{"title":"Decoupling Mechanical Confinement and Fibrotic Extracellular Matrix Signaling in Vestibular Schwannoma Using Tunable 3D Hydrogels.","authors":"Melanie Fisher, Han Tn Nguyen, Rinky Ghosh, Yael Vodovotz, Yin Ren","doi":"10.1007/s12195-026-00911-3","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>Vestibular schwannoma (VS) progressively stiffens and remodels its extracellular matrix (ECM) during growth. However, how mechanical confinement and adhesive ECM signaling regulate schwannoma behavior <i>in vitro</i> remain incompletely defined.</p><p><strong>Methods: </strong>Human Nf2<sup>-/-</sup> schwannoma and primary VS cells established from fresh surgical specimens were cultured in complementary 3D hydrogel platforms. Biochemically inert agarose hydrogels spanning physiologic to pathologic stiffnesses created a non-adhesive mechanical confinement environment, while type I collagen hydrogels modeled an adhesive environment with a dense, fibrillar matrix characteristic of fibrotic tumor ECM. Hydrogel stiffness was quantified by rheology. Cell viability, proliferation, morphology, mechanosensitive signaling, and ECM remodeling were quantified. Mechanical stress was relieved by enzymatic degradation. YAP activity was pharmacologically inhibited, and transforming growth factor-β (TGF-β) was used to induce collagen remodeling.</p><p><strong>Results: </strong>Under non-adhesive confinement, increasing stiffness suppressed schwannoma reduced cell spreading, decreased N-cadherin expression, and increased nuclear YAP localization. Stress relief reversed YAP activation while enabling enhanced proliferative recovery and increased N-cadherin-associated adhesion. Cells under increased confinement exhibited increased sensitivity to YAP inhibition, indicating confinement-dependent reliance on mechanotransduction. In contrast, adhesive ECM conditions supported active matrix remodeling with increasing stiffness, including elevated activities of MMP9 and phosphorylated focal adhesion kinase (pFAK). TGF-β induced both collagen disorganization and SMAD3 nuclear localization, which was attenuated by YAP inhibition.</p><p><strong>Conclusions: </strong>Mechanical confinement and ECM composition drive distinct, context-dependent adaptation programs in VS. As stiffness increases, cells in non-adhesive environments adopt a reversible, YAP-associated stress response, while an adhesive ECM shifts behavior toward matrix remodeling and cell adhesion-driven signaling.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s12195-026-00911-3.</p>","PeriodicalId":9687,"journal":{"name":"Cellular and molecular bioengineering","volume":"19 3","pages":"311-326"},"PeriodicalIF":3.5000,"publicationDate":"2026-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13365291/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cellular and molecular bioengineering","FirstCategoryId":"5","ListUrlMain":"https://doi.org/10.1007/s12195-026-00911-3","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2026/6/1 0:00:00","PubModel":"eCollection","JCR":"Q3","JCRName":"BIOPHYSICS","Score":null,"Total":0}
引用次数: 0
Abstract
Purpose: Vestibular schwannoma (VS) progressively stiffens and remodels its extracellular matrix (ECM) during growth. However, how mechanical confinement and adhesive ECM signaling regulate schwannoma behavior in vitro remain incompletely defined.
Methods: Human Nf2-/- schwannoma and primary VS cells established from fresh surgical specimens were cultured in complementary 3D hydrogel platforms. Biochemically inert agarose hydrogels spanning physiologic to pathologic stiffnesses created a non-adhesive mechanical confinement environment, while type I collagen hydrogels modeled an adhesive environment with a dense, fibrillar matrix characteristic of fibrotic tumor ECM. Hydrogel stiffness was quantified by rheology. Cell viability, proliferation, morphology, mechanosensitive signaling, and ECM remodeling were quantified. Mechanical stress was relieved by enzymatic degradation. YAP activity was pharmacologically inhibited, and transforming growth factor-β (TGF-β) was used to induce collagen remodeling.
Results: Under non-adhesive confinement, increasing stiffness suppressed schwannoma reduced cell spreading, decreased N-cadherin expression, and increased nuclear YAP localization. Stress relief reversed YAP activation while enabling enhanced proliferative recovery and increased N-cadherin-associated adhesion. Cells under increased confinement exhibited increased sensitivity to YAP inhibition, indicating confinement-dependent reliance on mechanotransduction. In contrast, adhesive ECM conditions supported active matrix remodeling with increasing stiffness, including elevated activities of MMP9 and phosphorylated focal adhesion kinase (pFAK). TGF-β induced both collagen disorganization and SMAD3 nuclear localization, which was attenuated by YAP inhibition.
Conclusions: Mechanical confinement and ECM composition drive distinct, context-dependent adaptation programs in VS. As stiffness increases, cells in non-adhesive environments adopt a reversible, YAP-associated stress response, while an adhesive ECM shifts behavior toward matrix remodeling and cell adhesion-driven signaling.
Supplementary information: The online version contains supplementary material available at 10.1007/s12195-026-00911-3.
期刊介绍：
The field of cellular and molecular bioengineering seeks to understand, so that we may ultimately control, the mechanical, chemical, and electrical processes of the cell. A key challenge in improving human health is to understand how cellular behavior arises from molecular-level interactions. CMBE, an official journal of the Biomedical Engineering Society, publishes original research and review papers in the following seven general areas:
Molecular: DNA-protein/RNA-protein interactions, protein folding and function, protein-protein and receptor-ligand interactions, lipids, polysaccharides, molecular motors, and the biophysics of macromolecules that function as therapeutics or engineered matrices, for example.
Cellular: Studies of how cells sense physicochemical events surrounding and within cells, and how cells transduce these events into biological responses. Specific cell processes of interest include cell growth, differentiation, migration, signal transduction, protein secretion and transport, gene expression and regulation, and cell-matrix interactions.
Mechanobiology: The mechanical properties of cells and biomolecules, cellular/molecular force generation and adhesion, the response of cells to their mechanical microenvironment, and mechanotransduction in response to various physical forces such as fluid shear stress.
Nanomedicine: The engineering of nanoparticles for advanced drug delivery and molecular imaging applications, with particular focus on the interaction of such particles with living cells. Also, the application of nanostructured materials to control the behavior of cells and biomolecules.
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