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Inflammation is a hallmark of AVS, and secreted cytokines from pro\u2010inflammatory macrophages are thought to contribute to valve fibro\u2010calcification 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\u00a0vitro hydrogel culture platform to culture male and female valvular interstitial cells (VICs) and characterize the sex\u2010specific effects of inflammatory cytokines on VIC activation to myofibroblasts and osteoblast\u2010like cells. Our data reveal that tumor necrosis factor alpha (TNF\u2010\u03b1) modulates female\u2010specific myofibroblast activation via MAPK\/ERK signaling, nuclear chromatin availability, and osteoblast\u2010like differentiation via RUNX2 nuclear localization. In parallel, our data also suggest that male\u2010specific myofibroblast deactivation in response to TNF\u2010\u03b1 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.<\/jats:p>","DOI":"10.1002\/jbm.a.37885","type":"journal-article","created":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T05:56:22Z","timestamp":1741067782000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Secreted Cytokines From Inflammatory Macrophages Modulate Sex Differences in Valvular Interstitial Cells on Hydrogel Biomaterials"],"prefix":"10.1002","volume":"113","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3637-1992","authenticated-orcid":false,"given":"Nicole E.","family":"F\u00e9lix V\u00e9lez","sequence":"first","affiliation":[{"name":"Shu Chien\u2010Gene Lay Department of Bioengineering University of California  San Diego California USA"},{"name":"Sanford Consortium for Regenerative Medicine  San Diego California 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