Electrophysiological and contractile function of cardiomyocytes derived from human embryonic stem cells

Abstract

Human embryonic stem cells have emerged as the prototypical source from which cardiomyocytes can be derived for use in drug discovery and cell therapy. However, such applications require that these cardiomyocytes (hESC-CMs) faithfully recapitulate the physiology of adult cells, especially in relation to their electrophysiological and contractile function. We review what is known about the electrophysiology of hESC-CMs in terms of beating rate, action potential characteristics, ionic currents, and cellular coupling as well as their contractility in terms of calcium cycling and contraction. We also discuss the heterogeneity in cellular phenotypes that arises from variability in cardiac differentiation, maturation, and culture conditions, and summarize present strategies that have been implemented to reduce this heterogeneity. Finally, we present original electrophysiological data from optical maps of hESC-CM clusters.

Fig. 1

Optical action potentials and activation properties of spontaneously beating cell clusters from H9 EBs. (A) Action potentials recorded from two clusters. The green traces are single recording sites within each cluster (75 and 209 sites in left and right panels, respectively). The black traces are spatial averages of all recording sites within each cluster. Scale bar is 100 ms. (Left) Beating cluster with short APD and prominent phase 4 depolarization. (Right) Beating cluster with long APD and quiescent phase 4. (B) Action potentials from clusters derived from 22 different EBs. Each panel is a spatially averaged action potential from a single cluster. All panels are normalized to 1 second time window for comparison among different spontaneous beating rates. Scale bars are 100 ms. Note that different AP morphologies clearly exist among the EB population.

Fig. 2

APD restitution in a beating cell cluster from an H9 EB. (A) Spatially averaged action potentials of the cluster when paced at 1 Hz to 4 Hz with 0.5 Hz intervals; scale bar is 100 ms. (B) Corresponding APD80 as function of cycle length (CL).

Fig. 3

Conduction properties of a beating cell cluster from an H9 EB. (A) Isochrones of 2 ms intervals and local conduction velocity vectors superimposed on activation map of the cluster subjected to 1 Hz electrical pacing. (B) Local conduction velocity magnitude map. Scale bars are 200 μm.