[II-JCKAP5-1-5] Investigation of the mechanisms of cardiomyopathy development using human iPS cell cardiomyocytes derived from Duchenne muscular dystrophy patients.
キーワード：Duchenne muscular dystrophy, iPS cell, cardiomyopathy
Background: Duchenne muscular dystrophy (DMD) is a progressive muscle disease caused by abnormalities in the dystrophin gene, and the development of cardiomyopathy has a significant impact on survival. Various treatments are being developed, but there is no fundamental treatment because the pathogenesis of cardiomyopathy in DMD is not revealed clearly. Purpose: To reveal the mechanisms of the development of cardiomyopathy by using DMD iPS cells (iPSCs). Method: The iPSCs in this study were established from an Exon 44-deficient DMD patient at the age of 2 years (D-iPS). The patient developed heart failure at the age of 10 and is currently undergoing treatment. In addition, control iPSCs (C-iPS) were established from the patient's healthy father, and isogenic-control iPSCs (R-iPS) were produced by knocking in Exon 44 by using CRISPR/Cas9 system in D-iPS. Cardiomyocytes (CMs) were differentiated from each iPSC, and various assays for investigating CMs activity were performed. Results: D-iPS-CMs showed longer action potential duration (FPD) than C-iPS-CMs and R-iPS-CMs at baseline (without stimulation) measured by the MED64 system. FPD tended to become more prolonged with beta-agonist administration only in D-iPS-CMs. Discussion: Cardiomyocytes from DMD patients have fragile cell membranes due to dystrophin deficiency and are known to have elevated intracellular calcium concentrations. In this study, by evaluating FPD changes in each iPSC-CM, it was suggested that CM injury is more likely to occur in D-iPS-CMs due to cardiac stress.