Simultaneous measurement of excitation-contraction coupling parameters identifies mechanisms underlying contractile responses of hiPSC-derived cardiomyocytes

Van Meer, Berend J.; Krotenberg, Ana; Sala, Luca; Davis, Richard P; Eschenhagen, Thomas; Denning, Chris; Tertoolen, Leon G J; Mummery, Christine L

Abstract

Cardiomyocytes from human induced pluripotent stem cells (hiPSC-CMs) are increasingly recognized as valuable for determining the effects of drugs on ion channels but they do not always accurately predict contractile responses of the human heart. This is in part attributable to their immaturity but the sensitivity of measurement tools may also be limiting. Measuring action potential, calcium flux or contraction individually misses critical information that is captured when interrogating the complete excitation-contraction coupling cascade simultaneously. Here, we develop an hypothesis-based statistical algorithm that identifies mechanisms of action. We design and build a high-speed optical system to measure action potential, cytosolic calcium and contraction simultaneously using fluorescent sensors. These measurements are automatically processed, quantified and then assessed by the algorithm. Multiplexing these three critical physical features of hiPSC-CMs allows identification of all major drug classes affecting contractility with detection

Citation

Van Meer, B. J., Krotenberg, A., Sala, L., Davis, R. P., Eschenhagen, T., Denning, C., …Mummery, C. L. (2019). Simultaneous measurement of excitation-contraction coupling parameters identifies mechanisms underlying contractile responses of hiPSC-derived cardiomyocytes. Nature Communications, 10, Article 4325. https://doi.org/10.1038/s41467-019-12354-8

• Journal Article Type: Article
• Acceptance Date: Aug 23, 2019
• Online Publication Date: Sep 20, 2019
• Publication Date: Sep 20, 2019
• Deposit Date: Aug 29, 2019
• Publicly Available Date: Sep 20, 2019
• Journal: Nature Communications
• Electronic ISSN: 2041-1723
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 10
• Article Number: 4325
• DOI: https://doi.org/10.1038/s41467-019-12354-8
• Keywords: General Biochemistry, Genetics and Molecular Biology; General Physics and Astronomy; General Chemistry
• Public URL: https://nottingham-repository.worktribe.com/output/2515978
• Publisher URL: https://www.nature.com/articles/s41467-019-12354-8
• Additional Information: Received: 8 November 2018; Accepted: 4 September 2019; First Online: 20 September 2019; : C.L.M. is co-founder of Pluriomics bv (now Ncardia bv). The remaining authors declare no competing interests.
• Contract Date: Aug 29, 2019