University of Oulu

Koivumäki JT, Naumenko N, Tuomainen T, Takalo J, Oksanen M, Puttonen KA, Lehtonen Š, Kuusisto J, Laakso M, Koistinaho J and Tavi P (2018) Structural Immaturity of Human iPSC-Derived Cardiomyocytes: In Silico Investigation of Effects on Function and Disease Modeling. Front. Physiol. 9:80. doi: 10.3389/fphys.2018.00080

Structural immaturity of human iPSC-derived cardiomyocytes : in silico investigation of effects on function and disease modeling

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Author: Koivumäki, Jussi T.1; Naumenko, Nikolay1; Tuomainen, Tomi1;
Organizations: 1A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
2Department of Biomedical Science, University of Sheffield, Sheffield, United Kingdom
3Biophysics, Department of Physics, University of Oulu, Oulu, Finland
4Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio University Hospital, Kuopio, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 3.2 MB)
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Language: English
Published: Frontiers Media, 2018
Publish Date: 2018-03-19


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 calciumtransientmorphology 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.

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Series: Frontiers in physiology
ISSN: 1664-042X
ISSN-E: 1664-042X
ISSN-L: 1664-042X
Volume: 9
Article number: 80
DOI: 10.3389/fphys.2018.00080
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
3112 Neurosciences
114 Physical sciences
Funding: This work was supported by Academy of Finland (#267637, to PT) Academy of Finland (#292540, to JKu, ML, JKo, PT) Sigrid Juselius Foundation (to PT), the Finnish Foundation for Cardiovascular Research (to JTK) and the Finnish-Norwegian Medical Foundation (to JTK).
Copyright information: © 2018 Koivumäki, Naumenko, Tuomainen, Takalo, Oksanen, Puttonen, Lehtonen, Kuusisto, Laakso, Koistinaho and Tavi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.