Sarcomere function activates a p53-dependent DNA damage response that promotes polyploidization and limits in vivo cell engraftment


Human cardiac regeneration is limited by low cardiomyocyte replicative rates and progressive polyploidization by unclear mechanisms. To study this process, we engineer a human cardiomyocyte model to track replication and polyploidization using fluorescently tagged cyclin B1 and cardiac troponin T. Using time-lapse imaging, in vitro cardiomyocyte replication patterns recapitulate the progressive mononuclear polyploidization and replicative arrest observed in vivo. Single-cell transcriptomics and chromatin state analyses reveal that polyploidization is preceded by sarcomere assembly, enhanced oxidative metabolism, a DNA damage response, and p53 activation. CRISPR knockout screening reveals p53 as a driver of cell-cycle arrest and polyploidization. Inhibiting sarcomere function, or scavenging ROS, inhibits cell-cycle arrest and polyploidization. Finally, we show that cardiomyocyte engraftment in infarcted rat hearts is enhanced 4-fold by the increased proliferation of troponin-knockout cardiomyocytes. Thus, the sarcomere inhibits cell division through a DNA damage response that can be targeted to improve cardiomyocyte replacement strategies. Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Authors Pettinato AM, Yoo D, VanOudenhove J, Chen YS, Cohn R, Ladha FA, Yang X, Thakar K, Romano R, Legere N, Meredith E, Robson P, Regnier M, Cotney JL, Murry CE, Hinson JT
Journal Cell reports
Publication Date 2021 May 4;35(5):109088
PubMed 33951429
PubMed Central PMC8161465
DOI 10.1016/j.celrep.2021.109088

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