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EMBRYONIC STEM CELLS

Functional Properties of Human Embryonic Stem Cell–Derived Cardiomyocytes: Intracellular Ca²⁺ Handling and the Role of Sarcoplasmic Reticulum in the Contraction

^a Rappaport Family Institute for Research in the Medical Sciences, Rappaport Faculty of Medicine, Technion, Haifa, Israel;
^b Departments of Oncology and
^c Obstetrics and Gynecology, Rambam Medical Center, Haifa, Israel;
^d Sohnis and Forman Center of Excellence for Stem Cell and Tissue Regeneration Research, Rappaport Faculty of Medicine, Technion, Haifa, Israel

Key Words. Human embryonic stem cell-derived cardiomyocytes • Excitation-contraction coupling • [Ca²⁺]_i transients • Contractions • Sarcoplasmic reticulum

Correspondence: Ofer Binah, Ph.D., Rappaport Institute, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, P.O. Box 9697, Haifa 31096, Israel. Telephone: 972-48295262; Fax: 972-48513919; e-mail: binah{at}tx.technion.ac.il Joseph Itskovitz-Eldor, M.D., Department of Obstetrics and Gynecology, Rambam Medical Center, Haifa, Israel. Telephone: 972-48542536; e-mail: itskovitz{at}rambam.health.gov.il

Since cardiac transplantation is limited by the small availability of donor organs, regeneration of the diseased myocardium by cell transplantation is an attractive therapeutic modality. To determine the compatibility of human embryonic stem cell-derived cardiomyocytes (hESC-CMs) (7 to 55 days old) with the myocardium, we investigated their functional properties regarding intracellular Ca²⁺ handling and the role of the sarcoplasmic reticulum in the contraction. The functional properties of hESC-CMs were investigated by recording simultaneously [Ca²⁺]_i transients and contractions. Additionally, we performed Western blot analysis of the Ca²⁺-handling proteins SERCA2, calsequestrin, phospholamban, and Na⁺/Ca²⁺ exchanger (NCX). Our major findings are, first, that hESC-CMs displayed temporally related [Ca²⁺]_i transients and contractions, negative force-frequency relations, and lack of post-rest potentiation. Second, ryanodine, thapsigargin, and caffeine did not affect the [Ca²⁺]_i transient and contraction, indicating that at this developmental stage, contraction depends on transsarcolemmal Ca²⁺ influx rather than on sarcoplasmic reticulum Ca²⁺ release. Third, in agreement with the notion that a voltage-dependent Ca²⁺ current is present in hESC-CMs and contributes to the mechanical function, verapamil completely blocked contraction. Fourth, whereas hESC-CMs expressed SERCA2 and NCX at levels comparable to those of the adult porcine myocardium, calsequestrin and phospholamban were not expressed. Our study shows for the first time that functional properties related to intracellular Ca²⁺ handling of hESC-CMs differ markedly from the adult myocardium, probably due to immature sarcoplasmic reticulum capacity.

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