Creating cell-specific computational models of stem cell-derived cardiomyocytes using optical experiments

Area of Science:

• Cardiology
• Computational Biology
• Stem Cell Research

Background:

• Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) are valuable for cardiac research but exhibit immature electrophysiology and lab-specific variability.
• Existing mathematical models often fail to capture the full range of iPSC-CM phenotypic heterogeneity.
• Genetic backgrounds of iPSC donors further contribute to variability in cell responses.

Purpose of the Study:

• To develop a computational pipeline for calibrating cell preparation-specific electrophysiological parameters in iPSC-CMs.
• To address limitations in current iPSC-CM models regarding phenotypic variability and maturation differences.
• To optimize experimental protocols for generating sufficient data for accurate parameter calibration.

Main Methods:

• Utilized a genetic algorithm (GA) to tune ion channel parameters within a mathematical model of iPSC-CM physiology.
• Generated in silico datasets by simulating various experimental protocols on a population of models with known conductance variations.
• Calibrated model parameters using voltage and calcium transient data under varied conditions, including electrical pacing, ion channel blockade, and buffer ion concentration changes.

Main Results:

• Calibrating to voltage and calcium transient data under varied experimental conditions significantly improved model parameter estimates.
• Model predictions for unseen channel block responses were enhanced after calibration.
• Normalized fluorescence recordings, a higher-throughput method, sufficiently informed conductance parameters, similar to patch clamp recordings.

Conclusions:

• The developed computational pipeline can determine cell line-specific ion channel properties in iPSC-CMs.
• This approach aids in understanding the mechanisms underlying variability in iPSC-CM perturbation responses.
• The pipeline offers a method to improve the accuracy and applicability of iPSC-CM models in cardiac research.