{"doi":"10.1002/jbm.a.37885","title":"Secreted Cytokines From Inflammatory Macrophages Modulate Sex Differences in Valvular Interstitial Cells on Hydrogel Biomaterials","abstract":"Patients with aortic valve stenosis (AVS) experience fibrosis and/or calcification in valve tissue, which leads to heart failure if left untreated. Inflammation is a hallmark of AVS, and secreted cytokines from pro-inflammatory macrophages are thought to contribute to valve fibro-calcification by driving the activation of valvular interstitial cells (VICs) to myofibroblasts. However, the molecular mechanisms by which inflammatory cytokines differentially regulate myofibroblast activation as a function of biological sex are not fully defined. Here, we developed an in vitro hydrogel culture platform to culture male and female valvular interstitial cells (VICs) and characterize the sex-specific effects of inflammatory cytokines on VIC activation to myofibroblasts and osteoblast-like cells. Our data reveal that tumor necrosis factor alpha (TNF-α) modulates female-specific myofibroblast activation via MAPK/ERK signaling, nuclear chromatin availability, and osteoblast-like differentiation via RUNX2 nuclear localization. In parallel, our data also suggest that male-specific myofibroblast deactivation in response to TNF-α occurs via alternative pathways outside of MAPK/ERK signaling. Collectively, hydrogel biomaterials as cell culture platforms are critical for distinguishing sex differences in cellular phenotypes.","journal":"Journal of Biomedical Materials Research Part A","year":2025,"id":510588,"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":19,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9539,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1367687,"name":"Kristi Tu","orcid":null,"position":1,"is_corresponding":false},{"id":1072795,"name":"Peng Guo","orcid":"0000-0001-5585-292X","position":2,"is_corresponding":false},{"id":577558,"name":"Ryan Reeves","orcid":"0000-0001-7887-964X","position":3,"is_corresponding":false},{"id":448946,"name":"Brian A. Aguado","orcid":"0000-0002-4449-9806","position":4,"is_corresponding":false},{"id":1366992,"name":"Nicole E. Félix Vélez","orcid":"0000-0002-3637-1992","position":0,"is_corresponding":true}],"reference_count":50,"raw_metadata":null,"created_at":"2026-07-19T02:47:36.538276Z","pmid":"39995146","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":[]}