Calcium signalling of human pluripotent stem cell‐derived cardiomyocytes

Abstract

Loss of cardiomyocytes (CMs), which lack the innate ability to regenerate, due to ageing or pathophysiological conditions (e.g. myocardial infarction or MI) is generally considered irreversible, and can lead to conditions from cardiac arrhythmias to heart failure. Human (h) pluripotent stem cells (PSCs), including embryonic stem cells (ESC) and induced pluripotent stem cells (iPSCs), can self-renew while maintaining their pluripotency to differentiate into all cell types, including CMs. Therefore, hPSCs provide a potential unlimited ex vivo source of human CMs for disease modelling, drug discovery, cardiotoxicity screening and cell-based heart therapies. As a fundamental property of working CMs, Ca 2+ signalling and its role in excitation-contraction coupling are well described. However, the biology of these processes in hPSC-CMs is just becoming understood. Here we review what is known about the immature Ca 2+ -handling properties of hPSC-CMs, at the levels of global transients and sparks, and the underlying molecular basis in relation to the development of various in vitro approaches to drive their maturation.

Electrophysiological properties and calcium handling of embryonic stem cell-derived cardiomyocytes

“…They have fewer mitochondria 5 and are predominantly glycolytic 7 . Ca 2+ handling is also significantly different from that of their adult counterpart displaying slower kinetics and smaller amplitude 8 . This review will primarily focus on the electrophysiological properties and Ca 2+ handling features of ESC-CMs during differentiation into adult cardiomyocytes.…”

A New System for Profiling Drug-Induced Calcium Signal Perturbation in Human Embryonic Stem Cell–Derived Cardiomyocytes

“…7–9 Previous studies in single mammalian cells showed that subtle changes in Ca 2+ signaling dynamics, which did not perturb steady-state Ca 2+ homeostasis, had profound consequences for cell phenotype. 6,10–12 In this study, we extend these approaches to profile Ca 2+ signal organization in spontaneously contractile, functionally coupled hSCCMs.…”

Population-Based Mechanistic Modeling Allows for Quantitative Predictions of Drug Responses across Cell Types

“…In general, iPSC-CMs are considered to possess an immature phenotype that more closely resembles fetal than adult heart cells. 3,4 This is seen both structurally, in the fact that iPSC-CMs lack transverse tubules and a regular organization of sarcomeres, 27 and functionally, in features such as the contribution of sarcoplasmic reticulum Ca 2+ release 3 and the densities of particular K + channels. 28 Because of these physiological differences, drug responses observed in iPSC-CMs and adult myocytes are also expected to diverge.…”

“…Because these cells are a readily obtainable and renewable source of human cardiac myocytes, they are gaining popularity as a potential platform to screen drugs for toxicity. 1,2 The cells, however, exhibit immature physiology compared with ventricular myocytes from adult hearts, 3,4 and it remains unclear how well drug tests performed in iPSC-CMs will recapitulate the effects observed in human hearts.…”