Lessons from the heart: mirroring electrophysiological characteristics during cardiac development to in vitro differentiation of stem cell derived cardiomyocytes

Abstract

The ability of human pluripotent stem cells (hPSCs) to differentiate into any cell type of the three germ layers makes them a very promising cell source for multiple purposes, including regenerative medicine, drug discovery, and as a model to study disease mechanisms and progression. One of the first specialized cell types to be generated from hPSC was cardiomyocytes (CM), and differentiation protocols have evolved over the years and now allow for robust and large-scale production of hPSC-CM. Still, scientists are struggling to achieve the same, mainly ventricular, phenotype of the hPSC-CM in vitro as their adult counterpart in vivo. In vitro generated cardiomyocytes are generally described as fetal-like rather than adult. In this review, we compare the in vivo development of cardiomyocytes to the in vitro differentiation of hPSC into CM with focus on electrophysiology, structure and contractility. Furthermore, known epigenetic changes underlying the differences between adult human CM and CM differentiated from pluripotent stem cells are described. This should provide the reader with an extensive overview of the current status of human stem cell-derived cardiomyocyte phenotype and function. Additionally, the reader will gain insight into the underlying signaling pathways and mechanisms responsible for cardiomyocyte development.

Keywords: AP; ATP sensitive potassium current; CICR; CM; Cardiac development; Cardiomyocyte; Differentiation; HF; I(Ca,L); I(Ca,T); I(K,ATP); I(K,Ach); I(K1); I(Kr); I(Ks); I(Kur); I(Na); I(f); I(to); L-type calcium current; MI; Pluripotent stem cell; RMP; SR; T-type calcium current; acethylcholine activated potassium current; action potential; calcium induced calcium release; cardiomyocyte; funny or pacemaker current; hESC; hPSC; heart failure; hiPSC; human embryonic stem cell; human induced pluripotent stem cell; human pluripotent stem cell (either hESC and/or hiPSC); inward rectifier potassium current; lncRNA; long non-coding RNA; miRNA; microRNA; myocardial infarction; rapid delayed rectifier potassium current; resting membrane potential; sarcoplasmatic reticulum; slow delayed rectifier potassium current; sodium current; transient outward potassium current; ultrarapid delayed rectifier potassium current.