Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are widely used in cardiac tissue engineering, but their immature and heterogeneous electrophysiological phenotype remains a major limitation for functional tissue design and translational applications. Model-informed analysis may help bridge this gap by linking tissue-level measurements to the underlying cellular mechanisms that govern maturation-related behavior.
In this work, we combined optical mapping (OM) recordings and computational modeling to characterize the electrophysiological state of bioengineered hiPSC-CM tissues under two culture conditions: standard medium (SM) and hormonal treatment (HT). Voltage and calcium signals were extracted from OM recordings acquired after two weeks of culture. The Kernik hiPSC-CM model implemented in openCARP was calibrated to the experimental data using a genetic algorithm that optimized key ionic conductances to reproduce action potential and calcium-transient biomarkers as well as the recorded waveforms. In addition, transcriptomic trends were qualitatively compared with the model-inferred conductance changes to assess biological plausibility.
The optimized models reproduced the main experimental features in both conditions and revealed clear condition-specific electrophysiological differences. Both SM and HT remained consistent with an overall immature-like phenotype, characterized by short APD90 values and persistent spontaneous activity. However, HT showed a lower spontaneous beating rate, altered conductances related to repolarization and calcium handling, and greater variability in the inferred parameter space, suggesting a distinct and more heterogeneous electrophysiological state. Partial agreement between transcriptomic and model-inferred trends further supported the biological relevance of several inferred conductance changes.
Overall, this model-informed framework enabled mechanistic characterization of bioengineered hiPSC-CM tissues beyond conventional waveform analysis alone. By linking tissue-level OM recordings with inferred ionic remodeling, this approach may support the evaluation and optimization of maturation strategies in engineered cardiac tissues.