Promotion of maturation of human pluripotent stem cell-derived cardiomyocytes via treatment with the peroxisome proliferator-activated receptor alpha agonist Fenofibrate

Seul-Gi Lee ^1,2, Jooeon Rhee ², Jin Seok ²

⁰Department of Stem Cell Biology, School of Medicine, Konkuk University, Gwangjin-Gu, Seoul 05029, Republic of Korea.

Stem Cells Translational Medicine +

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June 30, 2024

View abstract on PubMed

Summary

Maturing human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) using fenofibrate enhances their function. This improved maturation is crucial for accurate preclinical cardiotoxicity assessment in drug development.

Area Of Science

Cardiology
Stem Cell Biology
Pharmacology

Background

Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) are vital for cardiotoxicity assessment and disease modeling.
Physiological immaturity of hPSC-CMs hinders accurate drug response prediction and disease modeling.
Maturation strategies are essential to improve the utility of hPSC-CMs.

Purpose Of The Study

To investigate the role of peroxisome proliferator-activated receptor alpha (PPARα) in hPSC-CM maturation.
To evaluate the effects of fenofibrate (Feno), a PPARα agonist, on hPSC-CM maturation and function.
To assess the utility of matured hPSC-CMs in preclinical cardiotoxicity evaluation.

Main Methods

Treatment of hPSC-CMs with fenofibrate to upregulate PPARα expression.
Assessment of hPSC-CMs' structural, metabolic, and electrophysiological properties.
Multi-electrode array (MEA) based cardiotoxicity evaluation using arrhythmia-inducing drugs.

Main Results

Fenofibrate treatment promoted structural, mitochondrial metabolism, and electrophysiological maturation of hPSC-CMs.
Matured hPSC-CMs showed distinct electrophysiological parameters compared to control cells.
Dose-dependent drug responses in cardiotoxicity assays were similar between control and fenofibrate-treated groups.

Conclusions

PPARα activation, via fenofibrate, effectively matures hPSC-CMs.
Matured hPSC-CMs offer improved models for preclinical cardiotoxicity assessment.
Enhanced hPSC-CMs are necessary for reliable new drug development and cardiac research.

Keywords:

PPARα drug response fenofibrate field potential human pluripotent stem cell-derived cardiomyocytes maturation