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

Area of Science:

• Cardiovascular Biology
• Cellular Biology
• Regenerative Medicine

Background:

• Human cardiac regeneration is hindered by limited cardiomyocyte replication and polyploidization.
• The precise mechanisms driving these processes remain largely unknown.

Purpose of the Study:

• To investigate the mechanisms underlying cardiomyocyte polyploidization and replicative arrest.
• To identify molecular targets for enhancing cardiomyocyte proliferation and cardiac repair strategies.

Main Methods:

• Engineered human cardiomyocyte models with fluorescently tagged proteins (cyclin B1, cardiac troponin T).
• Utilized time-lapse imaging, single-cell transcriptomics, and chromatin state analyses.
• Performed CRISPR knockout screening and targeted inhibition of sarcomere function and reactive oxygen species (ROS).

Main Results:

• In vitro models recapitulated in vivo patterns of cardiomyocyte polyploidization and arrest.
• Polyploidization correlated with sarcomere assembly, oxidative metabolism, DNA damage response, and p53 activation.
• p53 was identified as a key driver of cell-cycle arrest; inhibiting sarcomere function or ROS reduced polyploidization.
• Knocking out troponin enhanced cardiomyocyte proliferation and 4-fold improved engraftment in infarcted rat hearts.

Conclusions:

• Sarcomere assembly inhibits cardiomyocyte division via a p53-mediated DNA damage response.
• Targeting this sarcomere-driven pathway offers a novel strategy to promote cardiomyocyte proliferation.
• Enhancing cardiomyocyte replication holds promise for improving cardiac regeneration and treating heart disease.