A human population-based organotypic in vitro model for cardiotoxicity screening

Area of Science:

• Cardiovascular Research
• Pharmacology
• Toxicology
• Stem Cell Biology

Background:

• Assessing inter-individual variability in responses to xenobiotics (drugs and environmental chemicals) is a major challenge.
• Existing methods can characterize pharmacokinetic variability but not pharmacodynamic variability.
• There is a need for reliable in vitro models to study these differences.

Purpose of the Study:

• To demonstrate the feasibility of characterizing inter-individual variability in drug responses using human induced pluripotent stem cell (iPSC)-derived cardiomyocytes.
• To test the hypothesis that genetic variability in iPSC-derived cardiomyocytes leads to reproducible differences in baseline function and drug responses.

Main Methods:

• Generated iPSC-derived cardiomyocytes from 27 healthy donors.
• Measured baseline and drug-induced effects on kinetic Ca2+ flux and live cell imaging.
• Treated cells with cardiotoxic drugs: isoproterenol, propranolol, and cisapride.
• Evaluated gene expression in a subset of donors.
• Assessed reproducibility across batches and time.

Main Results:

• iPSC-derived cardiomyocytes exhibited reproducible, donor-specific differences in baseline function.
• Significant inter-individual variability was observed in responses to cardiotoxic drugs.
• Phenotypic responses were reproducible across experimental batches and time.

Conclusions:

• Human iPSC-derived cardiomyocytes from a population panel provide a feasible, reproducible in vitro model for assessing inter-individual variability in drug-induced cardiotoxicity.
• This model can serve as an animal replacement for rapid screening of drugs and chemicals.
• The approach can be extended to other iPSC-derived cell types to study xenobiotic responses.