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Population-based toxicity screening in human induced pluripotent stem cell-derived cardiomyocytes
Sarah D Burnett1, Alexander D Blanchette1, Fabian A Grimm1
1Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX 77843-4458, USA.
Toxicology and Applied Pharmacology
|August 20, 2019
Summary
Environmental chemicals pose a cardiotoxicity risk, yet are rarely tested. This study demonstrates a human cell model to assess chemical cardiotoxicity and individual variability, advancing safety testing.
Area of Science:
- Cardiovascular toxicology
- Stem cell biology
- Environmental health
Background:
- Cardiotoxicity is a significant pharmaceutical safety concern, but environmental chemicals are seldom evaluated for this risk.
- Human cardiovascular risk varies significantly, yet susceptibility to chemical-induced cardiotoxicity is poorly understood.
- Human induced pluripotent stem cell (iPSC)-derived cardiomyocytes offer a promising in vitro model for assessing drug and chemical effects.
Purpose of the Study:
- To investigate the feasibility of using a population-based model of iPSC-derived cardiomyocytes to assess cardiotoxicity hazard and inter-individual variability of chemical exposures.
- To quantify chemical-specific variability in potency and population variability in cardiotoxicity.
- To establish an innovative tool for population-based cardiotoxicity screening.
Main Methods:
- Concentration-response screening of 134 chemicals using iPSC-derived cardiomyocytes from 43 diverse individuals.
- Measurement of kinetic calcium flux and high-content imaging following chemical exposure.
- Assessment of functional and cytotoxicity parameters across different chemicals and donors.
Main Results:
- Demonstrated reproducible inter-individual variability in baseline and chemical-induced effects on iPSC-derived cardiomyocytes.
- Quantified chemical-specific variability in potency and the degree of population variability.
- Established the feasibility of a population-based in vitro model for cardiotoxicity assessment.
Conclusions:
- An organotypic, population-based human in vitro model can quantitatively assess cardiotoxicity for chemicals with limited data.
- This approach advances in vitro toxicity testing, supporting a shift from animal models to human-relevant in vitro methods.
- Results provide a novel tool for population-based cardiotoxicity screening and risk assessment.
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