On-Chip Cellomics for Cardiotoxity: Cell Network Model For Re-Construction of Higher Complexity of Organs

摘要

Cells are minimum units reflecting epigenetic information, which is considered to map the history of a parallelprocessingrecurrent network of biochemical reactions, their behaviors cannot be explained by considering onlyconventional DNA information-processing events. We have developed methods and systems of analyzing epigeneticinformation in cells, as well as that of genetic information, to expand our understanding of how living systems aredetermined. The role of epigenetic information on cells, which complements their genetic information, was inferred bycomparing predictions from genetic information with cell behaviour observed under conditions chosen to revealadaptation processes and community effects. A system of analyzing epigenetic information was developed starting fromthe twin complementary viewpoints of cell regulation as an 'algebraic' system (emphasis on temporal aspects) and as a'geometric' system (emphasis on spatial aspects). The knowlege acquired from this study may lead to the use of cells thatfully control practical applications like cell-based drug screening and the regeneration of organs. As one of the practicalapplication, we have developed the on-chip cardiotoxity measurement system for monitoring the risk of the lethalventricular arrhythmia Torsade de pointes (TdP), which is the most common reason for the withdrawal or restricted use ofmany cardiovascular and non-cardiovascular drugs. The lack of an in vitro model to detect pro-arrhythmic effects onhuman heart cells hinders the development of new drugs. We also exploited the recently established human inducedpluripotent stem (hiPS) cells driven to differentiate into functional cardiomyocytes. The hiPS-derived cardiomyocytes(hiPS-CMs) were analyzed using our on-chip cardiotoxity measurement system. The application of ion channel inhibitorsresulted in dose-dependent changes to the field potential waveform, and these changes were identical to those induced inthe native cardiomyocytes. This study shows that hiPS-CMs represent a promising in vitro model for cardiacelectrophysiologic studies and drug screening.