{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T03:07:00Z","timestamp":1770433620161,"version":"3.49.0"},"posted":{"date-parts":[[2025,12,25]]},"group-title":"Biophysics","reference-count":95,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,12,25]],"date-time":"2025-12-25T00:00:00Z","timestamp":1766620800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000001","name":"U.S. National Science Foundation","doi-asserted-by":"crossref","award":["MCB 2426002"],"award-info":[{"award-number":["MCB 2426002"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000001","name":"U.S. National Science Foundation","doi-asserted-by":"crossref","award":["PHY 2310496"],"award-info":[{"award-number":["PHY 2310496"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Prebys Foundation Research Heroes grant"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,1,15]]},"abstract":"<jats:p>Single cells confined by the extracellular matrix can exhibit persistent rotational motion, yet the physical mechanisms underlying this chiral symmetry breaking remain unclear. Here, we address this gap with a cellular phase field model that couples cell deformation, cell polarization governed by stochastic excitable dynamics, and confinement. We identify the confinement strength as a bifurcation parameter determining three regimes: strong confinement prevents rotation through spatial constraints, intermediate confinement induces stochastic transitions between chiral and non-chiral states, and weak confinement allows persistent rotational motion. For the intermediate regime, we develop a semi-Markovian renewal process framework that characterizes the stochastic dynamics through dwell time statistics, transition probabilities and first-passage times. For the weak confinement regime, we reveal that a mechanochemical feedback enables coherent rotations despite internal noise through the reduction of local excitability mediated by mechanical contraction. We formalize this feedback analytically using Kramers escape theory. Experiments on epithelial MCF10A cells in Matrigel validate predictions for the weak confinement regime. Our results establish a theoretical approach for understanding single-cell chiral symmetry breaking under confinement, with implications for controlling single-cell dynamics by tuning extracellular matrix properties.<\/jats:p>","DOI":"10.64898\/2025.12.23.696323","type":"posted-content","created":{"date-parts":[[2025,12,25]],"date-time":"2025-12-25T23:45:12Z","timestamp":1766706312000},"source":"Crossref","is-referenced-by-count":0,"title":["Single-cell chiral symmetry breaking under confinement"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7051-3918","authenticated-orcid":false,"given":"Sebasti\u00e1n","family":"Echeverr\u00eda-Alar","sequence":"first","affiliation":[{"name":"Department of Physics, University of California, San Diego, California 92093, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Badri Narayanan","family":"Narasimhan","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of California, San Diego, California 92093, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie I","family":"Fraley","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of California, San Diego, California 92093, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3833-7197","authenticated-orcid":false,"given":"Wouter-Jan","family":"Rappel","sequence":"additional","affiliation":[{"name":"Department of Physics, University of California, San Diego, California 92093, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026020605531188000_2025.12.23.696323v3.1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2406293121"},{"key":"2026020605531188000_2025.12.23.696323v3.2","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1137\/S0036139903437424","volume":"65","year":"2004","journal-title":"SIAM Journal on Applied Mathematics"},{"key":"2026020605531188000_2025.12.23.696323v3.3","doi-asserted-by":"publisher","DOI":"10.1103\/PhysRevLett.83.1247"},{"key":"2026020605531188000_2025.12.23.696323v3.4","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04889-6"},{"key":"2026020605531188000_2025.12.23.696323v3.5","doi-asserted-by":"crossref","first-page":"033006","DOI":"10.1103\/PRXLife.2.033006","volume":"2","year":"2024","journal-title":"PRX Life"},{"key":"2026020605531188000_2025.12.23.696323v3.6","doi-asserted-by":"publisher","DOI":"10.1103\/PhysRevLett.110.228701"},{"key":"2026020605531188000_2025.12.23.696323v3.7","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1119578109"},{"key":"2026020605531188000_2025.12.23.696323v3.8","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.1038\/s41567-021-01336-7","volume":"17","year":"2021","journal-title":"Nature physics"},{"key":"2026020605531188000_2025.12.23.696323v3.9","unstructured":"S. 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