Maturation of human iPSC derived cardiomyocyte by continuous electrical pacing stimulation

Abstract

Human iPS cell-derived cardiomyocyte (hiPSC-CM) is conceptually promising as an unlimited source of human cardiomyocytes for cardiac pharmacological assessment including pre-clinical safety testing. Currently, cardiomyocytes could be differentiated with high efficiency but remain immature in their structure and function, demonstrating fetal gene expression, disorganized morphology, and contractile functions that differ from those of adult cardiomyocytes. As such, pharmacological assessment using hiPSC-CMs may be inaccurate and of limited utility. As cardiomyocytes in a heart are regularly exposed to electrical stimulation and mechanical stress, bio-engineering approaches become more prevalent as a tool for hiPSC-CM maturation. However, the mechanisms by which electrical stimulation enhances cardiomyocyte maturation remain poorly explored. Visualization of sarcomere network immunostaining withα-actinin and motion field imaging of beating cardiomyocytes enabled us to quantitatively evaluate the structural and the functional maturation of a hiPSC-CM (iCell-cardiomyocyte², CDI Fujifilm) induced by continuous electrical stimulations. The electrical stimulation did not alter spontaneous activity of hiPSC-CM in a week, whereas it altered sarcomere length after 4-weeks electrical stimulation. Thus, the combined analysis showed that structural and functional maturation occur at different times, indicating distinct molecular mechanisms.