Sarcomere function activates a p53-dependent DNA damage response that promotes polyploidization and limits in vivo cell engraftment
| Autor: | Jennifer VanOudenhove, Rachel Cohn, Justin Cotney, Xiulan Yang, Yu-Sheng Chen, Charles E. Murry, Paul Robson, J. Travis Hinson, Anthony M. Pettinato, Ketan Thakar, Dasom Yoo, Feria A. Ladha, Emily Meredith, Nicolas Legere, Michael Regnier, Robert Romano |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Sarcomeres
0301 basic medicine Cell division QH301-705.5 DNA damage Cell cardiomyocytes Biology Sarcomere Article General Biochemistry Genetics and Molecular Biology Cell therapy 03 medical and health sciences 0302 clinical medicine medicine Animals Humans Biology (General) Cyclin B1 Cell Proliferation P53 single-cell genomics cardiac regeneration food and beverages Cell cycle Rats Chromatin Cell biology Disease Models Animal 030104 developmental biology medicine.anatomical_structure cell cycle sarcomere Tumor Suppressor Protein p53 030217 neurology & neurosurgery DNA Damage |
| Zdroj: | Cell Reports, Vol 35, Iss 5, Pp 109088-(2021) Cell reports |
| ISSN: | 2211-1247 |
| Popis: | SUMMARY 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. Graphical Abstract In brief Pettinato et al. engineer human cardiomyocyte models to study replication and polyploidization using single-cell transcriptomics, chromatin-state analysis, and a CRISPR screen. This reveals how the sarcomere promotes polyploidization through enhanced oxidative metabolism, DNA damage, and p53. Exploiting this pathway improves in vivo cardiomyocyte replacement strategies. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|