Differentiation of Human Embryonic Stem Cells to Cardiomyocytes

TLDR

Cardiomyocytes derived from human embryonic stem cells could help restore heart function after myocardial infarction or heart failure. The study induced cardiomyocyte differentiation of hES cells using a novel method and compared their electrophysiological properties and coupling to primary human fetal cardiomyocytes. hES cells were cocultured with mouse visceral‑endoderm–like cells to trigger differentiation. The resulting cells beat, expressed sarcomeric markers, displayed ventricular‑like electrophysiology, formed functional gap junctions, and responded to verapamil via α1c calcium channels, demonstrating their similarity to fetal cardiomyocytes and offering a model for transplantation therapies.

Abstract

Background— Cardiomyocytes derived from human embryonic stem (hES) cells could be useful in restoring heart function after myocardial infarction or in heart failure. Here, we induced cardiomyocyte differentiation of hES cells by a novel method and compared their electrophysiological properties and coupling with those of primary human fetal cardiomyocytes. Methods and Results— hES cells were cocultured with visceral-endoderm (VE)–like cells from the mouse. This initiated differentiation to beating muscle. Sarcomeric marker proteins, chronotropic responses, and ion channel expression and function were typical of cardiomyocytes. Electrophysiology demonstrated that most cells resembled human fetal ventricular cells. Real-time intracellular calcium measurements, Lucifer yellow injection, and connexin 43 expression demonstrated that fetal and hES-derived cardiomyocytes are coupled by gap junctions in culture. Inhibition of electrical responses by verapamil demonstrated the presence of functional α 1c -calcium ion channels. Conclusions— This is the first demonstration of induction of cardiomyocyte differentiation in hES cells that do not undergo spontaneous cardiogenesis. It provides a model for the study of human cardiomyocytes in culture and could be a step forward in the development of cardiomyocyte transplantation therapies.