期刊
EUROPEAN HEART JOURNAL
卷 34, 期 15, 页码 1147-1156出版社
OXFORD UNIV PRESS
DOI: 10.1093/eurheartj/ehs418
关键词
Reentrant arrhythmia; Human ES; iPS cells; Cardiac cell sheet; Spiral wave; Drug screening
资金
- Japan Society for the Promotion of Science [22-7076, 23710269, 23310087]
- Health Labor Science Research Grant [Nano-001]
- World Premier International Research Center Initiative
- Ministry of Education, Culture, Sports, Science and Technology in Japan
- Grants-in-Aid for Scientific Research [23310087, 10J07076, 23710269] Funding Source: KAKEN
Development of a human cell-derived reentrant arrhythmia model is needed for studying the mechanisms of disease and accurate drug response. 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. 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.
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