{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T19:19:37Z","timestamp":1772047177051,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1013279","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T00:00:00Z","timestamp":1771977600000}}],"reference-count":50,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T00:00:00Z","timestamp":1771545600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Australian Research Council Discovery Project","award":["DP230100485"],"award-info":[{"award-number":["DP230100485"]}]},{"name":"Postgraduate Research Scholarship in Mathematics and Statistics","award":["SC4238"],"award-info":[{"award-number":["SC4238"]}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>The cornea is a self-renewing, multilayered tissue maintained with remarkable precision. Its outermost layer, the corneal epithelium, consists of five to seven stratified cell layers, sustained by two coordinated processes: the centripetal migration of transit amplifying cells (TACs) from peripheral limbal epithelial stem cells (LESCs), and delamination (vertical movement) of cells between layers. Despite this well-organized renewal, the mechanisms governing epithelial stratification remain largely unknown.<\/jats:p>\n                  <jats:p>In this study, we present a two-dimensional Voronoi cell-based model that captures the dynamics of epithelial stratification. Our model incorporates two distinct epithelial layers\u2014the basal and the suprabasal layers\u2014and accounts for key cellular processes. These processes are mediated by mechanical interactions such as cell-substrate adhesion, as well as horizontal and vertical intercellular forces.<\/jats:p>\n                  <jats:p>Our simulations show that cell delamination, which drives stratification, is strongly linked to TAC proliferation. In contrast, LESC division remains largely unchanged, suggesting that TACs buffer LESC activity, consistent with the slow-cycling nature of stem cells. This reveals that processes weakening the cell-to-substrate interaction will enhance the turnover of epithelial cells without the need for external growth factor induction, which is a notable finding. Interestingly, while increased shedding promotes division and delamination, excessive shedding leads to mechanical compensation through cell stretching in the upper layers. This mechanical response provides a simple, plausible explanation for the presence of enlarged cells in the superficial epithelial layers, while not excluding the potential contributions of other mechanisms. Our model reveals a direct link between the shedding rate and the centripetal velocity of clonal growth, predicting that increased surface cell loss accelerates cell movement-a response similar to wound healing, where cells rapidly migrate to restore the damaged area.<\/jats:p>\n                  <jats:p>These results highlight how cell size, migration, and turnover are tightly coupled, and offer deeper insights into how physical forces work together to maintain and rapidly restore epithelial integrity. Although the real cornea contains five to seven layers, this two-layer framework focuses on the key mechanical principles of stratification and can be viewed as a foundational step toward more comprehensive multilayer modelling.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1013279","type":"journal-article","created":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T18:55:06Z","timestamp":1771613706000},"page":"e1013279","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Intercellular forces driving stratification in a two-layer corneal epithelium: Insight from a Voronoi cell-based simulation model"],"prefix":"10.1371","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-1961-3650","authenticated-orcid":true,"given":"Neda","family":"Khodabakhsh Joniani","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Martinez-Martin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter S.","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4835-4663","authenticated-orcid":true,"given":"James Guy","family":"Lyons","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2026,2,20]]},"reference":[{"issue":"4","key":"pcbi.1013279.ref001","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.clae.2010.04.006","article-title":"Keratoconus: a review","volume":"33","author":"M Romero-Jim\u00e9nez","year":"2010","journal-title":"Cont Lens Anterior Eye."},{"issue":"1","key":"pcbi.1013279.ref002","doi-asserted-by":"crossref","first-page":"4959","DOI":"10.1038\/s41467-024-49008-3","article-title":"Impact of keratocyte differentiation on corneal opacity resolution and visual function recovery in male rats","volume":"15","author":"AK Riau","year":"2024","journal-title":"Nat Commun."},{"issue":"2","key":"pcbi.1013279.ref003","doi-asserted-by":"crossref","first-page":"190","DOI":"10.4103\/ijo.IJO_646_17","article-title":"Anatomy of cornea and ocular surface","volume":"66","author":"MS Sridhar","year":"2018","journal-title":"Indian J Ophthalmol."},{"issue":"6","key":"pcbi.1013279.ref004","first-page":"383","article-title":"The function of the corneal epithelium in health and disease. 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cell division in corneal and limbal epithelia","volume":"92","author":"F Castro-Mu\u00f1ozledo","year":"2011","journal-title":"Exp Eye Res."},{"issue":"6","key":"pcbi.1013279.ref029","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1046\/j.1524-475x.2001.00483.x","article-title":"Corneal stem cells in review","volume":"9","author":"JT Daniels","year":"2001","journal-title":"Wound Repair Regen."},{"issue":"3","key":"pcbi.1013279.ref030","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/S0092-8674(00)81867-X","article-title":"Regulatory mechanisms in stem cell biology","volume":"88","author":"SJ Morrison","year":"1997","journal-title":"Cell."},{"issue":"4","key":"pcbi.1013279.ref031","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1242\/dev.110.4.1001","article-title":"Stem cells: attributes, cycles, spirals, pitfalls and uncertainties. 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Brodland","year":"2004","journal-title":"Appl Mech Rev."},{"issue":"4","key":"pcbi.1013279.ref035","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1006\/jtbi.2000.2000","article-title":"Simulated brain tumor growth dynamics using a three-dimensional cellular automaton","volume":"203","author":"AR Kansal","year":"2000","journal-title":"J Theor Biol."},{"key":"pcbi.1013279.ref036","doi-asserted-by":"crossref","first-page":"051910","DOI":"10.1103\/PhysRevE.71.051910","article-title":"Multicellular tumor spheroid in an off-lattice Voronoi-Delaunay cell model","volume":"71","author":"G Schaller","year":"2005","journal-title":"Phys Rev E Stat Nonlin Soft Matter Phys."},{"key":"pcbi.1013279.ref037","doi-asserted-by":"crossref","first-page":"110052","DOI":"10.1016\/j.jtbi.2019.110052","article-title":"Enhancing oncolytic virotherapy: observations from a Voronoi cell-based model","volume":"485","author":"AL Jenner","year":"2020","journal-title":"J Theor Biol."},{"issue":"1","key":"pcbi.1013279.ref038","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pcbi.1010104","article-title":"Examining the efficacy of localised gemcitabine therapy for the treatment of pancreatic cancer using a hybrid agent-based model","volume":"19","author":"AL Jenner","year":"2023","journal-title":"PLoS Comput Biol."},{"issue":"36","key":"pcbi.1013279.ref039","doi-asserted-by":"crossref","first-page":"11258","DOI":"10.1073\/pnas.1502029112","article-title":"Mechanical control of mitotic progression in single animal cells","volume":"112","author":"CJ Cattin","year":"2015","journal-title":"Proc Natl Acad Sci U S A."},{"issue":"3","key":"pcbi.1013279.ref040","first-page":"245","article-title":"Roles of the cytoskeleton, cell adhesion and rho signalling in mechanosensing and mechanotransduction","volume":"161","author":"K Ohashi","year":"2017","journal-title":"J Biochem."},{"issue":"7643","key":"pcbi.1013279.ref041","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1038\/nature21407","article-title":"Mechanical stretch triggers rapid epithelial cell division through Piezo1","volume":"543","author":"SA Gudipaty","year":"2017","journal-title":"Nature."},{"issue":"16","key":"pcbi.1013279.ref042","doi-asserted-by":"crossref","first-page":"1890","DOI":"10.1091\/mbc.E18-05-0295","article-title":"Cellular crowding influences extrusion and proliferation to facilitate epithelial tissue repair","volume":"30","author":"JJ Franco","year":"2019","journal-title":"Mol Biol Cell."},{"issue":"10","key":"pcbi.1013279.ref043","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.3109\/02713689609017655","article-title":"The cell shedding rate of the corneal epithelium\u2013a comparison of collection methods","volume":"15","author":"H Ren","year":"1996","journal-title":"Curr Eye 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