Differentiation of human embryonic stem cells to cardiomyocytes: role of coculture with visceral endoderm-like cells

Christine Mummery, Dorien Ward-van Oostwaard, Pieter Doevendans, Rene Spijker, Stieneke van den Brink, Rutger Hassink, Marcel van der Heyden, Tobias Opthof, Martin Pera, Aart Brutel de la Riviere, Robert Passier, Leon Tertoolen
Circulation 2003 June 3, 107 (21): 2733-40

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 alpha1c-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.

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