{"doi":"10.1016/j.celrep.2021.109088","title":"Sarcomere function activates a p53-dependent DNA damage response that promotes polyploidization and limits in vivo cell engraftment","abstract":"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.","journal":"Cell Reports","year":2021,"id":175351,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":22,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9505,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":716394,"name":"Dasom Yoo","orcid":null,"position":1,"is_corresponding":false},{"id":355757,"name":"Jennifer VanOudenhove","orcid":"0000-0001-8206-5542","position":2,"is_corresponding":false},{"id":704848,"name":"Yusheng Chen","orcid":"0000-0002-7785-4181","position":3,"is_corresponding":false},{"id":627245,"name":"Rachel Cohn","orcid":null,"position":4,"is_corresponding":false},{"id":704844,"name":"Feria A. Ladha","orcid":"0000-0002-8576-3976","position":5,"is_corresponding":false},{"id":555210,"name":"Xiulan Yang","orcid":null,"position":6,"is_corresponding":false},{"id":255236,"name":"Ketan Thakar","orcid":"0000-0002-6680-1527","position":7,"is_corresponding":false},{"id":391173,"name":"Robert Romano","orcid":"0000-0002-1947-3233","position":8,"is_corresponding":false},{"id":716395,"name":"Nicolas Legere","orcid":null,"position":9,"is_corresponding":false},{"id":704847,"name":"Emily Meredith","orcid":"0000-0003-1550-1935","position":10,"is_corresponding":false},{"id":295946,"name":"Paul Robson","orcid":"0000-0002-0191-3958","position":11,"is_corresponding":false},{"id":347667,"name":"Michael Regnier","orcid":"0000-0001-5437-9851","position":12,"is_corresponding":false},{"id":339250,"name":"Justin Cotney","orcid":"0000-0001-8230-2157","position":13,"is_corresponding":false},{"id":366668,"name":"Charles E. Murry","orcid":"0000-0003-3862-6773","position":14,"is_corresponding":false},{"id":255238,"name":"J. Travis Hinson","orcid":"0000-0003-1455-113X","position":15,"is_corresponding":false},{"id":704845,"name":"Anthony M. Pettinato","orcid":"0000-0001-5623-8315","position":0,"is_corresponding":true}],"reference_count":94,"raw_metadata":null,"created_at":"2026-07-18T23:47:11.249697Z","pmid":"33951429","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}