An integrated platform for simultaneous multi-well field potential recording and Fura-2-based calcium transient ratiometry in human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes

Rast, Georg; Weber, Johannes Heinrich; Disch, C H; Schuck, Elmar; Ittrich, Carina; Guth, Brian D.

doi:10.1016/j.vascn.2015.04.005

Cited by 17 publications

(16 citation statements)

References 28 publications

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“…Moreover, it reproduces well the in vitro data by Ma et al (43) with ion channel blockers (Figure S4 in the Supporting Material), I f block and hyperkalemia experiments as (33) (see Supporting Information) and alternans in ischemia-like conditions as (15) (Figure S5 in the Supporting Material). Finally, the CaTr amplitude of 160 nM is in agreement with data by Rast et al (44), recorded from hiPS-CM ensembles incubated at 37°C (calibrated Fura-2-based photometry measures) and not used for model calibration.…”

Section: Resultssupporting

confidence: 89%

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

Paci

Passini

Klimas

et al. 2019

Preprint

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12High-throughput in vitro drug assays have been impacted by recent advances in human induced 13 pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) technology and by contact-free all-14 optical systems simultaneously measuring action potential (AP) and Ca 2+ transient (CaTr). 15 Parallel computational advances have shown that in silico models can predict drug effects with 16 high accuracy. In this work, we combine these in vitro and in silico technologies and 17 demonstrate the utility of high-throughput experimental data to refine in silico hiPS-CM 18 populations, and to predict and explain drug action mechanisms. Optically-obtained hiPS-CM 19 AP and CaTr were used from spontaneous activity and under pacing in control and drug 20 conditions at multiple doses. 21 An updated version of the Paci2018 model was developed to refine the description of hiPS-22 CM spontaneous electrical activity; a population of in silico hiPS-CMs was constructed and 23 calibrated using the optically-recorded AP and CaTr. We tested five drugs (astemizole, 24 dofetilide, ibutilide, bepridil and diltiazem), and compared simulations against in vitro optical 25 recordings. 26 Our simulations showed that physiologically-accurate population of models can be obtained 27 by integrating AP and CaTr control records. Thus constructed population of models predicted 28 correctly the drug effects and occurrence of adverse episodes, even though the population was 29 optimized only based on control data and in vitro drug testing data were not deployed during 30 its calibration. Furthermore, the in silico investigation yielded mechanistic insights, e.g. 31through simulations, bepridil's more pro-arrhythmic action in adult cardiomyocytes compared 32 to hiPS-CMs could be traced to the different expression of ion currents in the two. 33Therefore, our work: i) supports the utility of all-optical electrophysiology in providing high-34 content data to refine experimentally-calibrated populations of in silico hiPS-CMs, ii) offers 35 insights into certain limitations when translating results obtained in hiPS-CMs to humans and 36 iii) shows the strength of combining high-throughput in vitro and population in silico 37 approaches. 38 39 3 Significance 40We demonstrate the integration of human in silico drug trials and optically-recorded 41 simultaneous action potential and calcium transient data from human induced pluripotent stem 42 cell-derived cardiomyocytes (hiPS-CMs) for prediction and mechanistic investigations of drug 43 action. We propose a population of in silico models i) based on a new hiPS-CM model 44 recapitulating the mechanisms underlying hiPS-CM automaticity and ii) calibrated with all-45 optical measurements. We used our in silico population to predict and evaluate the effects of 5 46 drugs and the underlying biophysical mechanisms, obtaining results in agreement with our 47 experiments and one independent dataset. This work supports the use of high-content, high-48 quality all-optical electrophysiology data to develop, calibrate ...

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Section: Resultssupporting

confidence: 89%

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

Paci

Passini

Klimas

et al. 2019

Preprint

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“…For chemical and genetically encoded Ca 2 + ‐sensitive dyes, the situation is easier, mainly due to the slower kinetics of Ca 2 + fluxes. These probes have already been widely used for high‐throughput screening in both disease modelling and drug development with encouraging results (Kaestner et al , 2014; Huebsch et al , 2015; Lu et al , 2015; Rast et al , 2015; Dempsey et al , 2016; Klimas et al , 2016). Ca 2 + ‐handling also affects cell contractility, which can also be measured, as recent examples with sophisticated optical mapping systems show (Herron et al , 2012; Hayakawa et al , 2014; Maddah et al , 2015).…”

Section: Assays and Readoutsmentioning

confidence: 99%

“…The combination of engineering and biology has allowed the precise quantification of contractile force in hPSC‐CMs (Ribeiro et al , 2015a), although it has been demonstrated that substrate stiffness plays a major role in the quantification of absolute force values (Feinberg et al , 2012; Ribeiro et al , 2015b). More recently, integrated technologies capable of simultaneously quantifying multiple parameters are being implemented with the view to providing reliable, high‐throughput tools for early preclinical stages of drug development (Hochbaum et al , 2014; Kijlstra et al , 2015; Rast et al , 2015; Song et al , 2015; Dempsey et al , 2016; Klimas et al , 2016). …”

Section: Assays and Readoutsmentioning

confidence: 99%

Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come?

Sala

Bellin

Mummery

2016

British J Pharmacology

107

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Cardiotoxicity is a severe side effect of drugs that induce structural or electrophysiological changes in heart muscle cells. As a result, the heart undergoes failure and potentially lethal arrhythmias. It is still a major reason for drug failure in preclinical and clinical phases of drug discovery. Current methods for predicting cardiotoxicity are based on guidelines that combine electrophysiological analysis of cell lines expressing ion channels ectopically in vitro with animal models and clinical trials. Although no new cases of drugs linked to lethal arrhythmias have been reported since the introduction of these guidelines in 2005, their limited predictive power likely means that potentially valuable drugs may not reach clinical practice. Human pluripotent stem cell‐derived cardiomyocytes (hPSC‐CMs) are now emerging as potentially more predictive alternatives, particularly for the early phases of preclinical research. However, these cells are phenotypically immature and culture and assay methods not standardized, which could be a hurdle to the development of predictive computational models and their implementation into the drug discovery pipeline, in contrast to the ambitions of the comprehensive pro‐arrhythmia in vitro assay (CiPA) initiative. Here, we review present and future preclinical cardiotoxicity screening and suggest possible hPSC‐CM‐based strategies that may help to move the field forward. Coordinated efforts by basic scientists, companies and hPSC banks to standardize experimental conditions for generating reliable and reproducible safety indices will be helpful not only for cardiotoxicity prediction but also for precision medicine.Linked ArticlesThis article is part of a themed section on New Insights into Cardiotoxicity Caused by Chemotherapeutic Agents. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.21/issuetoc

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“…The cytosolic calcium level in the group co-treated with PG and RU486 was similar to that of the VE group. In a separate experiment, treatment with the L-type Ca 2+ channel blocker nifedipine [26] resulted in decreased levels of cytosolic calcium in the control group and the group co-treated with PG and RU486, but not in the PG-treated group. There are two possible explanations for the lack of a reaction to nifedipine: the lower expression of Trpv2 as determined by the mRNA and protein expression, and/or defective TRPV2 function.…”

Section: Discussionmentioning

confidence: 90%

Inhibitory effect of progesterone during early embryonic development: Suppression of myocardial differentiation and calcium-related transcriptome by progesterone in mESCs

Kang

Choi

Jeung

2016

Reproductive Toxicology

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An integrated platform for simultaneous multi-well field potential recording and Fura-2-based calcium transient ratiometry in human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes

Cited by 17 publications

References 28 publications

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

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

Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come?

Inhibitory effect of progesterone during early embryonic development: Suppression of myocardial differentiation and calcium-related transcriptome by progesterone in mESCs

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