Comparison of 10 Control hPSC Lines for Drug Screening in an Engineered Heart Tissue Format

Area of Science:

• Cardiovascular Research
• Stem Cell Biology
• Pharmacology

Background:

• Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) are crucial for cardiac research and drug screening.
• Routine cardiac differentiation protocols are established, leading to commercial availability of hiPSC-CM.
• A systematic evaluation of control hiPSC-CM lines for functional consistency and drug screening suitability is lacking.

Purpose of the Study:

• To systematically evaluate the functional characteristics of 10 different control hiPSC-CM lines.
• To assess the suitability of these hiPSC-CM lines for drug screening applications.
• To investigate the impact of inter-line variability on contractile function and drug responses.

Main Methods:

• Ten control hiPSC-CM lines (5 commercial, 5 academic) were differentiated and cast into engineered heart tissue (EHT).
• Spontaneous and stimulated EHT contractions were analyzed for contractile force and kinetics.
• Seven inotropic indicator compounds were tested on 8 hiPSC-CM lines to evaluate drug response accuracy.

Main Results:

• Significant variability was observed in baseline contractile force, kinetics, and rate among different hiPSC-CM lines (e.g., relaxation time: 118-471 ms).
• Qualitative accuracy of responses to inotropic compounds (e.g., BayK-8644, isoprenaline) ranged from 80% to 93% across cell lines.
• Despite wide baseline differences, the qualitative drug response patterns showed less variability.

Conclusions:

• Large baseline functional differences among control hiPSC-CM lines highlight the need for isogenic controls in disease modeling.
• Variability in hiPSC-CM lines is less critical for drug screening but necessitates using multiple cell lines per study.
• Standardized evaluation and careful selection of hiPSC-CM lines are important for reliable research outcomes.