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

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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.
Funding Information
  • MEXT | Japan Society for the Promotion of Science (18K15120, 18KK0461, 17H04176)
  • Japan Agency for Medical Research and Development (19bm0104001h0007, 19bm0204003h0107, 19bm0804008h0103, 20bm0804022h0001, 19bk0104095h0001)
  • Fondation Leducq (18CVD05)
  • a grant from Takeda Pharmaceutical Company Limited SECOM Science and Technology Foundation

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