Establishment of pathological models using iPS cell-derived cardiomyocytes and their application to drug discovery and toxicity tests

Abstract

Since human iPS cells can be differentiated into various cells, they are expected to be applied to toxicity tests, disease mechanism studies, and drug discovery screening. However, pluripotent stem cell-derived cardiomyocytes are closer to fetal myocardium than adult cardiac tissue cardiomyocytes, which hinders their application to toxicity test systems and drug discovery research. We are conducting various approaches to induce cardiomyocyte maturation. Using genome editing technology, we have created iPS cell lines in which we can monitor the expression of troponin I1 and troponin I3, whose expressions change during cardiomyocyte maturation, by observing the expression of a reporter fluorescent dye and have conducted screening using a compound library. Through the screening, compounds that induce cardiomyocyte maturation were identified. Cardiomyocytes treated with these compounds showed gene expression profiles, mitochondria function, and cell morphology closer to mature cardiomyocytes found in adult heart tissues. Mature iPS cell-derived cardiomyocytes are expected to improve disease models and the accuracy of toxicity tests.

In addition, we are conducting pathological model studies of cardiac diseases, such as hypertrophic cardiomyopathy and genetic arrhythmias. Cardiomyocytes derived from hypertrophic cardiomyopathy iPS cells showed cellular hypertrophy and disordered sarcomere structures, and we are looking for compounds that improve these changes.

In this symposium, I would like to report on the development of a method for producing mature cardiomyocytes from iPS cells and the progress of research on the construction of pathological models and toxicity testing systems using iPS cell technology.