An impedance-based approach using human iPSC-derived cardiomyocytes significantly improves in vitro prediction of in vivo cardiotox liabilities

Koci, Bryan; Luerman, Gregory C.; Duenbostell, Anika; Kettenhofen, Ralf; Bohlen, Heribert; Coyle, Luke; Knight, Brian L.; Ku, Warren W.; Volberg, Walter A.; Woska, Joseph R.; Brown, Martha P.

doi:10.1016/j.taap.2017.05.023

Cited by 30 publications

(18 citation statements)

References 21 publications

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“…Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs)/human embryonic stem cell-derived cardiomyocytes (hESC-CMs) expressing cardiac-specific factors and structural proteins provide an alternative model for drug screening in vitro [5]. These cells are derived from human cells, have similar mechanical and electrical activities as adult cardiomyocytes, and are more reliable in evaluating cardiotoxicity than other cell lines [6]. Cardio non-labeled cell function analysis and culture system (Cardio-NLCS) combined hiPSC-CMs is a hybrid device supporting highly resolved impedance-based contractility measurements and electric field potential recordings that will become a more powerful and reliable means of detecting cardiotoxicity [2].…”

Section: Introductionmentioning

confidence: 99%

An integrated characterization of contractile, electrophysiological, and structural cardiotoxicity of Sophora tonkinensis Gapnep. in human pluripotent stem cell-derived cardiomyocytes

Wang

et al. 2019

Stem Cell Res Ther

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BackgroundCardiotoxicity remains an important concern in drug discovery and clinical medication. Meanwhile, Sophora tonkinensis Gapnep. (S. tonkinensis) held great value in the clinical application of traditional Chinese medicine, but cardiotoxic effects were reported, with matrine, oxymatrine, cytisine, and sophocarpine being the primary toxic components.MethodsIn this study, impedance and extracellular field potential (EFP) of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were recorded using the cardio non-labeled cell function analysis and culture system (Cardio-NLCS). The effects of matrine, oxymatrine, cytisine, and sophocarpine (2, 10, 50 μM) on cell viability; level of lactate dehydrogenase (LDH), creatine kinase MB isoenzyme (CK-MB), and cardiac troponin I (CTn-I); antioxidant activities; production of reactive oxygen species (ROS) and malondialdehyde (MDA); and disruption of intracellular calcium homeostasis were also added into the integrated assessment.ResultsThe results showed that matrine and sophocarpine dose-dependently affected both impedance and EFP, while oxymatrine and cytisine altered impedance significantly. Our study also indicated that cardiotoxicity of matrine, oxymatrine, cytisine, and sophocarpine was related to the disruption of calcium homeostasis and oxidative stress. Four alkaloids of S. tonkinensis showed significant cardiotoxicity with dose dependence and structural cardiotoxicity synchronized with functional changes of cardiomyocytes.ConclusionsThis finding may provide guidance for clinical meditation management. Furthermore, this study introduced an efficient and reliable approach, which offers alternative options for evaluating the cardiotoxicity of the listed drugs and novel drug candidates.Electronic supplementary materialThe online version of this article (10.1186/s13287-018-1126-4) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

An integrated characterization of contractile, electrophysiological, and structural cardiotoxicity of Sophora tonkinensis Gapnep. in human pluripotent stem cell-derived cardiomyocytes

Wang

et al. 2019

Stem Cell Res Ther

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“…seemed to increase perinuclear mitochondrial polarization, which can be an early feature of apoptosis (Sanchez-Alcazar et al, 2000;Giovannini et al, 2002;Iijima et al, 2003;Liu et al, 2005;Cao et al, 2007;Silva et al, 2016). Electrophysiologically, DOX has previously been reported to affect beat period, spike amplitude and corrected field potential duration in a time and dose-dependent manner (Abassi et al, 2012;Koci et al, 2017). A 24 h DOX exposure in human iPSC-derived cardiomyocytes induced arrhythmic beating at 10 μM DOX and caused a complete arrest of heart beating at 100 μM (Koci et al, 2017).…”

Section: Discussionmentioning

confidence: 95%

“…Electrophysiologically, DOX has previously been reported to affect beat period, spike amplitude and corrected field potential duration in a time and dose-dependent manner (Abassi et al, 2012;Koci et al, 2017). A 24 h DOX exposure in human iPSC-derived cardiomyocytes induced arrhythmic beating at 10 μM DOX and caused a complete arrest of heart beating at 100 μM (Koci et al, 2017). Interestingly, DOX showed both acute and chronic electrophysiological effects with abnormal beating patterns worsening with prolonged time after treatment (Maillet et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Doxorubicin triggers bioenergetic failure and p53 activation in mouse stem cell-derived cardiomyocytes

Cunha‐Oliveira

Ferreira

Coelho

et al. 2018

Toxicology and Applied Pharmacology

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Doxorubicin (DOX) is a widely used anticancer drug that could be even more effective if its clinical dosage was not limited because of delayed cardiotoxicity. Beating stem cell-derived cardiomyocytes are a preferred in vitro model to further uncover the mechanisms of DOX-induced cardiotoxicity. Our objective was to use cultured induced-pluripotent stem cell(iPSC)-derived mouse cardiomyocytes (Cor.At) to investigate the effects of DOX on cell and mitochondrial metabolism, as well as on stress responses. Non-proliferating and beating Cor.At cells were treated with 0.5 or 1 μM DOX for 24 h, and morphological, functional and biochemical changes associated with mitochondrial bioenergetics, DNA-damage response and apoptosis were measured. Both DOX concentrations decreased ATP levels and SOD2 protein levels and induced p53-dependent caspase activation. However, differential effects were observed for the two DOX concentrations. The highest concentration induced a high degree of apoptosis, with increased nuclear apoptotic morphology, PARP-1 cleavage and decrease of some OXPHOS protein subunits. At the lowest concentration, DOX increased the expression of p53 target transcripts associated with mitochondria-dependent apoptosis and decreased transcripts related with DNA-damage response and glycolysis. Interestingly, cells treated with 0.5 μM DOX presented an increase in PDK4 transcript levels, accompanied by an increase in phospho-PDH and decreased PDH activity. This was accompanied by an apparent decrease in basal and maximal oxygen consumption rates (OCR) and in basal extracellular acidification rate (ECAR). Cells pre-treated with the PDK inhibitor dichloroacetate (DCA), with the aim of restoring PDH activity, partially recovered OCR and ECAR. The results suggest that the higher DOX concentration mainly induces p53-dependent apoptosis, whereas for the lower DOX concentration the cardiotoxic effects involve bioenergetic failure, unveiling PDH as a possible therapeutic target to decrease DOX cardiotoxicity.

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“…Furthermore, even after differentiation, optimal culture conditions still have not been established for PSC-CMs 62 . Regardless, based on measurements of contractility and multi-electrode array (MEA) field potential, PSC-CMs are predictive of drug toxicity, 63,64 and unlike primary CMs, they can be reasonably assessed in parallel and high-throughput assays. However, the “black box” underlying functional maturation remains; the mechanistic insight into cardiotoxicity from these models will not be widely accepted until the physiological maturation pathways of CMs can be further elucidated.…”

Section: Single Cell Models Of Cardiomyocyte Physiologymentioning

confidence: 99%

Modeling cardiac complexity: Advancements in myocardial models and analytical techniques for physiological investigation and therapeutic development in vitro

et al. 2019

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Cardiomyopathies, heart failure, and arrhythmias or conduction blockages impact millions of patients worldwide and are associated with marked increases in sudden cardiac death, decline in the quality of life, and the induction of secondary pathologies. These pathologies stem from dysfunction in the contractile or conductive properties of the cardiomyocyte, which as a result is a focus of fundamental investigation, drug discovery and therapeutic development, and tissue engineering. All of these foci require in vitro myocardial models and experimental techniques to probe the physiological functions of the cardiomyocyte. In this review, we provide a detailed exploration of different cell models, disease modeling strategies, and tissue constructs used from basic to translational research. Furthermore, we highlight recent advancements in imaging, electrophysiology, metabolic measurements, and mechanical and contractile characterization modalities that are advancing our understanding of cardiomyocyte physiology. With this review, we aim to both provide a biological framework for engineers contributing to the field and demonstrate the technical basis and limitations underlying physiological measurement modalities for biologists attempting to take advantage of these state-of-the-art techniques.

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An impedance-based approach using human iPSC-derived cardiomyocytes significantly improves in vitro prediction of in vivo cardiotox liabilities

Cited by 30 publications

References 21 publications

An integrated characterization of contractile, electrophysiological, and structural cardiotoxicity of Sophora tonkinensis Gapnep. in human pluripotent stem cell-derived cardiomyocytes

An integrated characterization of contractile, electrophysiological, and structural cardiotoxicity of Sophora tonkinensis Gapnep. in human pluripotent stem cell-derived cardiomyocytes

Doxorubicin triggers bioenergetic failure and p53 activation in mouse stem cell-derived cardiomyocytes

Modeling cardiac complexity: Advancements in myocardial models and analytical techniques for physiological investigation and therapeutic development in vitro

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