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

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 (ERR gamma) 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 ERR gamma 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 ERR gamma -treated hiPSC-CMs have a mature cellular property consistent with neonatal CMs and are useful for disease modeling and regenerative medicine. Cardiomyocytes (CMs) derived from human induced pluripotent stem cells (hiPSCs) suffer from limited maturation. Here the authors identify ERR gamma agonist as a factor that enhances cardiac morphological, metabolic, contractile and electrical maturation of hiPSC-derived CMs with T-tubule formation.