title: Development of a reentrant arrhythmia model in human pluripotent stem cell-derived cardiac cell sheets.
abstract: OBJECTIVE
  Development of a human cell-derived reentrant arrhythmia model is needed for studying the mechanisms of disease and accurate drug response.
  
  
  RESULTS
  We differentiated human pluripotent stem cells (hPSCs) into cardiomyocytes, and then re-plated them into cell sheets that proved capable of forming electrically coupled assemblies. We monitored the function of these re-plated sheets optically with the Ca(2+) sensitive dye Fluo-4, and found that they generated characteristic waves of activity whose velocity and patterns of propagation depended upon the concentration of sodium channel blockers; lidocaine and tetrodotoxin, and also the time after re-plating, as well as the applied stimulation frequency. Importantly, reentrant spiral-wave propagation could be generated in these sheets by applying high-frequency stimulation, particularly when cell-density in the sheets was relatively low. This was because cardiac troponin T-positive cells were more non-homogeneously distributed at low cell densities. Especially in such sheets, we could terminate spiral waves by administering the anti-arrhythmic drugs; nifekalant, E-4031, sotalol, and quinidine. We also found that in these sheets, nifekalant showed a clear dose-dependent increase in the size of the unexcitable 'cores' of these induced spiral waves, an important parallel with the treatment for ventricular tachycardia in the clinical situation, which was not shown properly in cardiac-cell sheets derived from dissociated rodent hearts.
  
  
  CONCLUSIONS
  We have succeeded in creating from hPSCs a valuable type of cardiomyocyte sheet that is capable of generating reentrant arrhythmias, and thus is demonstrably useful for screening and testing all sorts of drugs with anti-arrhythmic potential.
authors.affiliation: Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, iCeMS Research Building, Yoshida Honmachi, Kyoto 606-8501, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Kadota
authors.forename: Itsunari
authors.initials: I
authors.lastname: Minami
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Morone
authors.forename: John E
authors.initials: JE
authors.lastname: Heuser
authors.forename: Konstantin
authors.initials: K
authors.lastname: Agladze
authors.forename: Norio
authors.initials: N
authors.lastname: Nakatsuji
mesh_terms: D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000473:pathology*; D018929:Cell Culture Techniques / Q000379:methods; D002454:Cell Differentiation; D003896:Desmosomes / Q000648:ultrastructure; D004558:Electric Stimulation; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D008955:Models, Cardiovascular; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000473:pathology*; D039904:Pluripotent Stem Cells / Q000473:pathology*; D012518:Sarcomeres / Q000648:ultrastructure; D026941:Sodium Channel Blockers / Q000494:pharmacology; D023822:Tissue Engineering / Q000379:methods*; D056969:Voltage-Sensitive Dye Imaging / Q000379:methods
chemical_list: D000889:Anti-Arrhythmia Agents; D026941:Sodium Channel Blockers