title: Autonomous beating rate adaptation in human stem cell-derived cardiomyocytes.
abstract: The therapeutic success of human stem cell-derived cardiomyocytes critically depends on their ability to respond to and integrate with the surrounding electromechanical environment. Currently, the immaturity of human cardiomyocytes derived from stem cells limits their utility for regenerative medicine and biological research. We hypothesize that biomimetic electrical signals regulate the intrinsic beating properties of cardiomyocytes. Here we show that electrical conditioning of human stem cell-derived cardiomyocytes in three-dimensional culture promotes cardiomyocyte maturation, alters their automaticity and enhances connexin expression. Cardiomyocytes adapt their autonomous beating rate to the frequency at which they were stimulated, an effect mediated by the emergence of a rapidly depolarizing cell population, and the expression of hERG. This rate-adaptive behaviour is long lasting and transferable to the surrounding cardiomyocytes. Thus, electrical conditioning may be used to promote cardiomyocyte maturation and establish their automaticity, with implications for cell-based reduction of arrhythmia during heart regeneration.
authors.affiliation: Department of Biomedical Engineering, Columbia University, New York, New York 10027, USA.|College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
authors.forename: George
authors.initials: G
authors.lastname: Eng
authors.affiliation: Department of Biomedical Engineering, Columbia University, New York, New York 10027, USA.|College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
authors.forename: Benjamin W
authors.initials: BW
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, Columbia University, New York, New York 10032, USA.
authors.forename: Lev
authors.initials: L
authors.lastname: Protas
authors.affiliation: McEwen Centre for Regenerative Medicine, University Health Network, Toronto, Ontario, Canada M5G1L7.
authors.forename: Mark
authors.initials: M
authors.lastname: Gagliardi
authors.affiliation: Department of Pathology and Cell Biology, Columbia University, New York, New York 10032, USA.
authors.forename: Kristy
authors.initials: K
authors.lastname: Brown
authors.affiliation: Department of Pharmacology, Columbia University, New York, New York 10032, USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Kass
authors.affiliation: McEwen Centre for Regenerative Medicine, University Health Network, Toronto, Ontario, Canada M5G1L7.
authors.forename: Gordon
authors.initials: G
authors.lastname: Keller
authors.affiliation: Department of Pharmacology, Columbia University, New York, New York 10032, USA.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Robinson
authors.affiliation: Department of Biomedical Engineering, Columbia University, New York, New York 10027, USA.|Department of Medicine, Columbia University, New York, New York 10032, USA.
authors.forename: Gordana
authors.initials: G
authors.lastname: Vunjak-Novakovic
mesh_terms: D002454:Cell Differentiation / Q000502:physiology; D017630:Connexins / Q000378:metabolism; D000072237:ERG1 Potassium Channel; D004558:Electric Stimulation; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D046529:Microscopy, Electron, Transmission; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism / Q000648:ultrastructure; D039904:Pluripotent Stem Cells / Q000166:cytology
chemical_list: D017630:Connexins; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human