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Herein, bottlebrush polymers are synthesized and crosslinked to form poly(ethylene glycol)\u2010based hydrogels and used to study how strain\u2010stiffening behavior affects human mesenchymal stromal cells (hMSCs). By tailoring the bottlebrush polymer length, the critical stress associated with the onset of network stiffening is systematically varied, and a unique protrusion\u2010rich hMSC morphology emerges only at critical stresses within a biologically accessible stress regime. Local cell\u2010matrix interactions are quantified using 3D traction force microscopy and small molecule inhibitors are used to identify cellular machinery that plays a critical role in hMSC mechanosensing of the engineered, strain\u2010stiffening microenvironment. Collectively, this study demonstrates how covalently crosslinked bottlebrush polymer hydrogels can recapitulate strain\u2010stiffening biomechanical cues at biologically relevant stresses and be used to probe how nonlinear elastic matrix properties regulate cellular processes.<\/jats:p>","DOI":"10.1002\/adma.202403198","type":"journal-article","created":{"date-parts":[[2024,4,24]],"date-time":"2024-04-24T05:53:46Z","timestamp":1713938026000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Nonlinear Elastic Bottlebrush Polymer Hydrogels Modulate Actomyosin Mediated Protrusion Formation in Mesenchymal Stromal Cells"],"prefix":"10.1002","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7616-3880","authenticated-orcid":false,"given":"Monica L.","family":"Ohnsorg","sequence":"first","affiliation":[{"name":"Department of Chemical and Biological Engineering University of Colorado Boulder  Boulder CO 80308 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