Circulating Traveling Wave Enhance the Maturation of Cardiomyocytes in Self-organized Tissue Ring.

Directed differentiation methods allowed high purity cardiomyocytes (CMs) differentiated from human pluripotent stem cells (hPSCs). However, their immaturity nature indicated early cardiac development, and might limit the applications in drug development and regenerative therapy. Here we showed a platform that promote the three-dimensional self-organized tissue rings (SOTRs) within which high-frequency action potential, named travelling waves (TWs), spontaneously originated and travelled robustly and continuously for months without any external stimulation. A mathematical model was used to simulate and interpret the origination of TWs within SOTRs. After two weeks training, SOTRs with TWs showed matured structural organization, increased cardiac gene expression and enhanced Ca²⁺ handling properties in a frequency-related manner, compared with control group without TWs. Thus, the self-pacing SOTRs may be used for promoting the cardiomyocytes maturation and the platform can serve as an economical and practical system for future scaling-up production of matured hPSCs-CMs.