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Updated: Jul 2, 2025
High-Throughput Cardiotoxicity Screening Using Mature Human Induced Pluripotent Stem Cell-Derived Cardiomyocyte Monolayers
Published on: March 24, 2023
A safety screening platform for individualized cardiotoxicity assessment
Verena Schwach1, Rolf H Slaats1, Carla Cofiño-Fabres1
1Applied Stem Cell Technologies, TechMed Centre, University of Twente, Drienerlolaan 5, 7500 AE Enschede, the Netherlands.
Abstract:
Cardiotoxicity remains a major cause of drug withdrawal, partially due to lacking predictability of animal models. Additionally, risk of cardiotoxicity following treatment of cancer patients is treatment limiting. It is unclear which patients will develop heart failure following therapy. Human pluripotent stem cell (hPSC)-derived cardiomyocytes present an unlimited cell source and may offer individualized solutions to this problem. We developed a platform to predict molecular and functional aspects of cardiotoxicity. Our platform can discriminate between the different cardiotoxic mechanisms of existing and novel anthracyclines Doxorubicin, Aclarubicin, and Amrubicin. Doxorubicin and Aclarubicin unlike Amrubicin substantially affected the transcriptome, mitochondrial membrane integrity, contractile force and transcription factor availability. Cardiomyocytes recovered fully within two or three weeks, corresponding to the intermittent clinical treatment regimen. Our system permits the study of hPSC-cardiomyocyte recovery and the effects of accumulated dose after multiple dosing, allowing individualized cardiotoxicity evaluation, which effects millions of cancer patients treated annually.
Insights
Human stem cell-derived heart cells predict drug-induced cardiotoxicity, aiding personalized cancer therapy by identifying risks before heart failure occurs.
Area of Science:
- Stem cell biology
- Cardiovascular toxicology
- Pharmacology
Background:
- Drug-induced cardiotoxicity is a significant clinical challenge, leading to treatment withdrawal and limiting cancer therapy efficacy.
- Current animal models lack predictability for human cardiotoxicity, and identifying at-risk patients remains difficult.
- Human pluripotent stem cell (hPSC)-derived cardiomyocytes offer a scalable and potentially personalized approach to assess drug safety.
Purpose of the Study:
- To develop and validate a platform using hPSC-cardiomyocytes for predicting molecular and functional cardiotoxicity.
- To differentiate cardiotoxic mechanisms of anthracyclines (Doxorubicin, Aclarubicin, Amrubicin).
- To evaluate the potential for individualized cardiotoxicity assessment in cancer patients.
Main Methods:
- Utilized a platform based on hPSC-derived cardiomyocytes to assess cardiotoxicity.
- Analyzed molecular (transcriptome, transcription factors) and functional (contractile force, mitochondrial integrity) endpoints.
- Investigated the effects of Doxorubicin, Aclarubicin, and Amrubicin, including recovery and repeated dosing.
Main Results:
- The platform successfully discriminated between the cardiotoxic profiles of Doxorubicin, Aclarubicin, and Amrubicin.
- Doxorubicin and Aclarubicin significantly impacted transcriptome, mitochondrial function, contractility, and transcription factor availability, unlike Amrubicin.
- Cardiomyocytes demonstrated full recovery within 2-3 weeks, mirroring clinical intermittent dosing, and the system allowed evaluation of cumulative dose effects.
Conclusions:
- hPSC-cardiomyocyte platform accurately predicts anthracycline cardiotoxicity mechanisms and severity.
- The system enables the study of cardiomyocyte recovery and cumulative toxicity, paving the way for personalized risk assessment.
- This approach has the potential to improve cancer patient safety by predicting and mitigating heart failure risk.
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