrants careful characterization of the metabolic properties of iPSC-CMs.MethodsHere, we examined the effect of maturation protocols on healthy iPSC-CMs applied in 23 studies and compared fold changes in functional metabolic characteristics to assess the level of maturation. In addition, pathological metabolic remodeling was assessed in 13 iPSC-CM studies that focus on hypertrophic cardiomyopathy (HCM), which is characterized by abnormalities in metabolism.ResultsMatured iPSC-CMs were characterized by mitochondrial maturation, increased oxidative capacity and enhanced fatty acid use for energy production. HCM iPSC-CMs presented varying degrees of metabolic remodeling ranging from compensatory to energy depletion stages, likely due to the different types of mutations and clinical phenotypes modeled. HCM further displayed early onset hypertrophy, independent of the type of mutation or disease stage.ConclusionsMaturation strategies improve the metabolic characteristics of iPSC-CMs, but not to the level of the adult heart. Therefore, a combination of maturation strategies might prove to be more effective. Due to early onset hypertrophy, HCM iPSC-CMs may be less suitable to detect early disease modifiers in HCM and might prove more useful to examine the effects of gene editing and new drugs in advanced disease stages. With this review, we provide an overview of the assays used for characterization of cardiac metabolism in iPSC-CMs and advise on which metabolic assays to include in future maturation and disease modeling studies.

Dataset Information

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

Publications

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

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