scholarly journals In Silico Populations Optimized on Optogenetic Recordings Predict Drug Effects in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

2018 ◽  
Author(s):  
Michelangelo Paci ◽  
Elisa Passini ◽  
Aleksandra Klimas ◽  
Stefano Severi ◽  
Jari Hyttinen ◽  
...  
Keyword(s):  
Stem Cell ◽  
In Silico ◽  
Pluripotent Stem Cell ◽  
Drug Effects ◽  
Induced Pluripotent Stem Cell ◽  
Induced Pluripotent

scholarly journals Ion Channel Expression and Electrophysiology of Singular Human (Primary and Induced Pluripotent Stem Cell-Derived) Cardiomyocytes

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3370
Author(s):  
Christina Schmid ◽  
Najah Abi-Gerges ◽  
Michael Georg Leitner ◽  
Dietmar Zellner ◽  
Georg Rast
Keyword(s):  
Stem Cell ◽  
Single Cell ◽  
Pluripotent Stem Cell ◽  
Quantitative Polymerase Chain Reaction ◽  
Drug Effects ◽  
Induced Pluripotent Stem Cell ◽  
Ionic Currents ◽  
Human Cardiomyocytes ◽  
Ventricular Cells ◽  
Induced Pluripotent

Subtype-specific human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are promising tools, e.g., to assess the potential of drugs to cause chronotropic effects (nodal hiPSC-CMs), atrial fibrillation (atrial hiPSC-CMs), or ventricular arrhythmias (ventricular hiPSC-CMs). We used single-cell patch-clamp reverse transcriptase-quantitative polymerase chain reaction to clarify the composition of the iCell cardiomyocyte population (Fujifilm Cellular Dynamics, Madison, WI, USA) and to compare it with atrial and ventricular Pluricytes (Ncardia, Charleroi, Belgium) and primary human atrial and ventricular cardiomyocytes. The comparison of beating and non-beating iCell cardiomyocytes did not support the presence of true nodal, atrial, and ventricular cells in this hiPSC-CM population. The comparison of atrial and ventricular Pluricytes with primary human cardiomyocytes showed trends, indicating the potential to derive more subtype-specific hiPSC-CM models using appropriate differentiation protocols. Nevertheless, the single-cell phenotypes of the majority of the hiPSC-CMs showed a combination of attributes which may be interpreted as a mixture of traits of adult cardiomyocyte subtypes: (i) nodal: spontaneous action potentials and high HCN4 expression and (ii) non-nodal: prominent INa-driven fast inward current and high expression of SCN5A. This may hamper the interpretation of the drug effects on parameters depending on a combination of ionic currents, such as beat rate. However, the proven expression of specific ion channels supports the evaluation of the drug effects on ionic currents in a more realistic cardiomyocyte environment than in recombinant non-cardiomyocyte systems.

scholarly journals All-optical electrophysiology refines populations of in silico human iPS-CMs for drug evaluation

2019 ◽  
Author(s):  
M Paci ◽  
E Passini ◽  
A Klimas ◽  
S Severi ◽  
J Hyttinen ◽  
...  
Keyword(s):  
High Throughput ◽  
In Silico ◽  
Pluripotent Stem Cell ◽  
Drug Effects ◽  
Induced Pluripotent Stem Cell ◽  
Drug Action ◽  
Drug Trials ◽  
All Optical ◽  
Induced Pluripotent

AbstractHigh-throughput in vitro drug assays have been impacted by recent advances in human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) technology and by contact-free all-optical systems simultaneously measuring action potential (AP) and Ca2+ transient (CaTr). Parallel computational advances have shown that in silico models can predict drug effects with high accuracy. In this work, we combine these in vitro and in silico technologies and demonstrate the utility of high-throughput experimental data to refine in silico hiPS-CM populations, and to predict and explain drug action mechanisms. Optically-obtained hiPS-CM AP and CaTr were used from spontaneous activity and under pacing in control and drug conditions at multiple doses.An updated version of the Paci2018 model was developed to refine the description of hiPS-CM spontaneous electrical activity; a population of in silico hiPS-CMs was constructed and calibrated using the optically-recorded AP and CaTr. We tested five drugs (astemizole, dofetilide, ibutilide, bepridil and diltiazem), and compared simulations against in vitro optical recordings.Our simulations showed that physiologically-accurate population of models can be obtained by integrating AP and CaTr control records. Thus constructed population of models predicted correctly the drug effects and occurrence of adverse episodes, even though the population was optimized only based on control data and in vitro drug testing data were not deployed during its calibration. Furthermore, the in silico investigation yielded mechanistic insights, e.g. through simulations, bepridil’s more pro-arrhythmic action in adult cardiomyocytes compared to hiPS-CMs could be traced to the different expression of ion currents in the two.Therefore, our work: i) supports the utility of all-optical electrophysiology in providing high-content data to refine experimentally-calibrated populations of in silico hiPS-CMs, ii) offers insights into certain limitations when translating results obtained in hiPS-CMs to humans and shows the strength of combining high-throughput in vitro and population in silico approaches.SignificanceWe demonstrate the integration of human in silico drug trials and optically-recorded simultaneous action potential and calcium transient data from human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) for prediction and mechanistic investigations of drug action. We propose a population of in silico models i) based on a new hiPS-CM model recapitulating the mechanisms underlying hiPS-CM automaticity and ii) calibrated with all-optical measurements. We used our in silico population to predict and evaluate the effects of 5 drugs and the underlying biophysical mechanisms, obtaining results in agreement with our experiments and one independent dataset. This work supports the use of high-content, high-quality all-optical electrophysiology data to develop, calibrate and validate computer models of hiPS-CM for in silico drug trials.

scholarly journals Uninterrupted monitoring of drug effects in human-induced pluripotent stem cell-derived cardiomyocytes with bioluminescence Ca2+ microscopy

2018 ◽  
Vol 11 (1) ◽  
Author(s):  
Kazushi Suzuki ◽  
Takahito Onishi ◽  
Chieko Nakada ◽  
Shunsuke Takei ◽  
Matthew J. Daniels ◽  
...  
Keyword(s):  
Stem Cell ◽  
Pluripotent Stem Cell ◽  
Drug Effects ◽  
Induced Pluripotent Stem Cell ◽  
Induced Pluripotent
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