New cell models and assays in cardiac safety profiling

Meyer, Thomas; Sartipy, Peter; Blind, Franziska; Leisgen, Christine; Guenther, Elke

doi:10.1517/17425225.3.4.507

Cited by 12 publications

(9 citation statements)

References 74 publications

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“…In the last 30 years, side effect of drugs on cardiac ion channels were one major cause for drug withdrawals from the market. Currently, the FDA requires screenings for cardiac safety with cell lines overexpressing the hERG K + -channel, because this channel is responsible for most of the drug effects on cardiac repolarization 5 – 7 . However, the electrical activity of cardiomyocytes and generation of APs are regulated by many other Na + , Ca 2+ or K + channels that are not present in such heterologous expression systems which is why screening of drug effects in cardiomyocytes would be beneficial 8 .…”

Section: Introductionmentioning

confidence: 99%

Frequency-dependent drug screening using optogenetic stimulation of human iPSC-derived cardiomyocytes

Lapp

Bruegmann

Malan

et al. 2017

Sci Rep

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Side effects on cardiac ion channels are one major reason for new drugs to fail during preclinical evaluation. Herein we propose a simple optogenetic screening tool measuring extracellular field potentials (FP) from paced cardiomyocytes to identify drug effects over the whole physiological heart range, which is essential given the rate-dependency of ion channel function and drug action. Human induced pluripotent stem cell-derived cardiomyocytes were transduced with an adeno-associated virus to express Channelrhodopsin2 and plated on micro-electrode arrays. Global pulsed illumination (470 nm, 1 ms, 0.9 mW/mm2) was applied at frequencies from 1 to 2.5 Hz, which evoked FP simultaneously in all cardiomyocytes. This synchronized activation allowed averaging of FP from all electrodes resulting in one robust FP signal for analysis. Field potential duration (FPD) was ~25% shorter at 2.5 Hz compared to 1 Hz. Inhibition of hERG channels prolonged FPD only at low heart rates whereas Ca2+ channel block shortened FPD at all heart rates. Optogenetic pacing also allowed analysis of the maximum downstroke velocity of the FP to detect drug effects on Na+ channel availability. In principle, the presented method is well scalable for high content cardiac toxicity screening or personalized medicine for inherited cardiac channelopathies.

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Section: Introductionmentioning

confidence: 99%

Frequency-dependent drug screening using optogenetic stimulation of human iPSC-derived cardiomyocytes

Lapp

Bruegmann

Malan

et al. 2017

Sci Rep

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“…Thus, physiologically relevant in vitro models for human cardiomyocytes are currently limited. This has led in the creation of alternative models, such as isolation of cardiomyocytes from various newborn animals or production of genetically engineered cell lines overexpressing certain target proteins (e.g., ion channels) [1]. All of these models, however, share significant limitations with respect to their basic physiological differences compared to human cardiomyocytes as well as high costs and ethical questions.…”

Section: Introductionmentioning

confidence: 99%

Cardiac Differentiation of Pluripotent Stem Cells

Rajala

Pekkanen-Mattila

Aalto‐Setälä

2011

Stem Cells International

109

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The ability of human pluripotent stem cells to differentiate towards the cardiac lineage has attracted significant interest, initially with a strong focus on regenerative medicine. The ultimate goal to repair the heart by cardiomyocyte replacement has, however, proven challenging. Human cardiac differentiation has been difficult to control, but methods are improving, and the process, to a certain extent, can be manipulated and directed. The stem cell-derived cardiomyocytes described to date exhibit rather immature functional and structural characteristics compared to adult cardiomyocytes. Thus, a future challenge will be to develop strategies to reach a higher degree of cardiomyocyte maturation in vitro, to isolate cardiomyocytes from the heterogeneous pool of differentiating cells, as well as to guide the differentiation into the desired subtype, that is, ventricular, atrial, and pacemaker cells. In this paper, we will discuss the strategies for the generation of cardiomyocytes from pluripotent stem cells and their characteristics, as well as highlight some applications for the cells.

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“…Several noncardiovascular drugs were found to cause unanticipated cardiotoxicity and were withdrawn from the market in the late 1990s (reviewed in [12,13]), heightening concerns over cardiotoxicity within the pharmacological industry. Because of limited supplies of human cardiomyocytes, assessment of cardiotoxicity is traditionally carried out in models that use genetically modified cells or nonhuman cardiac cells (reviewed in [12,13]). hESCs represent a more appropriate and reliable cell resource for cardiotoxicity testing.…”

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confidence: 99%

Efficient Generation and Cryopreservation of Cardiomyocytes Derived from Human Embryonic Stem Cells

Hassanipour

et al. 2010

Regen. Med.

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Aim Human embryonic stem cells (hESCs) represent a novel cell source to treat diseases such as heart failure and for use in drug screening. In this study, we aim to promote efficient generation of cardiomyocytes from hESCs by combining the current optimal techniques of controlled growth of undifferentiated cells and specific induction for cardiac differentiation. We also aim to examine whether these methods are scalable and whether the differentiated cells can be cryopreserved. Methods & results hESCs were maintained without conditioned medium or feeders and were sequentially treated with activin A and bone morphogenetic protein-4 in a serum-free medium. This led to differentiation into cell populations containing high percentages of cardiomyocytes. The differentiated cells expressed appropriate cardiomyocyte markers and maintained contractility in culture, and the majority of the cells displayed working chamber (atrial and ventricular) type electrophysiological properties. In addition, the cell growth and differentiation process was adaptable to large culture formats. Moreover, the cardiomyocytes survived following cryopreservation, and viable cardiac grafts were detected after transplantation of cryopreserved cells into rat hearts following myocardial infarctions. Conclusion These results demonstrate that cardiomyocytes of high quality can be efficiently generated and cryopreserved using hESCs maintained in serum-free medium, a step forward towards the application of these cells to human clinical use or drug discovery.

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New cell models and assays in cardiac safety profiling

Cited by 12 publications

References 74 publications

Frequency-dependent drug screening using optogenetic stimulation of human iPSC-derived cardiomyocytes

Frequency-dependent drug screening using optogenetic stimulation of human iPSC-derived cardiomyocytes

Cardiac Differentiation of Pluripotent Stem Cells

Efficient Generation and Cryopreservation of Cardiomyocytes Derived from Human Embryonic Stem Cells

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