Interplay between calcium cycling and sarcomeres directs cardiomyocyte redifferentiation and maturation during regeneration

Zebrafish hearts can regenerate by replacing damaged tissue with new cardiomyocytes. Although the steps leading up to the proliferation of surviving cardiomyocytes have been extensively studied, little is known about the mechanisms that control proliferation and redifferentiation to a mature state. We found that the cardiac dyad, a structure that regulates calcium handling and excitation-contraction coupling, played a key role in the redifferentiation process. A component of the cardiac dyad called leucine-rich repeat–containing 10 (Lrrc10) acted as a negative regulator of proliferation, prevented cardiomegaly, and induced redifferentiation. We found that its function was conserved in mammalian cardiomyocytes. This study highlights the importance of the underlying mechanisms required for heart regeneration and their application to the generation of fully functional cardiomyocytes. Overall design: Samples 1-6: Border zone zebrafish cardiomyocytes were FACS sorted based on nppa:mCitrine levels at 7 and 21 after cardiac injury to identify transcriptomic changes over time. Sample 7: iPS CMs from two separate culture plates were transfected with a LRRC10-mCherry fusion construct and sequenced independent of fluorescence where untransfected cells function as an internal control.