In Silico Identification of the Key Ionic Currents Modulating Human Pluripotent Stem Cell-Derived Cardiomyocytes Towards an Adult Phenotype

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provide a promising resource for regenerative therapies. However, their immature phenotype and heterogeneities raise concern for arrhythmia when hiPSC-CMs are inserted into the native tissue. In silico models can improve understanding of the electrophysiological differences between hiPSC-CMs and adult cardiomyocytes and inform risk predictions. Our aim is to conduct a sensitivity analysis to identify the main ionic currents determining differences in electrophysiological properties between the Paci2020 model (hiPSC-CMs) and the ToR-ORd model (human ventricular cardiomyocytes). Our simulations highlighted the fast $Na^{+}$ current as the key modulator of upstroke velocity, while the inward and rapid delayed rectifier $K^{+}$ currents mainly contributed to a decrease of diastolic potential and action potential duration, respectively. In conclusion, we identified an increase of the conductance of these currents essential to modulate the biomarkers of the hiPSC-CM model towards the adult phenotype.