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Functional properties of human embryonic stem cells-derived cardiomyocytes: Intracellular Ca2+ handling and the role of sarcoplasmic reticulum in the contraction.

Dolnikov K, Shilkrut M, Zeevi-Levin N, Gerecht-Nir S, Amit M, Danon A, Itskovitz-Eldor J, Binah O

Rappaport Faculty of Medicine, Technion, Haifa, Israel.

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 cells-derived cardiomyocytes (hESC-CM, 7-55 days old) with the myocardium, we investigated their functional properties respecting intracellular Ca(2+) handling and the role of the sarcoplasmic reticulum in the contraction. The functional properties of hESC-CM were investigated by recording simultaneously [Ca(2+)]i transients and contraction. Additionally, we performed Western blot analysis of the Ca(2+)-handling proteins SERCA2, calsequestrin, phospholamban and Na(+)/Ca(2+) exchanger (NCX). Our major findings are: (1) hESC-CM displayed temporallyrelated [Ca(2+)]i transients and contraction, negative force-frequency relations and lack of postrest potentiation. (2) Ryanodine, thapsigargin and caffeine did not affect the [Ca(2+)]i transient and contraction, indicating that at this developmental stage, contraction depends on transsarcolemmal Ca(2+) influx rather than on sarcoplasmic reticulum Ca(2+) release. (3) In agreement with the notion that a voltage-dependent Ca(2+) current is present in hESC-CM and contributes to the mechanical function, verapamil completely blocked contraction. (4) While hESC-CM expressed SERCA2 and the Na(+)/Ca(2+) exchanger (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 Ca(2+)-handling of hESC-CM differ markedly from the adult myocardium, probably due to immature sarcoplasmic reticulum capacity.

Published 2 December 2005 in Stem Cells.
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