Cardiac subtype characterization using all-optical action potential imaging.

Abstract

This editorial refers to ‘Subtype-specific promoter-driven action potential imaging for precise disease modelling and drug testing in human induced pluripotent stem cell-derived cardiomyocytes’, by Z. Chen et al. doi: 10.1093/eurheartj/ehw189. Cellular modelling of human heart disease has been hampered by several limitations, including difficult accessibility of human cardiac tissues and low proliferative capacity of freshly dissociated human cardiomyocytes (CMs). The advent of human pluripotent stem cells (hPSCs), which include both human embryonic stem cells (ESCs) and human induced pluripotent stem cells (iPSCs), has provided an unprecedented opportunity to generate potentially limitless quantities of hPSC-derived somatic cell types (including human CMs) for studying disease mechanisms, identifying novel drug targets, and accelerating drug screening.1 However, two major limitations must be overcome before such wide-ranging application of iPSC-CM technology is possible. The first problem is that current cardiac differentiation methods produce a heterogeneous population of ventricular-, atrial-, and nodal-like cells.2–4 Despite efforts to produce a more enriched population of a specific cardiac phenotype to model specific cardiac diseases (e.g. atrial fibrillation, ventricular arrhythmias, etc.), no effective and validated strategies are yet available. A second limitation is that iPSC-CMs are assessed by low-throughput functional assays, primarily the labour-intensive patch-clamp electrophysiology, which considerably slows the pace of identification and characterization of the disease and/or drug-induced cellular phenotypes. Therefore, there is an urgent need to develop sensitive, scalable, and high-throughput functional assays to capitalize fully on our ability to generate iPSC-CMs at an industrial scale.5,6 Over the past two decades, membrane voltage-sensitive dyes (VSDs) have been used as an alternative to patch-clamp electrophysiology to record both cardiac action potential (AP) and calcium transients. However, the use of VSDs in AP recordings is limited by the indiscriminate cell staining and dye-mediated acute phototoxicity, especially in the setting of repeated single-cell measurement. …