{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T06:15:24Z","timestamp":1783318524007,"version":"3.54.6"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T00:00:00Z","timestamp":1783296000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000272","name":"National Institute for Health and Care Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007126","name":"Syracuse University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007126","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>Stratified epithelial tissues such as the skin epidermis maintain barrier integrity during development and homeostasis through the coordinated action of cell proliferation, differentiation, delamination, and tissue-scale mechanical forces. During development, the orientation of cell division within the basal layer plays a pivotal role in tissue stratification; however, the mechanical principles linking the orientation of the division plane to these processes across developmental stages remain poorly understood. Here, we expand a recently developed three-dimensional vertex model for stratified epithelia, composed of the basement membrane, basal, and suprabasal layers, to study the mechanical and structural impact of cell divisions with a wider range of orientations. The model integrates developmental stage via specific changes in heterotypic interfacial tensions (arising from actomyosin cortical contractility and adhesion molecules at the basal\u2013suprabasal interface) and tissue stiffness that have been quantified previously in experiments. By systematically varying background mechanical parameters, we investigate how heterotypic tension, division orientation, and tissue fluidity collectively influence the outcome of cell division. Our goal is to uncover the strategies that the embryo may employ to generate stratified phenotypes at different developmental stages, recognizing that these strategies might evolve over time. Although our focus is on the embryonic developmental stages of the epidermis, this framework may also be extended to investigate transformed cells, such as in cancer, to explore how altered division orientation contributes to precancerous or transformed phenotypes.<\/jats:p>","DOI":"10.3389\/fcell.2026.1844381","type":"journal-article","created":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T05:38:37Z","timestamp":1783316317000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["A predictive model for coupling cell division orientation to tissue mechanics during epithelial morphogenesis"],"prefix":"10.3389","volume":"14","author":[{"given":"Somiealo","family":"Azote","sequence":"first","affiliation":[{"name":"Department of Physics and BioInspired Institute, Syracuse University","place":["Syracuse, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajendra Singh","family":"Negi","sequence":"additional","affiliation":[{"name":"Department of Physics and BioInspired Institute, Syracuse University","place":["Syracuse, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"No (Arnold)","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Physics and BioInspired Institute, Syracuse University","place":["Syracuse, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Lisa","family":"Manning","sequence":"additional","affiliation":[{"name":"Department of Physics and BioInspired Institute, Syracuse University","place":["Syracuse, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"eaah4701","DOI":"10.1126\/science.aah4701","article-title":"Coupling organelle inheritance with mitosis to balance growth and differentiation","volume":"355","author":"Asare","year":"2017","journal-title":"Science"},{"key":"B2","doi-asserted-by":"publisher","first-page":"021011","DOI":"10.1103\/PhysRevX.6.021011","article-title":"Motility-driven glass and jamming transitions in biological tissues","volume":"6","author":"Bi","year":"2016","journal-title":"Phys. Rev. X"},{"key":"B3","doi-asserted-by":"publisher","first-page":"e47102","DOI":"10.7554\/eLife.47102","article-title":"Epithelial geometry regulates spindle orientation and progenitor fate during formation of the Mammalian epidermis","volume":"8","author":"Box","year":"2019","journal-title":"Elife"},{"key":"B4","doi-asserted-by":"publisher","first-page":"2327","DOI":"10.1016\/j.cub.2014.08.029","article-title":"A unique set of centrosome proteins requires pericentrin for spindle-pole localization and spindle orientation","volume":"24","author":"Chen","year":"2014","journal-title":"Curr. Biol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1038\/nature05574","article-title":"A single type of progenitor cell maintains normal epidermis","volume":"446","author":"Clayton","year":"2007","journal-title":"Nature"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1692","DOI":"10.1038\/s41556-022-01021-8","article-title":"Gradual differentiation uncoupled from cell cycle exit generates heterogeneity in the epidermal stem cell layer","volume":"24","author":"Cockburn","year":"2022","journal-title":"Nat. Cell Biology"},{"key":"B7","doi-asserted-by":"publisher","first-page":"9133","DOI":"10.1039\/c9sm00916g","article-title":"Glassy dynamics in models of confluent tissue with mitosis and apoptosis","volume":"15","author":"Czajkowski","year":"2019","journal-title":"Soft Matter"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1101\/2020.07.24.219493","article-title":"Epidermal stratification is uncoupled from centrosome-dependent cell division orientation of the basal progenitors","author":"Damen","year":"2020","journal-title":"bioRxiv"},{"key":"B9","doi-asserted-by":"publisher","first-page":"3227","DOI":"10.1038\/s41467-021-23386-4","article-title":"High proliferation and delamination during skin epidermal stratification","volume":"12","author":"Damen","year":"2021","journal-title":"Nat. Commun."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1106","DOI":"10.15252\/embr.201642292","article-title":"Regulation of mitotic spindle orientation: an integrated view","volume":"17","author":"di Pietro","year":"2016","journal-title":"EMBO Reports"},{"key":"B11","doi-asserted-by":"publisher","first-page":"2259","DOI":"10.1016\/j.bpj.2018.10.028","article-title":"Tissue flow induces cell shape changes during organogenesis","volume":"115","author":"Erdemci-Tandogan","year":"2018","journal-title":"Biophysical Journal"},{"key":"B12","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1038\/ncb2269","article-title":"External forces control mitotic spindle positioning","volume":"13","author":"Fink","year":"2011","journal-title":"Nat. Cell Biology"},{"key":"B13","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1038\/s41586-020-2695-9","article-title":"Mechanics of a multilayer epithelium instruct tumour architecture and function","volume":"585","author":"Fiore","year":"2020","journal-title":"Nature"},{"key":"B14","doi-asserted-by":"publisher","first-page":"dev194100","DOI":"10.1242\/dev.194100","article-title":"Regulatory mechanisms governing epidermal stem cell function during development and homeostasis","volume":"147","author":"Flora","year":"2020","journal-title":"Development"},{"key":"B15","doi-asserted-by":"publisher","first-page":"2227","DOI":"10.1016\/S0006-3495(98)77932-9","article-title":"Viscoelastic properties of living embryonic tissues: a quantitative study","volume":"74","author":"Forgacs","year":"1998","journal-title":"Biophysical Journal"},{"key":"B16","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1101\/2024.12.26.630435","article-title":"Epithelium stratifies via nucleation and growth induced by foam-geometric instability","author":"Fukamachi","year":"2024","journal-title":"bioRxiv"},{"key":"B17","doi-asserted-by":"publisher","first-page":"011033","DOI":"10.1103\/physrevx.11.011033","article-title":"Cell and nucleus shape as an indicator of tissue fluidity in carcinoma","volume":"11","author":"Grosser","year":"2021","journal-title":"Phys. Rev. X"},{"key":"B18","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1016\/j.devcel.2014.01.014","article-title":"Rab11 endosomes contribute to mitotic spindle organization and orientation","volume":"28","author":"Hehnly","year":"2014","journal-title":"Dev. Cell"},{"key":"B19","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1038\/s41567-019-0516-6","article-title":"Stress relaxation in epithelial monolayers is controlled by the actomyosin cortex","volume":"15","author":"Khalilgharibi","year":"2019","journal-title":"Nat. Physics"},{"key":"B20","doi-asserted-by":"publisher","first-page":"741","DOI":"10.1016\/j.ceb.2013.07.008","article-title":"Mechanisms of spindle positioning: cortical force generators in the limelight","volume":"25","author":"Kotak","year":"2013","journal-title":"Curr. Opinion Cell Biology"},{"key":"B21","doi-asserted-by":"publisher","first-page":"013005","DOI":"10.1103\/l5r5-pb9t","article-title":"Cell rearrangement progression along the apical-basal axis is linked with 3d epithelial tissue structure","volume":"4","author":"Kusaka","year":"2026","journal-title":"PRX Life"},{"key":"B22","doi-asserted-by":"publisher","first-page":"e1011724","DOI":"10.1371\/journal.pcbi.1011724","article-title":"Differences in boundary behavior in the 3d vertex and voronoi models","volume":"20","author":"Lawson-Keister","year":"2024","journal-title":"PLoS Computational Biology"},{"key":"B23","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1038\/nature03922","article-title":"Asymmetric cell divisions promote stratification and differentiation of mammalian skin","volume":"437","author":"Lechler","year":"2005","journal-title":"Nature"},{"key":"B24","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1038\/nature18958","article-title":"Asymmetric division of contractile domains couples cell positioning and fate specification","volume":"536","author":"Ma\u00eetre","year":"2016","journal-title":"Nature"},{"key":"B25","doi-asserted-by":"publisher","first-page":"e2418111122","DOI":"10.1073\/pnas.2418111122","article-title":"Dynamic forces drive cell and organ morphology changes during embryonic development","volume":"122","author":"Manna","year":"2025","journal-title":"Proc. Natl. Acad. Sci."},{"key":"B26","doi-asserted-by":"publisher","first-page":"3205","DOI":"10.1039\/c6sm02580c","article-title":"Cell division and death inhibit glassy behaviour of confluent tissues","volume":"13","author":"Matoz-Fernandez","year":"2017","journal-title":"Soft Matter"},{"key":"B27","doi-asserted-by":"publisher","first-page":"022002","DOI":"10.1088\/1367-2630\/aaaa13","article-title":"A geometrically controlled rigidity transition in a model for confluent 3d tissues","volume":"20","author":"Merkel","year":"2018","journal-title":"New J. Phys."},{"key":"B28","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1016\/j.stem.2018.09.005","article-title":"Homeostatic epidermal stem cell self-renewal is driven by local differentiation","volume":"23","author":"Mesa","year":"2018","journal-title":"Cell Stem Cell"},{"key":"B29","doi-asserted-by":"publisher","first-page":"414","DOI":"10.1016\/j.cell.2011.01.016","article-title":"Influence of cell geometry on division-plane positioning","volume":"144","author":"Minc","year":"2011","journal-title":"Cell"},{"key":"B30","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1038\/s41556-017-0005-z","article-title":"Adhesion forces and cortical tension couple cell proliferation and differentiation to drive epidermal stratification","volume":"20","author":"Miroshnikova","year":"2018","journal-title":"Nat. Cell Biology"},{"key":"B31","doi-asserted-by":"publisher","first-page":"887","DOI":"10.1083\/jcb.201307001","article-title":"apkc\u03bb controls epidermal homeostasis and stem cell fate through regulation of division orientation","volume":"202","author":"Niessen","year":"2013","journal-title":"J. Cell Biol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"2549","DOI":"10.1016\/j.bpj.2020.03.028","article-title":"A mechanical instability in planar epithelial monolayers leads to cell extrusion","volume":"118","author":"Okuda","year":"2020","journal-title":"Biophysical J."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1040","DOI":"10.1038\/nmat4357","article-title":"Unjamming and cell shape in the asthmatic airway epithelium","volume":"14","author":"Park","year":"2015","journal-title":"Nat. Materials"},{"key":"B34","doi-asserted-by":"publisher","first-page":"1007","DOI":"10.1242\/jcs.081406","article-title":"Mitotic spindle misorientation in cancer\u2013out of alignment and into the fire","volume":"124","author":"Pease","year":"2011","journal-title":"J. Cell Science"},{"key":"B35","doi-asserted-by":"publisher","first-page":"1471","DOI":"10.1126\/science.aaf7012","article-title":"Spatiotemporal coordination of stem cell commitment during epidermal homeostasis","volume":"352","author":"Rompolas","year":"2016","journal-title":"Science"},{"key":"B36","doi-asserted-by":"publisher","first-page":"093043","DOI":"10.1088\/1367-2630\/ac23f1","article-title":"Geometric signatures of tissue surface tension in a three-dimensional model of confluent tissue","volume":"23","author":"Sahu","year":"2021","journal-title":"New J. Phys."},{"key":"B37","doi-asserted-by":"publisher","first-page":"8440","DOI":"10.1038\/s41467-025-62882-9","article-title":"Mechanical control of cell fate decisions in the skin epidermis","volume":"16","author":"Sahu","year":"2025","journal-title":"Nat. Commun."},{"key":"B38","doi-asserted-by":"publisher","first-page":"203718","DOI":"10.1016\/j.cdev.2021.203718","article-title":"3d viscoelastic drag forces contribute to cell shape changes during organogenesis in the zebrafish embryo","volume":"168","author":"Sanematsu","year":"2021","journal-title":"Cells and Dev."},{"key":"B39","doi-asserted-by":"publisher","first-page":"5298","DOI":"10.1016\/j.cell.2024.07.031","article-title":"Dynamic regulation of tissue fluidity controls skin repair during wound healing","volume":"187","author":"Sarate","year":"2024","journal-title":"Cell"},{"key":"B40","doi-asserted-by":"publisher","first-page":"068404","DOI":"10.1103\/ky2j-5nwx","article-title":"Reentrant rigidity transition in planar epithelia with volume and area elasticity","volume":"136","author":"Sarkar","year":"2026","journal-title":"Phys. Rev. Lett."},{"key":"B41","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1038\/nmeth.4101","article-title":"In vivo quantification of spatially varying mechanical properties in developing tissues","volume":"14","author":"Serwane","year":"2017","journal-title":"Nat. Methods"},{"key":"B42","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1126\/science.141.3579.401","article-title":"Reconstruction of tissues by dissociated cells: some morphogenetic tissue movements and the sorting out of embryonic cells may have a common explanation","volume":"141","author":"Steinberg","year":"1963","journal-title":"Science"},{"key":"B43","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1016\/j.biomaterials.2018.03.052","article-title":"Src activation decouples cell division orientation from cell geometry in mammalian cells","volume":"170","author":"Sun","year":"2018","journal-title":"Biomaterials"},{"key":"B44","doi-asserted-by":"publisher","first-page":"218402","DOI":"10.1103\/physrevlett.132.218402","article-title":"Cell division and motility enable hexatic order in biological tissues","volume":"132","author":"Tang","year":"2024","journal-title":"Phys. Review Letters"},{"key":"B45","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1038\/nature05786","article-title":"Experimental and theoretical study of mitotic spindle orientation","volume":"447","author":"Th\u00e9ry","year":"2007","journal-title":"Nature"},{"key":"B46","doi-asserted-by":"publisher","first-page":"088102","DOI":"10.1103\/PhysRevLett.125.088102","article-title":"Migrating epithelial monolayer flows like a maxwell viscoelastic liquid","volume":"125","author":"Tlili","year":"2020","journal-title":"Phys. Rev. Lett."},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.64898\/2026.02.08.704529","article-title":"Tissue-scale mechanics controls differentiation strategy and dynamics of epithelial multilayering","author":"Villeneuve","year":"2026","journal-title":"bioRxiv"},{"key":"B48","doi-asserted-by":"publisher","first-page":"749","DOI":"10.1016\/j.ceb.2013.08.003","article-title":"Oriented divisions, fate decisions","volume":"25","author":"Williams","year":"2013","journal-title":"Curr. Opinion Cell Biology"},{"key":"B49","doi-asserted-by":"publisher","first-page":"043148","DOI":"10.1103\/physrevresearch.4.043148","article-title":"Topologically-protected interior for three-dimensional confluent cellular collectives","volume":"4","author":"Zhang","year":"2022","journal-title":"Phys. Rev. Res."},{"key":"B50","doi-asserted-by":"publisher","first-page":"073301","DOI":"10.1088\/1367-2630\/ade81e","article-title":"Enhanced extracellular matrix remodeling due to embedded spheroid fluidization","volume":"27","author":"Zhang","year":"2025","journal-title":"New J. Phys."}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2026.1844381\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T05:38:38Z","timestamp":1783316318000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2026.1844381\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,6]]},"references-count":50,"alternative-id":["10.3389\/fcell.2026.1844381"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2026.1844381","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,6]]},"article-number":"1844381"}}