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

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

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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 sensitivities higher than individual measurement of action potential, cytosolic calcium or contraction.

Original languageEnglish
Article number4325
Number of pages9
JournalNature communications
Volume10
Issue number1
DOIs
Publication statusPublished - 20 Sep 2019

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Induced Pluripotent Stem Cells
Excitation Contraction Coupling
Cardiac Myocytes
Action Potentials
contraction
Calcium
calcium
excitation
Optical Devices
drugs
Ion Channels
Pharmaceutical Preparations
stem cells
Stem cells
multiplexing
Multiplexing
Optical systems
cascades
high speed
Fluxes

Cite this

van Meer, Berend J. ; Krotenberg, Ana ; Sala, Luca ; Davis, Richard P. ; Eschenhagen, Thomas ; Denning, Chris ; Tertoolen, Leon G.J. ; Mummery, Christine L. / Simultaneous measurement of excitation-contraction coupling parameters identifies mechanisms underlying contractile responses of hiPSC-derived cardiomyocytes. In: Nature communications. 2019 ; Vol. 10, No. 1.
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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.

In: Nature communications, Vol. 10, No. 1, 4325, 20.09.2019.

Research output: Contribution to journalArticleAcademicpeer-review

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AU - Eschenhagen, Thomas

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