{"doi":"10.1093/stcltm/szae032","title":"The <i>HH-GLI2-CKS1B</i> network regulates the proliferation-to-maturation transition of cardiomyocytes","abstract":"Cardiomyocyte (CM) proliferation and maturation are highly linked processes, however, the extent to which these processes are controlled by a single signaling axis is unclear. Here, we show the previously undescribed role of Hedgehog (HH)-GLI2-CKS1B cascade in regulation of the toggle between CM proliferation and maturation. Here we show downregulation of GLI-signaling in adult human CM, adult murine CM, and in late-stage hiPSC-CM leading to their maturation. In early-stage hiPSC-CM, inhibition of HH- or GLI-proteins enhanced CM maturation with increased maturation indices, increased calcium handling, and transcriptome. Mechanistically, we identified CKS1B, as a new effector of GLI2 in CMs. GLI2 binds the CKS1B promoter to regulate its expression. CKS1B overexpression in late-stage hiPSC-CMs led to increased proliferation with loss of maturation in CMs. Next, analysis of datasets of patients with heart disease showed a significant enrichment of GLI2-signaling in patients with ischemic heart failure (HF) or dilated-cardiomyopathy (DCM) disease, indicating operational GLI2-signaling in the stressed heart. Thus, the Hh-GLI2-CKS1B axis regulates the proliferation-maturation transition and provides targets to enhance cardiac tissue engineering and regenerative therapies.","journal":"Stem Cells Translational Medicine","year":2024,"id":444687,"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":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.956,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":583398,"name":"Lauren Kelly","orcid":"0000-0002-0646-1890","position":1,"is_corresponding":false},{"id":1260626,"name":"Nicholas Stan","orcid":null,"position":2,"is_corresponding":false},{"id":438326,"name":"Yasuhiko Kawakami","orcid":"0000-0002-0043-9705","position":3,"is_corresponding":false},{"id":288568,"name":"Juan E. Abrahante","orcid":"0000-0002-9074-4307","position":4,"is_corresponding":false},{"id":366156,"name":"Alessandro Magli","orcid":"0000-0003-3874-2838","position":5,"is_corresponding":false},{"id":732190,"name":"Brenda M. Ogle","orcid":"0000-0001-7613-7490","position":6,"is_corresponding":false},{"id":654049,"name":"Bhairab N. Singh","orcid":"0000-0002-9356-052X","position":7,"is_corresponding":false},{"id":995151,"name":"Christina Waldron","orcid":"0000-0003-0286-6599","position":0,"is_corresponding":true}],"reference_count":69,"raw_metadata":null,"created_at":"2026-07-19T02:01:37.886033Z","pmid":"38761090","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":[]}