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Updated: Dec 23, 2025
High-Throughput Cardiotoxicity Screening Using Mature Human Induced Pluripotent Stem Cell-Derived Cardiomyocyte Monolayers
Published on: March 24, 2023
Development and evaluation of next-generation cardiotoxicity assay based on embryonic stem cell-derived
Bokyeong Ryu1, Seong Woo Choi2, Seul-Gi Lee2
1Department of Laboratory Animal Medicine, College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea.
Abstract:
In accordance with requirements of the ICH S7B safety pharmacology guidelines, numerous next-generation cardiotoxicity studies using human stem cell-derived cardiomyocytes (CMs) are being conducted globally. Although several stem cell-derived CMs are being developed for commercialization, there is insufficient research to verify if these CMs can replace animal experiments. In this study, in vitro high-efficiency CMs derived from human embryonic stem cells (hESC-CMs) were compared with Sprague-Dawley rats as in vivo experimental animals, and primary cultured in vitro rat-CMs for cardiotoxicity tests. In vivo rats were administrated with two consecutive injections of 100 mg/kg isoproterenol, 15 mg/kg doxorubicin, or 100 mg/kg nifedipine, while in vitro rat-CMs and hESC-CMs were treated with 5 μM isoproterenol, 5 μM doxorubicin, and 50 μM nifedipine. We have verified the equivalence of hESC-CMs assessments over various molecular biological markers, morphological analysis. Also, we have identified the advantages of hESC-CMs, which can distinguish between species variability, over electrophysiological analysis of ion channels against cardiac damage. Our findings demonstrate the possibility and advantage of high-efficiency hESC-CMs as next-generation cardiotoxicity assessment. [BMB Reports 2020; 53(8): 437-441].
Insights
Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) show promise for replacing animal testing in cardiotoxicity studies. These advanced in vitro models offer advantages in assessing cardiac damage and species variability.
Area of Science:
- Cardiovascular Pharmacology
- Stem Cell Biology
- Toxicology
Background:
- International Council for Harmonisation S7B guidelines mandate cardiotoxicity studies.
- Next-generation safety pharmacology relies on stem cell-derived cardiomyocytes (CMs).
- Existing stem cell-derived CMs require further validation to replace animal models.
Purpose of the Study:
- To compare the efficacy of human embryonic stem cell-derived cardiomyocytes (hESC-CMs) against in vivo animal models and primary rat CMs for cardiotoxicity assessment.
- To evaluate the potential of hESC-CMs as a replacement for animal testing in cardiotoxicity evaluations.
- To identify advantages of hESC-CMs in assessing cardiac damage, including species variability.
Main Methods:
- In vivo cardiotoxicity testing using Sprague-Dawley rats with isoproterenol, doxorubicin, and nifedipine.
- In vitro cardiotoxicity testing using primary rat cardiomyocytes and hESC-CMs exposed to the same cardiotoxic agents.
- Assessment of molecular biological markers, morphological changes, and electrophysiological analysis of ion channels.
Main Results:
- hESC-CMs demonstrated equivalent assessments to in vivo rats and primary rat CMs across molecular and morphological markers.
- hESC-CMs effectively identified cardiac damage induced by isoproterenol, doxorubicin, and nifedipine.
- Electrophysiological analysis revealed hESC-CMs' ability to distinguish species variability, a key advantage over traditional methods.
Conclusions:
- High-efficiency hESC-CMs are a viable and advantageous alternative for next-generation cardiotoxicity assessments.
- hESC-CMs show potential to replace animal experiments in safety pharmacology, aligning with ICH S7B guidelines.
- The use of hESC-CMs offers improved assessment of cardiac safety and species-specific responses.
