Action potential-based MEA platform for in vitro screening of drug-induced cardiotoxicity using human iPSCs and rat neonatal myocytes

Jans, Danny; Callewaert, Geert; Krylychkina, Olga; Hoffman, Luis; Gullo, Francesco; Prodanov, Dimiter; Braeken, Dries

doi:10.1016/j.vascn.2017.05.003

Cited by 24 publications

(39 citation statements)

References 22 publications

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“…These two orthogonal domain signals and relevant parameters can be directly processed and extracted, such as the time delay between action potential initiation and muscle contraction initiation, which is particularly useful for drug screening to evaluate arrhythmogenic drug side effects. [66][67][68][69] Finally, the multi-parametric dose-dependent response of cardiomyocytes is studied using isoproterenol and feature extractions from their extracellular potentials and optomechanical signals are performed. Fig.…”

Section: Resultsmentioning

confidence: 99%

Multi-parametric cell profiling with a CMOS quad-modality cellular interfacing array for label-free fully automated drug screening

et al. 2018

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Cells are complex systems with concurrent multi-physical responses, and cell physiological signals are often encoded with spatiotemporal dynamics and further coupled with multiple cellular activities. However, most existing electronic sensors are only single-modality and cannot capture multi-parametric cellular responses. In this paper, a 1024-pixel CMOS quad-modality cellular interfacing array that enables multi-parametric cell profiling for drug development is presented. The quad-modality CMOS array features cellular impedance characterization, optical detection, extracellular potential recording, and biphasic current stimulation. The fibroblast transparency and surface adhesion are jointly monitored by cellular impedance and optical sensing modalities for comprehensive cell growth evaluation. Simultaneous current stimulation and opto-mechanical monitoring based on cardiomyocytes are demonstrated without any stimulation/sensing dead-zone. Furthermore, drug dose-dependent multi-parametric feature extractions in cardiomyocytes from their extracellular potentials and opto-mechanical signals are presented. The CMOS array demonstrates great potential for fully automated drug screening and drug safety assessments, which may substantially reduce the drug screening time and cost in future new drug development.

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Section: Resultsmentioning

confidence: 99%

Multi-parametric cell profiling with a CMOS quad-modality cellular interfacing array for label-free fully automated drug screening

et al. 2018

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“…Thus, human cardiomyocytes, especially patient-speci c cardiomyocytes, are needed to explore the mechanisms underlying the ion channel diseases. Indeed, the emergence of human induced pluripotent stem cells (iPSCs) provides a promising tool for recapitulating the phenotype of cardiac disease and for evaluating the e ciency of drug treatments (10)(11)(12). In recent years, BrS patient-speci c iPSC-CMs have been reported to be accurate disease models in vitro (13,14).…”

Section: Introductionmentioning

confidence: 99%

Comparative Analysis of Genetic Variations in the Nav1.5 Sodium Channel Subunits that Underlie Brugada Syndrome Using Patient-Specific iPSC-CMs

Zhu

Wang

Cui

et al. 2020

Preprint

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Background: Brugada syndrome (BrS) is an autosomal dominant disorder that causes a high predisposition to sudden cardiac death. Several genes have been reported to be associated with BrS. Considering that the heterogeneity in clinical manifestations may result from genetic variations, the application of patient-specific induced pluripotent stem (iPS) cell-derived cardiomyocytes (CMs) may help to reveal cell phenotype characteristics resulting from different genetic backgrounds. The present study was to compare the structural and electrophysiological characteristics of sodium channel subunits with different genetic variations and evaluate the safety of quinidine for use with BrS patient-specific iPSC-derived cardiomyocytes.Methods: Two BrS patient-specific iPS cell lines were constructed that carried missense mutations in SCN5A and SCN1B. One iPS cell line from a healthy volunteer was used as a control. The differentiated cardiomyocytes from the three groups were evaluated by flow cytometry, immunofluorescence staining, electron microscopy, as well as calcium transient and patch clamp analyses to assess different pathological phenotypes. Finally, we evaluated the drug responses to varying concentrations of quinidine by measuring the action potential.Results: Compared to the control group, BrS-CMs showed a significant reduction in sodium current, prolonged action potential duration and varying degrees of decreased Vmax, but no structural difference was observed. After applying different concentrations of quinidine, the disease-specific groups and the control group had a downward trend in maximal upstroke velocity, resting membrane potential and action potential amplitude, and exhibited prolonged action potential duration without increasing incidence of arrhythmic events.Conclusion: Both patient-specific iPSC-CMs recapitulated the BrS phenotype at the cellular level. Although the SCN5A variation led to a markedly lower sodium current than what was observed with the SCN1B variation, their responses to quinidine were quite similar. The present study provides an advantageous platform for exploring disease mechanisms and evaluating drug safety in vitro.

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“…Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are the gold standard for an increasing number of laboratories 1,2,3,4,5,6,7,8,9,10 . Beating embryoid bodies 11,12,13 and monolayer 3,7,10,11,12,13,14,15,16,17 differentiation are the preferred methods for cardiomyocyte production and the multielectrode array (MEA) has become a common modality for monitoring the electrodynamics of these networks 18,19,20 . While parameters that can be extracted from field potentials (FPs) such as beating rate, amplitude, duration and RR intervals are baseline electrophysiological responses of spontaneously beating monolayers 18,21,22,23 , the action potential (AP) components underlying these extracellular FP signals are difficult to extrapolate 24 .…”

Section: Introductionmentioning

confidence: 99%

“…Beating embryoid bodies 11,12,13 and monolayer 3,7,10,11,12,13,14,15,16,17 differentiation are the preferred methods for cardiomyocyte production and the multielectrode array (MEA) has become a common modality for monitoring the electrodynamics of these networks 18,19,20 . While parameters that can be extracted from field potentials (FPs) such as beating rate, amplitude, duration and RR intervals are baseline electrophysiological responses of spontaneously beating monolayers 18,21,22,23 , the action potential (AP) components underlying these extracellular FP signals are difficult to extrapolate 24 . Our recent publication on the discovery of an application of MEAs for direct recurrent AP measurements provides proof of methodology for exemplary intracellular AP readouts with an extensive waveform analysis at various repolarization phases across multiple batches of hiPSC-derived cardiomyocyte networks 3 .…”

Section: Introductionmentioning

confidence: 99%

“…A few laboratories have reported measuring APs from various electrogenic cells using custom-built MEAs 18,21,26,27,28,29,30 , but the reliability of using MEAs for consistent and recurrent AP measurements was not assessed. Currently, the gold standard patch-clamp technique is limited to terminal recordings 7,31 whereas, MEA-based AP measurements are transient and therefore can be conducted multiple times on the same cell.…”

Section: Introductionmentioning

confidence: 99%

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Human iPSC-Derived Cardiomyocyte Networks on Multiwell Micro-electrode Arrays for Recurrent Action Potential Recordings

Zlochiver

Kroboth

Beal

et al. 2019

JoVE

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Cardiac safety screening is of paramount importance for drug discovery and therapeutics. Therefore, the development of novel high-throughput electrophysiological approaches for hiPSC-derived cardiomyocyte (hiPSC-CM) preparations is much needed for efficient drug testing. Although multielectrode arrays (MEAs) are frequently employed for field potential measurements of excitable cells, a recent publication by Joshi-Mukherjee and colleagues described and validated its application for recurrent action potential (AP) recordings from the same hiPSC-CM preparation over days. The aim here is to provide detailed step-by-step methods for seeding CMs and for measuring AP waveforms via electroporation with high precision and a temporal resolution of 1 µs. This approach addresses the lack of easy-to-use methodology to gain intracellular access for high-throughput AP measurements for reliable electrophysiological investigations. A detailed work flow and methods for plating of hiPSC-CMs on multiwell MEA plates are discussed emphasizing critical steps wherever relevant. In addition, a custom-built MATLAB script for rapid data handling, extraction and analysis is reported for comprehensive investigation of the waveform analysis to quantify subtle differences in morphology for various AP duration parameters implicated in arrhythmia and cardiotoxicity.

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Action potential-based MEA platform for in vitro screening of drug-induced cardiotoxicity using human iPSCs and rat neonatal myocytes

Cited by 24 publications

References 22 publications

Multi-parametric cell profiling with a CMOS quad-modality cellular interfacing array for label-free fully automated drug screening

Multi-parametric cell profiling with a CMOS quad-modality cellular interfacing array for label-free fully automated drug screening

Comparative Analysis of Genetic Variations in the Nav1.5 Sodium Channel Subunits that Underlie Brugada Syndrome Using Patient-Specific iPSC-CMs

Human iPSC-Derived Cardiomyocyte Networks on Multiwell Micro-electrode Arrays for Recurrent Action Potential Recordings

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