Automated Dual-Mode Cell Monitoring To Simultaneously Explore Calcium Dynamics and Contraction–Relaxation Kinetics within Drug-Treated Stem Cell-Derived Cardiomyocytes

This manuscript proposes a new dual-mode cell imaging system for studying the relationships between calcium dynamics and the contractility process of cardiomyocytes derived from human-induced pluripotent stem cells. Practically, this dual-mode cell imaging system provides simultaneously both live cell calcium imaging and quantitative phase imaging based on digital holographic microscopy. Specifically, thanks to the development of a robust automated image analysis, simultaneous measurements of both intracellular calcium, a key player of excitation-contraction coupling, and the quantitative phase image-derived dry mass redistribution, reflecting the effective contractility, namely, the contraction and relaxation processes, were achieved. Practically, the relationships between calcium dynamics and the contraction–relaxation kinetics were investigated in particular through the application of two drugs─namely, isoprenaline and E-4031─known to act precisely on calcium dynamics. Specifically, this new dual-mode cell imaging system enabled us to establish that calcium regulation can be divided into two phases, an early phase influencing the occurrence of the relaxation process followed by a late phase, which although not having a significant influence on the relaxation process affects significantly the beat frequency. In combination with cutting-edge technologies allowing the generation of human stem cell-derived cardiomyocytes, this dual-mode cell monitoring approach therefore represents a very promising technique, particularly in the fields of drug discovery and personalized medicine, to identify compounds likely to act more selectively on specific steps that compose the cardiomyocyte contractility.