Does Enhanced Structural Maturity of hiPSC-Cardiomyocytes Better for the Detection of Drug-Induced Cardiotoxicity?

Area of Science:

• Cardiovascular Pharmacology
• Stem Cell Biology
• Drug Safety Assessment

Background:

• Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) are vital for drug-induced cardiotoxicity screening per ICH guidelines.
• Immature hiPSC-CMs may not fully replicate adult cardiomyocyte properties, potentially impacting toxicity detection.
• Enhancing hiPSC-CM structural maturity is explored to improve predictive accuracy in safety studies.

Purpose of the Study:

• To compare the efficacy of hiPSC-CMs cultured on standard fibronectin matrix (FM) versus a maturity-enhancing matrix (MM) for detecting drug-induced cardiotoxicity.
• To investigate if enhanced structural maturity of hiPSC-CMs improves the detection of drug-induced electrophysiological and contractile changes.
• To assess functional differences in hiPSC-CMs under varying culture conditions using high-throughput screening.

Main Methods:

• Cultured hiPSC-CMs in 2D monolayers on standard fibronectin matrix (FM) and CELLvo™ Matrix Plus (MM) to promote structural maturity.
• Assessed electrophysiology using voltage-sensitive fluorescent dyes and contractility using video technology in a high-throughput screening approach.
• Utilized 11 reference drugs to evaluate the functional responses of hiPSC-CMs in both FM and MM conditions.
• Performed RNA profiling for cardiac proteins to compare gene expression across the two culture conditions.

Main Results:

• No functionally relevant differences in electrophysiology were observed between hiPSC-CMs cultured on FM and MM.
• Contractility read-outs showed altered amplitude but no changes in the time course of contraction between the two matrix conditions.
• RNA profiling indicated similar cardiac protein RNA expression across both 2D culture types.
• Drug-induced cardiotoxicity detection efficacy was comparable between the standard FM and maturity-enhanced MM settings for electrophysiological effects.

Conclusions:

• hiPSC-CMs cultured on both standard fibronectin matrix and maturity-enhancing matrices are equally effective for detecting drug-induced electrophysiological effects in functional safety studies.
• Differences in contraction amplitude between the two matrix conditions may be attributed to cell-to-matrix adhesion variations.
• Enhanced structural maturity, while affecting contraction amplitude, did not significantly improve the detection of drug-induced electrophysiological cardiotoxicity in this study.