title: Developmental changes in electrophysiological characteristics of human-induced pluripotent stem cell-derived cardiomyocytes.
abstract: Previous studies proposed that throughout differentiation of human induced Pluripotent Stem Cell-derived cardiomyocytes (iPSC-CMs), only 3 types of action potentials (APs) exist: nodal-, atrial-, and ventricular-like.
  
  
  
  To investigate whether there are precisely 3 phenotypes or a continuum exists among them, we tested 2 hypotheses: (1) During culture development a cardiac precursor cell is present that-depending on age-can evolve into the 3 phenotypes. (2) The predominant pattern is early prevalence of a nodal phenotype, transient appearance of an atrial phenotype, evolution to a ventricular phenotype, and persistence of transitional phenotypes.
  
  
  
  To test these hypotheses, we (1) performed fluorescence-activated cell sorting analysis of nodal, atrial, and ventricular markers; (2) recorded APs from 280 7- to 95-day-old iPSC-CMs; and (3) analyzed AP characteristics.
  
  
  
  The major findings were as follows: (1) fluorescence-activated cell sorting analysis of 30- and 60-day-old cultures showed that an iPSC-CMs population shifts from the nodal to the atrial/ventricular phenotype while including significant transitional populations; (2) the AP population did not consist of 3 phenotypes; (3) culture aging was associated with a shift from nodal to ventricular dominance, with a transient (57-70 days) appearance of the atrial phenotype; and (4) beat rate variability was more prominent in nodal than in ventricular cardiomyocytes, while pacemaker current density increased in older cultures.
  
  
  
  From the onset of development in culture, the iPSC-CMs population includes nodal, atrial, and ventricular APs and a broad spectrum of transitional phenotypes. The most readily distinguishable phenotype is atrial, which appears only transiently yet dominates at 57-70 days of evolution.
authors.affiliation: Department of Physiology, Biophysics and System Biology; The Rappaport Institute; Rappaport Faculty of Medicine.
authors.forename: Meital
authors.initials: M
authors.lastname: Ben-Ari
authors.affiliation: The Rappaport Institute; Rappaport Faculty of Medicine.
authors.forename: Shulamit
authors.initials: S
authors.lastname: Naor
authors.affiliation: Rappaport Faculty of Medicine.
authors.forename: Naama
authors.initials: N
authors.lastname: Zeevi-Levin
authors.affiliation: Department of Physiology, Biophysics and System Biology; The Rappaport Institute; Rappaport Faculty of Medicine.
authors.forename: Revital
authors.initials: R
authors.lastname: Schick
authors.affiliation: Department of Physiology, Biophysics and System Biology; The Rappaport Institute; Rappaport Faculty of Medicine; Department of Biotechnology.
authors.forename: Ronen
authors.initials: R
authors.lastname: Ben Jehuda
authors.affiliation: Department of Physiology, Biophysics and System Biology; The Rappaport Institute; Rappaport Faculty of Medicine.
authors.forename: Irina
authors.initials: I
authors.lastname: Reiter
authors.affiliation: Faculty of Electrical Engineering, Technion, Haifa, Israel.
authors.forename: Amit
authors.initials: A
authors.lastname: Raveh
authors.affiliation: Faculty of Electrical Engineering, Technion, Haifa, Israel.
authors.forename: Inna
authors.initials: I
authors.lastname: Grijnevitch
authors.affiliation: Rappaport Faculty of Medicine.
authors.forename: Omri
authors.initials: O
authors.lastname: Barak
authors.affiliation: Departments of Pharmacology and Pediatrics, Columbia University, New York, New York.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Rosen
authors.affiliation: Rappaport Faculty of Medicine; Department of Obstetrics and Gynecology, Rambam, Haifa, Israel.
authors.forename: Amir
authors.initials: A
authors.lastname: Weissman
authors.affiliation: Department of Physiology, Biophysics and System Biology; The Rappaport Institute; Rappaport Faculty of Medicine. Electronic address: binah@tx.technion.ac.il.
authors.forename: Ofer
authors.initials: O
authors.lastname: Binah
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D016275:Atrial Function / Q000502:physiology*; D001283:Atrioventricular Node / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology; D054338:Cell Transdifferentiation / Q000502:physiology*; D002478:Cells, Cultured; D055724:Electrophysiological Phenomena; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000502:physiology*; D016276:Ventricular Function / Q000502:physiology*
keywords: Action potential; Beat rate variability; Development; iPSC-CMs