hiPSCs Derived Cardiac Cells for Drug and Toxicity Screening and Disease Modeling: What Micro- Electrode-Array Analyses Can Tell Us

Kussauer, Sophie; Dávid, Róbert; Lemcke, Heiko

doi:10.3390/cells8111331

Cited by 55 publications

(48 citation statements)

References 139 publications

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“…MEA is a label-free, non-invasive and cost-effective measurement at the high-throughput scale and with real-time observations. 42 The hiPSC-CMs-based MEA assay has emerged as a stable and reliable strategy for screening of compound-induced cardiac toxicity and was recommended to be used in CiPA. 43 The field potential signals are recognized as markers for depolarization and repolarization enabling the quantification of important beating parameters.…”

Section: Discussionmentioning

confidence: 99%

<p>Zinc Oxide Nanoparticles Induce Mitochondrial Biogenesis Impairment and Cardiac Dysfunction in Human iPSC-Derived Cardiomyocytes</p>

Li¹,

Li²,

Zhang³

et al. 2020

IJN

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Background: Zinc oxide nanoparticles (ZnO NPs) are one of the most widely used nanomaterials in a variety of fields such as industrial, pharmaceutical, and household applications. Increasing evidence suggests that ZnO NPs could elicit unignorable harmful effect to the cardiovascular system, but the potential deleterious effects to human cardiomyocytes remain to be elucidated. Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been increasingly used as a promising in vitro model of cardiomyocyte in various fields such as drug cardiac safety evaluation. Herein, the present study was designed to elucidate the cardiac adverse effects of ZnO NPs and explore the possible underlying mechanism using hiPSC-CMs. Methods: ZnO NPs were characterized by transmission electron microscopy and dynamic light scattering. The cytotoxicity induced by ZnO NPs in hiPSC-CMs was evaluated by determination of cell viability and lactate dehydrogenase release. Cellular reactive oxygen species (ROS) and mitochondrial membrane potential were measured by high-content analysis (HCA). Mitochondrial biogenesis was assayed by detection of mtDNA copy number and PGC-1α pathway. Moreover, microelectrode array techniques were used to investigate cardiac electrophysiological alterations. Results: We demonstrated that ZnO NPs concentration-and time-dependently elicited cytotoxicity in hiPSC-CMs. The results from HCA revealed that ZnO NPs exposure at lowcytotoxic concentrations significantly promoted ROS generation and induced mitochondrial dysfunction. We further demonstrated that ZnO NPs could impair mitochondrial biogenesis and inhibit PGC-1α pathway. In addition, ZnO NPs at insignificantly cytotoxic concentrations were found to trigger cardiac electrophysiological alterations as evidenced by decreases of beat rate and spike amplitude. Conclusion: Our findings unveiled the potential harmful effects of ZnO NPs to human cardiomyocytes that involve mitochondrial biogenesis and the PGC-1α pathway that could affect cardiac electrophysiological function.

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Section: Discussionmentioning

confidence: 99%

<p>Zinc Oxide Nanoparticles Induce Mitochondrial Biogenesis Impairment and Cardiac Dysfunction in Human iPSC-Derived Cardiomyocytes</p>

Li¹,

Li²,

Zhang³

et al. 2020

IJN

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“…In recent years, induced pluripotent stem cell (iPSC) technology has become a major technology in cardiovascular research as it enables efficient in vitro generation of functional cardiomyocytes (CM) without any ethical concerns. CM derived from iPSCs have been shown to be suitable for regenerative therapies and drug development [1][2][3]. However, the proper maturation is a common problem as iPSC-CM do not display the same morphological and functional features as their adult counterparts, rather resembling fetal CM [4,5].…”

Section: Introductionmentioning

confidence: 99%

“…Following image acquisition and data reconstruction, sarcomere length and z-disc thickness were determined. Sarcomere length was evaluated by measuring the distance between intensity peaks, corresponding to adjacent α-actinin labelled filaments(1)(2)(3)(4)(5). z-disc thickness was automatically analyzed, and the mean width of each filament was calculated.…”

mentioning

confidence: 99%

Quantitative Evaluation of the Sarcomere Network of Human hiPSC-Derived Cardiomyocytes Using Single-Molecule Localization Microscopy

Lemcke

Skorska

Lang

et al. 2020

IJMS

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The maturation of iPSC-derived cardiomyocytes is still a critical point for their application in cardiovascular research as well as for their clinical use. Although multiple differentiation protocols have been established, researchers failed to generate fully mature cardiomyocytes in vitro possessing identical phenotype-related and functional properties as their native adult counterparts. Besides electrophysiological and metabolic changes, the establishment of a well structured sarcomere network is important for the development of a mature cardiac phenotype. Here, we present a super resolution-based approach to quantitatively evaluate the structural maturation of iPSC-derived cardiomyocytes. Fluorescence labelling of the α-actinin cytoskeleton and subsequent visualization by photoactivated localization microscopy allows the acquisition of highly resolved images for measuring sarcomere length and z-disc thickness. Our image analysis revealed that iPSC and neonatal cardiomyocyte share high similarity with respect to their sarcomere organization, however, contraction capacity was inferior in iPSC-derived cardiac cells, indicating an early maturation level. Moreover, we demonstrate that this imaging approach can be used as a tool to monitor cardiomyocyte integrity, helping to optimize iPSC differentiation as well as somatic cell direct-reprogramming strategies.

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“…In particular, the potential torsadogenic effect of drugs is based on hERG (I Kr ) or I Ks (slow-delayed rectifier) outward currents inhibition with or without Nav1.5 (transient/late sodium currents, I Na /I NaL ) and Cav1.2 (L-Type Ca 2+ ) inward currents enhancement. The result is a delayed AP repolarization with increased incidence of early afterdepolarization (EADs), leading to ventricular arrhythmias such as TdP and ventricular fibrillation [112,[117][118][119]. Furthermore, a computational approach has been recently developed to recapitulate the human AP profile and drug-induced TdP [120][121][122].…”

Section: Single Cells Recordings With the Patch Clamp Technique Are Smentioning

confidence: 99%

Human Induced Pluripotent Stem Cells Derived from a Cardiac Somatic Source: Insights for an In-Vitro Cardiomyocyte Platform

Lodrini

Barile

Rocchetti

et al. 2020

IJMS

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Reprogramming of adult somatic cells into induced pluripotent stem cells (iPSCs) has revolutionized the complex scientific field of disease modelling and personalized therapy. Cardiac differentiation of human iPSCs into cardiomyocytes (hiPSC-CMs) has been used in a wide range of healthy and disease models by deriving CMs from different somatic cells. Unfortunately, hiPSC-CMs have to be improved because existing protocols are not completely able to obtain mature CMs recapitulating physiological properties of human adult cardiac cells. Therefore, improvements and advances able to standardize differentiation conditions are needed. Lately, evidences of an epigenetic memory retained by the somatic cells used for deriving hiPSC-CMs has led to evaluation of different somatic sources in order to obtain more mature hiPSC-derived CMs.

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hiPSCs Derived Cardiac Cells for Drug and Toxicity Screening and Disease Modeling: What Micro- Electrode-Array Analyses Can Tell Us

Cited by 55 publications

References 139 publications

<p>Zinc Oxide Nanoparticles Induce Mitochondrial Biogenesis Impairment and Cardiac Dysfunction in Human iPSC-Derived Cardiomyocytes</p>

<p>Zinc Oxide Nanoparticles Induce Mitochondrial Biogenesis Impairment and Cardiac Dysfunction in Human iPSC-Derived Cardiomyocytes</p>

Quantitative Evaluation of the Sarcomere Network of Human hiPSC-Derived Cardiomyocytes Using Single-Molecule Localization Microscopy

Human Induced Pluripotent Stem Cells Derived from a Cardiac Somatic Source: Insights for an In-Vitro Cardiomyocyte Platform

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