Simultaneous measurement of excitation-contraction coupling parameters identifies mechanisms underlying contractile responses of hiPSC-derived cardiomyocytes
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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: NAT COMMUN, Jahrgang 10, Nr. 1, 20.09.2019, S. 4325.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Simultaneous measurement of excitation-contraction coupling parameters identifies mechanisms underlying contractile responses of hiPSC-derived cardiomyocytes
AU - van Meer, Berend J
AU - Krotenberg, Ana
AU - Sala, Luca
AU - Davis, Richard P
AU - Eschenhagen, Thomas
AU - Denning, Chris
AU - Tertoolen, Leon G J
AU - Mummery, Christine L
PY - 2019/9/20
Y1 - 2019/9/20
N2 - 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.
AB - 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.
KW - Action Potentials
KW - Algorithms
KW - Calcium/metabolism
KW - Computational Biology
KW - Fluorescent Dyes
KW - Humans
KW - Induced Pluripotent Stem Cells/drug effects
KW - Ion Channels
KW - Myocardial Contraction/drug effects
KW - Myocytes, Cardiac/drug effects
KW - Optical Imaging
U2 - 10.1038/s41467-019-12354-8
DO - 10.1038/s41467-019-12354-8
M3 - SCORING: Journal article
C2 - 31541103
VL - 10
SP - 4325
JO - NAT COMMUN
JF - NAT COMMUN
SN - 2041-1723
IS - 1
ER -
