Epithelial-mesenchymal cell competition coordinates fate transitions across tissue compartments during lung development and fibrosis

Epithelial-mesenchymal cell competition coordinates fate transitions across tissue compartments during lung development and fibrosis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Biological Sciences - Article Epithelial-mesenchymal cell competition coordinates fate transitions across tissue compartments during lung development and fibrosis Stijn (P) De Langhe, Kylie Klinkhammer, Rachel Warren, Joseph Knopp, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6189965/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 21 Nov, 2025 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Abstract Morphogenesis and cell state transitions must be coordinated in time and space to produce a functional tissue. In this study, we reveal that lung mesenchymal Yap levels and fitness antagonize epithelial Yap levels and stemness during lung development and repair following bleomycin injury. Elevated mesenchymal Yap signaling and fitness antagonize epithelial Yap levels and stemness, accelerating alveolar epithelial differentiation while impairing branching during lung development or bronchiolization after bleomycin injury. Conversely, mesenchymal Snail/Slug sequesters Yap/Taz to direct an adipogenic differentiation program towards alveolar fibroblast 1 (AF1) during both lung development and the resolution of pulmonary fibrosis. On the other hand, Yap/Myc-Tead binding instructs a myogenic differentiation program. Through our experiments and modeling, we identify tissue-scale mechanical cooperation as a pivotal factor in orchestrating organ formation and regeneration. Biological sciences/Stem cells/Adult stem cells Health sciences/Diseases/Respiratory tract diseases Biological sciences/Developmental biology/Stem-cell niche Biological sciences/Developmental biology/Morphogenesis/Cell lineage Full Text Additional Declarations There is NO Competing Interest. Cite Share Download PDF Status: Published Journal Publication published 21 Nov, 2025 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6189965","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Biological Sciences - Article","associatedPublications":[],"authors":[{"id":436424740,"identity":"414bef65-08f5-4e54-bff5-b3a8242a9a4d","order_by":0,"name":"Stijn (P) De Langhe","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABCUlEQVRIiWNgGAWjYDCCA8wNIBLClmCwgQqz4dPCCNPCDNKSRqIWIDhMWAvf8cbGzwW/7sgx8J8/eMByx/lo/hnJBxg+lB3GqUXyzMFm6Zl9z4wZJJIZDkieuZ0740ZaAuOMc7i1GNxIbJDm7Tmc2CAB9Itk2+3chhs5Bsy8bXi03H/Y/Buopb6B/zBIy7nc+SAtf/FpucHYJs3z43ACAwPIYW0HcjeAtDDi0SJ5JrHNmrfhsGGbRLIBUEty7sYzzxIO9pxLx6mF7/jhw7d5/hyW5+c/+PizZJtd7rzjyQcf/CizxqkFDBjbIBHBLAHiCSRAEwNe8Aeq9QOI5CdCwygYBaNgFIwoAACK/2QeVv9R/wAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0003-3867-4572","institution":"Mayo Clinic Rochester Minnesota","correspondingAuthor":true,"prefix":"","firstName":"Stijn","middleName":"(P)","lastName":"De Langhe","suffix":""},{"id":436424741,"identity":"26b4ae81-d3a7-4205-a5b3-aa77014db252","order_by":1,"name":"Kylie Klinkhammer","email":"","orcid":"","institution":"Mayo Clinic Rochester","correspondingAuthor":false,"prefix":"","firstName":"Kylie","middleName":"","lastName":"Klinkhammer","suffix":""},{"id":436424742,"identity":"09a56071-d72c-412f-96b0-032c0f6cd64f","order_by":2,"name":"Rachel Warren","email":"","orcid":"","institution":"Mayo Clinic Rochester","correspondingAuthor":false,"prefix":"","firstName":"Rachel","middleName":"","lastName":"Warren","suffix":""},{"id":436424743,"identity":"b52e7295-2731-4c2b-ab9d-773d48763115","order_by":3,"name":"Joseph Knopp","email":"","orcid":"","institution":"Mayo clinic, rochester","correspondingAuthor":false,"prefix":"","firstName":"Joseph","middleName":"","lastName":"Knopp","suffix":""},{"id":436424744,"identity":"c92f8dcc-fe2c-42da-b88f-40fa4afc2e48","order_by":4,"name":"Toan Nguyen","email":"","orcid":"","institution":"Mayo clinic, rochester","correspondingAuthor":false,"prefix":"","firstName":"Toan","middleName":"","lastName":"Nguyen","suffix":""}],"badges":[],"createdAt":"2025-03-09 18:05:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6189965/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6189965/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41467-025-66690-z","type":"published","date":"2025-11-21T05:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":97770927,"identity":"3e4221e9-7aaf-455a-890c-97cb6ac1fe43","added_by":"auto","created_at":"2025-12-09 08:07:17","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":55011772,"visible":true,"origin":"","legend":"Article File","description":"","filename":"kyliepaper39reduced.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6189965/v1_covered_277f354f-ec7e-4d9e-813e-dc03563f9da8.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"\u003cp\u003eEpithelial-mesenchymal cell competition coordinates fate transitions across tissue compartments during lung development and fibrosis\u003c/p\u003e","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-6189965/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6189965/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Morphogenesis and cell state transitions must be coordinated in time and space to produce a functional tissue. 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