title: Functional properties of human embryonic stem cell-derived cardiomyocytes.
abstract: Regeneration of the diseased myocardium by cardiac cell transplantation is an attractive therapeutic modality. Yet, because the transplanted cardiomyocytes should functionally integrate within the diseased myocardium, it is preferable that their properties resemble those of the host. To determine the functional adaptability of human embryonic stem cell-derived cardiomyocytes (hESC-CM) to the host myocardium, the authors investigated the excitation-contraction (E-C) coupling and the responsiveness to common physiological stimuli. The main findings are: (1) hESC-CM readily respond to electrical pacing and generate corresponding [Ca(2+)](i) transients (measured by fura-2 fluorescence) and contractions (measured by video edge detector). (2) In contrast to the mature myocardium, hESC-CM display negative force-frequency relations. (3) The hESC-CM contraction is dependent on [Ca(2+)](o) and blocked by verapamil. (4) Surprisingly, ryanodine, the sarcoplasmic-endoplasmic reticulum Ca(2+)-ATPase inhibitor thapsigargin, and caffeine do not affect the [Ca(2+)](i) transient or contraction. Collectively, these results indicate that at the developmental stage of 45 to 60 days, the contraction is largely dependent on [Ca(2+)](o) rather than on sarcoplasmic reticulum (SR) Ca(2+) stores. The results show for the first time that the E-C coupling properties of hESC-CM differ from the adult myocardium, probably due to immature SR function. Based on these findings, genetic manipulation of hESC-CM toward the adult myocardium should be considered.
authors.affiliation: Rappaport Institute, Ruth and Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel.
authors.forename: Katya
authors.initials: K
authors.lastname: Dolnikov
authors.forename: Mark
authors.initials: M
authors.lastname: Shilkrut
authors.forename: Naama
authors.initials: N
authors.lastname: Zeevi-Levin
authors.forename: Asaf
authors.initials: A
authors.lastname: Danon
authors.forename: Sharon
authors.initials: S
authors.lastname: Gerecht-Nir
authors.forename: Joseph
authors.initials: J
authors.lastname: Itskovitz-Eldor
authors.forename: Ofer
authors.initials: O
authors.lastname: Binah
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation; D017690:Cell Transplantation; D006321:Heart / Q000196:embryology / Q000502:physiology; D006329:Heart Conduction System / Q000502:physiology; D006801:Humans; D051379:Mice; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000187:drug effects / Q000637:transplantation; D051381:Rats; D012433:Ryanodine / Q000494:pharmacology; D013234:Stem Cells / Q000166:cytology*; D019284:Thapsigargin / Q000494:pharmacology
chemical_list: D012433:Ryanodine; D019284:Thapsigargin; D002118:Calcium