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Structural Immaturity of Human iPSC-Derived Cardiomyocytes: In Silico Investigation of Effects on Function and Disease Modeling.

ABSTRACT: Background: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have emerged as a promising experimental tool for translational heart research and drug development. However, their usability as a human adult cardiomyocyte model is limited by their functional immaturity. Our aim is to analyse quantitatively those characteristics and how they differ from adult CMs. Methods and Results: We have developed a novel in silico model with all essential functional electrophysiology and calcium handling features of hiPSC-CMs. Importantly, the virtual cell recapitulates the immature intracellular ion dynamics that are characteristic for hiPSC-CMs, as quantified based our in vitro imaging data. The strong "calcium clock" is a source for a dual function of excitation-contraction coupling in hiPSC-CMs: action potential and calcium transient morphology vary substantially depending on the activation sequence of underlying ionic currents and fluxes that is altered in spontaneous vs. paced mode. Furthermore, parallel simulations with hiPSC-CM and adult cardiomyocyte models demonstrate the central differences. Results indicate that hiPSC-CMs translate poorly the disease specific phenotypes of Brugada syndrome, long QT Syndrome and catecholaminergic polymorphic ventricular tachycardia, showing less robustness and greater tendency for arrhythmic events than adult CMs. Based on a comparative sensitivity analysis, hiPSC-CMs share some features with adult CMs, but are still functionally closer to prenatal CMs than adult CMs. A database analysis of 3000 hiPSC-CM model variants suggests that hiPSC-CMs recapitulate poorly fundamental physiological properties of adult CMs. Single modifications do not appear to solve this problem, which is mostly contributed by the immaturity of intracellular calcium handling. Conclusion: Our data indicates that translation of findings from hiPSC-CMs to human disease should be made with great caution. Furthermore, we established a mathematical platform that can be used to improve the translation from hiPSC-CMs to human, and to quantitatively evaluate hiPSC-CMs development toward more general and valuable model for human cardiac diseases.

SUBMITTER: Koivumaki JT

PROVIDER: S-EPMC5808345 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Structural Immaturity of Human iPSC-Derived Cardiomyocytes: In Silico Investigation of Effects on Function and Disease Modeling.

Koivumäki Jussi T JT Naumenko Nikolay N Tuomainen Tomi T Takalo Jouni J Oksanen Minna M Puttonen Katja A KA Lehtonen Šárka Š Kuusisto Johanna J Laakso Markku M Koistinaho Jari J Tavi Pasi P

Frontiers in physiology 20180207

Background: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have emerged as a promising experimental tool for translational heart research and drug development. However, their usability as a human adult cardiomyocyte model is limited by their functional immaturity. Our aim is to analyse quantitatively those characteristics and how they differ from adult CMs. Methods and Results: We have developed a novel in silico model with all essential functional el ...[more]

PMID: 29467678

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Project description:BackgroundInduced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have emerged as a powerful tool for disease modeling, though their immature nature currently limits translation into clinical practice. Maturation strategies increasingly pay attention to cardiac metabolism because of its pivotal role in cardiomyocyte development and function. Moreover, aberrances in cardiac metabolism are central to the pathogenesis of cardiac disease. Thus, proper modeling of human cardiac disease warrants careful characterization of the metabolic properties of iPSC-CMs.MethodsHere, we examined the effect of maturation protocols on healthy iPSC-CMs applied in 23 studies and compared fold changes in functional metabolic characteristics to assess the level of maturation. In addition, pathological metabolic remodeling was assessed in 13 iPSC-CM studies that focus on hypertrophic cardiomyopathy (HCM), which is characterized by abnormalities in metabolism.ResultsMatured iPSC-CMs were characterized by mitochondrial maturation, increased oxidative capacity and enhanced fatty acid use for energy production. HCM iPSC-CMs presented varying degrees of metabolic remodeling ranging from compensatory to energy depletion stages, likely due to the different types of mutations and clinical phenotypes modeled. HCM further displayed early onset hypertrophy, independent of the type of mutation or disease stage.ConclusionsMaturation strategies improve the metabolic characteristics of iPSC-CMs, but not to the level of the adult heart. Therefore, a combination of maturation strategies might prove to be more effective. Due to early onset hypertrophy, HCM iPSC-CMs may be less suitable to detect early disease modifiers in HCM and might prove more useful to examine the effects of gene editing and new drugs in advanced disease stages. With this review, we provide an overview of the assays used for characterization of cardiac metabolism in iPSC-CMs and advise on which metabolic assays to include in future maturation and disease modeling studies.

Dataset Information

Structural Immaturity of Human iPSC-Derived Cardiomyocytes: In Silico Investigation of Effects on Function and Disease Modeling.

Publications

Structural Immaturity of Human iPSC-Derived Cardiomyocytes: <i>In Silico</i> Investigation of Effects on Function and Disease Modeling.

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