Reproducibility of drug-induced effects on the contractility of an engineered heart tissue derived from human pluripotent stem cells

Ayesha Arefin; Melissa Mendoza; Keri Dame; M Iveth Garcia; David G Strauss; Alexandre J S Ribeiro

doi:10.3389/fphar.2023.1212092

Reproducibility of drug-induced effects on the contractility of an engineered heart tissue derived from human pluripotent stem cells

Front Pharmacol. 2023 Jul 4:14:1212092. doi: 10.3389/fphar.2023.1212092. eCollection 2023.

Authors

Ayesha Arefin^{1

2}, Melissa Mendoza¹, Keri Dame¹, M Iveth Garcia¹, David G Strauss^{1

3}, Alexandre J S Ribeiro¹

Affiliations

¹ Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, United States.
² Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, United States.
³ Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, United States.

Abstract

Introduction: Engineered heart tissues (EHTs) are three-dimensional culture platforms with cardiomyocytes differentiated from human pluripotent stem cells (hPSCs) and were designed for assaying cardiac contractility. For drug development applications, EHTs must have a stable function and provide reproducible results. We investigated these properties with EHTs made with different tissue casting batches and lines of differentiated hPSC-cardiomyocytes and analyzed them at different times after being fabricated. Methods: A video-optical assay was used for measuring EHT contractile outputs, and these results were compared with results from motion traction analysis of beating hPSC-cardiomyocytes cultured as monolayers in two-dimensional cultures. The reproducibility of induced contractile variations was tested using compounds with known mechanistic cardiac effects (isoproterenol, EMD-57033, omecamtiv mecarbil, verapamil, ranolazine, and mavacamten), or known to be clinically cardiotoxic (doxorubicin, sunitinib). These drug-induced variations were characterized at different electrical pacing rates and variations in intracellular calcium transients were also assessed in EHTs. Results: To ensure reproducibility in experiments, we established EHT quality control criteria based on excitation-contraction coupling and contractile sensitivity to extracellular calcium concentration. In summary, a baseline contractile force of 0.2 mN and excitation-contraction coupling of EHTs were used as quality control criteria to select suitable EHTs for analysis. Overall, drug-induced contractile responses were similar between monolayers and EHTs, where a close relationship was observed between contractile output and calcium kinetics. Contractile variations at multiple time points after adding cardiotoxic compounds were also detectable in EHTs. Discussion: Reproducibility of drug-induced effects in EHTs between experiments and relative to published work on these cellular models was generally observed. Future applications for EHTs may require additional mechanistic criteria related to drug effects and cardiac functional outputs to be measured in regard to specific contexts of use.

Keywords: cardiotoxicity; contractility; drug development; microphysiological systems; pluripotent stem cells.

Grants and funding

The authors acknowledge support from the FDA Office of the Chief Scientist via Challenge Grant number 848.