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bioRxiv · 10.1101/2024.11.15.623805

Secreted cytokines from inflammatory macrophages modulate sex differences in valvular interstitial cells on hydrogel biomaterials

Felix Velez, N. E.·Tu, K.·Guo, P.·Reeves, R. R.·Aguado, B. A.
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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-) modulates female-specific myofibroblast activation via MAPK/ERK signaling, nuclear chromatin availability, and osteoblast-like differentiation via RUNX2 nuclear localization. Collectively, hydrogel biomaterials as cell culture platforms are critical for distinguishing sex differences in cellular phenotypes.

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Felix Velez, N. E., Tu, K., Guo, P., Reeves, R. R., Aguado, B. A.. 2024-11-15. Secreted cytokines from inflammatory macrophages modulate sex differences in valvular interstitial cells on hydrogel biomaterials. https://doi.org/10.1101/2024.11.15.623805

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