The Electrophysiological Effects of Cardiac Glycosides in Human iPSC-derived Cardiomyocytes and in Guinea Pig Isolated Hearts

Guo, Liang; Qian, Jian-Yong; Abrams, Rory; Tang, Hui; Weiser, Thomas; Sanders, Matthew J.; Kolaja, Kyle L.

doi:10.1159/000329966

Cited by 50 publications

(32 citation statements)

References 24 publications

(33 reference statements)

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“…2011b). This response is similar to that seen in isolated guinea pig hearts, which demonstrate QT shortening, increased contractility and increased arrhythmogenesis (Guo et al, 2011b).…”

Section: Figuresupporting

confidence: 82%

The case for induced pluripotent stem cell‐derived cardiomyocytes in pharmacological screening

Khan

Lyon

Harding

2013

British J Pharmacology

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The current drug screening models are deficient, particularly in detecting cardiac side effects. Human stem cell-derived cardiomyocytes could aid both early cardiotoxicity detection and novel drug discovery. Work over the last decade has generated human embryonic stem cells as potentially accurate sources of human cardiomyocytes, but ethical constraints and poor efficacy in establishing cell lines limit their use. Induced pluripotent stem cells do not require the use of human embryos and have the added advantage of producing patient-specific cardiomyocytes, allowing both generic and disease-and patient-specific pharmacological screening, as well as drug development through disease modelling. A critical question is whether sufficient standards have been achieved in the reliable and reproducible generation of 'adult-like' cardiomyocytes from human fibroblast tissue to progress from validation to safe use in practice and drug discovery. This review will highlight the need for a new experimental system, assess the validity of human induced pluripotent stem cell-derived cardiomyocytes and explore what the future may hold for their use in pharmacology. LINKED ARTICLESThis article is part of a themed section on Regenerative Medicine and Pharmacology: A Look to the Future. To view the other articles in this section visit http://dx

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“…2011b). This response is similar to that seen in isolated guinea pig hearts, which demonstrate QT shortening, increased contractility and increased arrhythmogenesis (Guo et al, 2011b).…”

Section: Figuresupporting

confidence: 82%

The case for induced pluripotent stem cell‐derived cardiomyocytes in pharmacological screening

Khan

Lyon

Harding

2013

British J Pharmacology

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“…3,19,32,43 These studies, as well as data presented here, show that contraction rates of mESC-derived cardiac cells are clearly affected by many compounds that are known positive or negative chronotropes, ion channel blockers, or hERG blockers. The use of human iPSCderived cardiomyocytes provides a number of additional advantages.…”

Section: Discussionsupporting

confidence: 67%

“…Human-induced pluripotent stem cell (iPSC)-derived cardiomyocytes are especially attractive as they recapitulate the expected genomic, biochemical, mechanical, and electrophysiological behaviors of human cardiomyocytes. [2][3][4][5] Furthermore, human iPSC-derived cardiomyocytes are derived from a single, infinitely expandable iPSC source and can be reproducibly differentiated in large quantities at high purity and cryopreserved until use, thus making them especially useful for large-scale and longitudinal investigations. 6 As human iPSC-derived cardiomyocytes express full cardiomyocyte functionality, the need has arisen for more robust and higher-throughput assay platforms able to assess multiple endpoints during preclinical drug development and safety testing.…”

Section: Introductionmentioning

confidence: 99%

Multiparameter In Vitro Assessment of Compound Effects on Cardiomyocyte Physiology Using iPSC Cells

Sirenko¹,

Crittenden²,

et al. 2013

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A large percentage of drugs fail in clinical studies due to cardiac toxicity; thus, development of sensitive in vitro assays that can evaluate potential adverse effects on cardiomyocytes is extremely important for drug development. Human cardiomyocytes derived from stem cell sources offer more clinically relevant cell-based models than those presently available. Human-induced pluripotent stem cell-derived cardiomyocytes are especially attractive because they express ion channels and demonstrate spontaneous mechanical and electrical activity similar to adult cardiomyocytes. Here we demonstrate techniques for measuring the impact of pharmacologic compounds on the beating rate of cardiomyocytes with ImageXpress Micro and FLIPR Tetra systems. The assays employ calcium-sensitive dyes to monitor changes in Ca 2+ fluxes synchronous with cell beating, which allows monitoring of the beat rate, amplitude, and other parameters. We demonstrate here that the system is able to detect concentration-dependent atypical patterns caused by hERG inhibitors and other ion channel blockers. We also show that both positive and negative chronotropic effects on cardiac rate can be observed and IC 50 values determined. This methodology is well suited for safety testing and can be used to estimate efficacy and dosing of drug candidates prior to clinical studies.

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“…Indeed, drugs have been withdrawn, despite their efficacy, in a large population due to risk to a rare population. An iPSC-based approach offers a solution to this problem and has been used in iPSC-derived cardiomyocytes to identify the adverse effects of cardiac glycosides [101]. Patients with adverse events can be identified and their iPSCs generated, and then these iPSCs can be used to extensively map the drug response and compare it with patients who had a beneficial effect.…”

Section: Personalized Medicinementioning

confidence: 99%

Induced Pluripotent Stem Cell Models to Enable In Vitro Models for Screening in the Central Nervous System

Hunsberger

Efthymiou

Malik

et al. 2015

Stem Cells and Development

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There is great need to develop more predictive drug discovery tools to identify new therapies to treat diseases of the central nervous system (CNS). Current nonpluripotent stem cell-based models often utilize non-CNS immortalized cell lines and do not enable the development of personalized models of disease. In this review, we discuss why in vitro models are necessary for translational research and outline the unique advantages of induced pluripotent stem cell (iPSC)-based models over those of current systems. We suggest that iPSC-based models can be patient specific and isogenic lines can be differentiated into many neural cell types for detailed comparisons. iPSC-derived cells can be combined to form small organoids, or large panels of lines can be developed that enable new forms of analysis. iPSC and embryonic stem cell-derived cells can be readily engineered to develop reporters for lineage studies or mechanism of action experiments further extending the utility of iPSC-based systems. We conclude by describing novel technologies that include strategies for the development of diversity panels, novel genomic engineering tools, new three-dimensional organoid systems, and modified high-content screens that may bring toxicology into the 21st century. The strategic integration of these technologies with the advantages of iPSC-derived cell technology, we believe, will be a paradigm shift for toxicology and drug discovery efforts.Disease Modeling D iseases of the central nervous system (CNS) affect a large number of people, but therapeutic intervention is hampered by the lack of useful models for many of these diseases. Current research on human subjects, particularly for drug discovery for CNS diseases, is severely (and appropriately) limited by ethical guidelines. Therefore, surrogate models are needed that share important anatomical, physiological, and genetic features to advance new treatments and therapies for CNS diseases [1].Developing rapid and effective therapies for CNS diseases requires the availability of in vitro models that accurately recapitulate disease phenotypes and predict patient treatment response. A proper model must be both sensitive and predictive while reflecting both normal and disease processes. Equally important, these models should enable the investigation of genetic and environmental risk factors contributing to diseases in a rapid and economical way. Currently used models often do not reflect a typical human response [2-4], despite efforts underway to better characterize these models and increase their preclinical value in predicting safety and efficacy in the clinic [5,6]. Therefore, there is a great need to develop disease-and patient-specific models from cells directly affected in CNS disorders. These cellbased models, we envision, could either replace or supplement current animal models and enable the efficient translation of basic research into the clinical setting. Limitations with current CNS modelsCurrently, drug discovery relies on the use of animalbased or cell-based models, ...

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The Electrophysiological Effects of Cardiac Glycosides in Human iPSC-derived Cardiomyocytes and in Guinea Pig Isolated Hearts

Cited by 50 publications

References 24 publications

The case for induced pluripotent stem cell‐derived cardiomyocytes in pharmacological screening

The case for induced pluripotent stem cell‐derived cardiomyocytes in pharmacological screening

Multiparameter In Vitro Assessment of Compound Effects on Cardiomyocyte Physiology Using iPSC Cells

Induced Pluripotent Stem Cell Models to Enable In Vitro Models for Screening in the Central Nervous System

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