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Changes in viscosity have been recently suggested as a regulator of cell locomotion. These novel studies focus on cell migration and spreading on glass substrates and through microchannels, and it remains a question whether viscosity impacts the cellular remodeling of extracellular matrices (ECMs). Here, we demonstrate that elevated viscosity induces cellular remodeling of collagen substrates and enhances cell spreading on ECM\u2010mimetic substrates. Our results expand on recent work showing that viscosity induces increased cellular forces and demonstrates that viscosity can drive local ECM densification. Our data further show that microtubules, Ras\u2010related C3 botulinum toxin substrate 1 (Rac1), actin\u2010related protein 2\/3 (Arp2\/3) complex, Rho\u2010associated protein kinase 1 (ROCK), and myosin are important regulators of viscosity\u2010induced ECM remodeling. In the context of viscosity\u2010induced cell spreading, cells cultured on glass and collagen substrates exhibit markedly different responses to pharmacological treatments, indicating that microtubules, Rac1, and Arp2\/3 play distinct roles in regulating cellular spreading depending on the substrate. In addition, our results demonstrate that high osmotic pressures override viscosity\u2010induced cell spreading by suppressing membrane ruffling. Our results demonstrate viscosity as a regulator of ECM remodeling and cell spreading in a fibrillar microenvironment. We also reveal a complex interplay between viscosity and osmolarity. We anticipate that our research can pave the way for future investigations into the crucial roles played by viscosity in both physiological and pathological conditions.<\/jats:p>","DOI":"10.1111\/febs.17306","type":"journal-article","created":{"date-parts":[[2024,11,12]],"date-time":"2024-11-12T01:30:11Z","timestamp":1731375011000},"page":"740-758","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Viscosity regulates cell spreading and cell\u2010extracellular matrix interactions"],"prefix":"10.1111","volume":"292","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7905-2916","authenticated-orcid":false,"given":"Hugh","family":"Xiao","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering Yale University  New Haven CT USA"},{"name":"Department of Pharmacological Sciences, Renaissance School of Medicine Stony Brook University  Stony Brook NY 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