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.
Highlights
One of the earliest maturation steps in cardiomyocytes (CMs) is the sarcomere protein isoform switch between TNNI1 and TNNI3
Once the selection cassette was removed (Fig. 1c), we confirmed the expression of emerald green fluorescent protein (EmGFP) in human induced pluripotent stem cells (hiPSCs)-CMs by flow cytometric analysis, which showed most cells were positive for cardiac Troponin T (Fig. 1d and e)
Regenerative therapies using engineered CMs and tissue models have benefited from growing knowledge of the molecular and cellular bases of cardiac differentiation and maturation. hiPSCs represent a major source of engineered differentiated CMs, but current hiPSC-CMs exhibit poor maturity
Summary
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). Isoform switching between TNNI1 (slow skeletal TnI; ssTnI) and TNNI3 (cardiac TnI; cTnI) occurs during the developmental transition from fetal to neonatal and postnatal stages and is followed by the eventual acquisition of functional hallmarks of cardiac maturation[7]. These hallmarks include an efficient conversion of energy, excitation–contraction coupling, a positive force–frequency relationship, anisotropy driven by the cellular alignment, and neonatal/adult CM-like electrophysiological properties with increased conduction velocity. Postnatal CMs in vivo display cell-cycle arrest, leading to a loss of proliferative capacity and regenerative potential
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