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

Leto Riebel1, Elisa Passini1, Francesca Margara1, Michelangelo Paci2, Jacopo Biasetti3, Blanca Rodriguez1
1University of Oxford, 2Tampere University, 3AstraZeneca


Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provide a promising resource for regenerative heart therapies. However, their immature electrophysiological phenotype can cause local heterogeneities and arrhythmias when inserting hiPSC-CMs in the native adult tissue. In silico models can provide a better understanding of the key mechanisms underlying electrophysiological differences in hiPSC-CMs and adult cardiomyocytes and inform risk predictions.

Our aim is to conduct a simulation study to identify the main ionic currents determining differences in electrophysiological properties between hiPSC-CMs and human ventricular cardiomyocytes.

We used the latest Paci2020 model (hiPSC-CMs) and the ToR-ORd model (human ventricular cardiomyocytes). Key action potential (AP) biomarkers were computed at 1Hz stimulation. A sensitivity analysis was conducted on the Paci model by scaling eleven ionic current conductances in the range [0-10] of their baseline values. Results were compared against the AP biomarkers and ionic current peaks obtained with the ToR-ORd model.

Our simulations highlighted that the peaks of the fast and late Na+, the transient outward K+ and the SERCA pump currents are significantly lower in Paci vs ToR-ORd (38%, 20%, 12% and 5% of the ToR-ORd value, respectively). The fast Na+ current conductance is the main modulator of upstroke velocity, e.g. a three-fold increase results in an increase from 118V/s to 244V/s, moving it closer to ToR-ORd (349V/s). Increasing the rapid delayed outward rectifier K+ current decreased AP duration at 90% repolarisation, e.g. from 481ms to 266ms for a two-fold increase, compared to 273ms in ToR-ORd. Upscaling the inward rectifier K+ current lowered the diastolic potential, e.g. from –74mV to –81mV for a two-fold increase, closer to –89mV in ToR-ORd.

In conclusion, we identified the fast Na+ current and the inward and rapid outward delayed rectifier K+ currents as the key modulators of hiPSC-CMs towards an adult phenotype.