Excitation–contraction coupling of human induced pluripotent stem cell-derived cardiomyocytes

Kane, Christopher; Couch, Liam S.; Terracciano, Cesare M.

doi:10.3389/fcell.2015.00059

Cited by 66 publications

(49 citation statements)

References 66 publications

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“…While the precise status of their maturation remains to be determined, a multi-stage, genome-wide analysis indicated that early or late PSC-CMs in culture resemble early embryonic or late embryonic/neonatal CMs, respectively (Uosaki et al, 2015). The absence of the extensive t-tubule network also supports their immaturity (Kane et al, 2015; Knollmann, 2013). The in vivo-incubated PSC-CMs, however, displayed features very similar to adult CMs in morphology, function, and gene expression.…”

Section: Discussionmentioning

confidence: 83%

Neonatal Transplantation Confers Maturation of PSC-Derived Cardiomyocytes Conducive to Modeling Cardiomyopathy

et al. 2017

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SUMMARY Pluripotent stem cells (PSCs) offer unprecedented opportunities for disease modeling and personalized medicine. However, PSC-derived cells exhibit fetal-like characteristics and remain immature in a dish. This has emerged as a major obstacle for their application for late-onset diseases. We previously showed that there is a neonatal arrest of long-term cultured PSC-derived cardiomyocytes (PSC-CMs). Here, we demonstrate that PSC-CMs mature into adult CMs when transplanted into neonatal hearts. PSC-CMs became similar to adult CMs in morphology, structure, and function within a month of the transplantation into rats. The similarity was further supported by single-cell RNA-sequencing analysis. Moreover, this in vivo maturation allowed patient-derived PSC-CMs to reveal the disease phenotype of arrhythmogenic right ventricular cardiomyopathy, which predominantly manifests in adults. This study lays a foundation for understanding human CM maturation and pathogenesis and can be instrumental in PSC-based modeling of adult heart diseases.

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Section: Discussionmentioning

confidence: 83%

Neonatal Transplantation Confers Maturation of PSC-Derived Cardiomyocytes Conducive to Modeling Cardiomyopathy

et al. 2017

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“…To extrapolate the findings in murine cardiomyocytes and rat hearts to a human model, hiPSC-CMs were used (25), and intracellular Ca 2+ and contraction were measured before (baseline) and after 15 min incubation with different Ang-(1-9) concentrations. A dose-dependent increase in Ca 2+ transient and contraction amplitudes was observed within concentrations 0.5 μmol/l to 2 μmol/l (data not shown) with no effect on parameters such as calcium transient upstroke, rate of decline, or contraction/relaxation times.…”

Section: Resultsmentioning

confidence: 99%

Gene Therapy With Angiotensin-(1-9) Preserves Left Ventricular Systolic Function After Myocardial Infarction

Fattah

Nather

McCarroll

et al. 2016

Journal of the American College of Cardiology

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BackgroundAngiotensin-(1-9) [Ang-(1-9)] is a novel peptide of the counter-regulatory axis of the renin-angiotensin-aldosterone system previously demonstrated to have therapeutic potential in hypertensive cardiomyopathy when administered via osmotic mini-pump. Here, we investigate whether gene transfer of Ang-(1-9) is cardioprotective in a murine model of myocardial infarction (MI).ObjectivesThe authors evaluated effects of Ang-(1-9) gene therapy on myocardial structural and functional remodeling post-infarction.MethodsC57BL/6 mice underwent permanent left anterior descending coronary artery ligation and cardiac function was assessed using echocardiography for 8 weeks followed by a terminal measurement of left ventricular pressure volume loops. Ang-(1-9) was delivered by adeno-associated viral vector via single tail vein injection immediately following induction of MI. Direct effects of Ang-(1-9) on cardiomyocyte excitation/contraction coupling and cardiac contraction were evaluated in isolated mouse and human cardiomyocytes and in an ex vivo Langendorff-perfused whole-heart model.ResultsGene delivery of Ang-(1-9) reduced sudden cardiac death post-MI. Pressure volume measurements revealed complete restoration of end-systolic pressure, ejection fraction, end-systolic volume, and the end-diastolic pressure volume relationship by Ang-(1-9) treatment. Stroke volume and cardiac output were significantly increased versus sham. Histological analysis revealed only mild effects on cardiac hypertrophy and fibrosis, but a significant increase in scar thickness. Direct assessment of Ang-(1-9) on isolated cardiomyocytes demonstrated a positive inotropic effect via increasing calcium transient amplitude and contractility. Ang-(1-9) increased contraction in the Langendorff model through a protein kinase A–dependent mechanism.ConclusionsOur novel findings showed that Ang-(1-9) gene therapy preserved left ventricular systolic function post-MI, restoring cardiac function. Furthermore, Ang-(1-9) directly affected cardiomyocyte calcium handling through a protein kinase A–dependent mechanism. These data emphasized Ang-(1-9) gene therapy as a potential new strategy in the context of MI.

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“…This effect was reported for Ca 2+ channel modulators on hiPS-derived cardiomyocytes in electrophysiological studies, where different hiPS-derived cell lines displayed different responses to those agents but their pharmacology was different from that observed in primary human heart cells [62,63].…”

Section: Camentioning

confidence: 86%

Mechano-Pharmacological Characterization of Cardiomyocytes Derived from Human Induced Pluripotent Stem Cells

Goßmann

Frotscher

Linder³

et al. 2016

Cell Physiol Biochem

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Background/Aims: Common systems for the quantification of cellular contraction rely on animal-based models, complex experimental setups or indirect approaches. The herein presented CellDrum technology for testing mechanical tension of cellular monolayers and thin tissue constructs has the potential to scale-up mechanical testing towards medium-throughput analyses. Using hiPS-Cardiac Myocytes (hiPS-CMs) it represents a new perspective of drug testing and brings us closer to personalized drug medication. Methods: In the present study, monolayers of self-beating hiPS-CMs were grown on ultra-thin circular silicone membranes and deflect under the weight of the culture medium. Rhythmic contractions of the hiPS-CMs induced variations of the membrane deflection. The recorded contraction-relaxation-cycles were analyzed with respect to their amplitudes, durations, time integrals and frequencies. Besides unstimulated force and tensile stress, we investigated the effects of agonists and antagonists acting on Ca²⁺ channels (S-Bay K8644/verapamil) and Na⁺ channels (veratridine/lidocaine). Results: The measured data and simulations for pharmacologically unstimulated contraction resembled findings in native human heart tissue, while the pharmacological dose-response curves were highly accurate and consistent with reference data. Conclusion: We conclude that the combination of the CellDrum with hiPS-CMs offers a fast, facile and precise system for pharmacological, toxicological studies and offers new preclinical basic research potential.

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Excitation–contraction coupling of human induced pluripotent stem cell-derived cardiomyocytes

Cited by 66 publications

References 66 publications

Neonatal Transplantation Confers Maturation of PSC-Derived Cardiomyocytes Conducive to Modeling Cardiomyopathy

Neonatal Transplantation Confers Maturation of PSC-Derived Cardiomyocytes Conducive to Modeling Cardiomyopathy

Gene Therapy With Angiotensin-(1-9) Preserves Left Ventricular Systolic Function After Myocardial Infarction

Mechano-Pharmacological Characterization of Cardiomyocytes Derived from Human Induced Pluripotent Stem Cells

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