{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:42:25Z","timestamp":1785433345758,"version":"3.56.0"},"posted":{"date-parts":[[2026,3,5]]},"group-title":"Cell Biology","reference-count":48,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T00:00:00Z","timestamp":1772668800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["5R00HL127267"],"award-info":[{"award-number":["5R00HL127267"]}],"id":[{"id":"https:\/\/ror.org\/012pb6c26","id-type":"ROR","asserted-by":"publisher"}]},{"award":["1R01HL171056"],"award-info":[{"award-number":["1R01HL171056"]}],"id":[{"id":"https:\/\/ror.org\/012pb6c26","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,5]]},"abstract":"<jats:title>Summary<\/jats:title>\n                <jats:p>Physical forces shape cell behavior, yet how they integrate with signaling to control fate and disease remains unclear. The alveolar epithelium is patterned by FGF signaling and mechanical stretch, but how these cues specify AT1 and AT2 cells is poorly understood. Here we show that cell membrane tension (CMT) is a conserved regulator of epithelial fate in mouse and human lungs. CMT drops before differentiation and is spatially patterned, defining where bipotent progenitors acquire AT1 or AT2 identity. Lower CMT enhances FGFR2 endocytosis and ERK signaling to drive AT2 differentiation and permits architectural remodeling that enables stretch-mediated YAP\/TAZ nuclear entry for AT1 maturation. \u03b2-catenin elevates CMT cell-intrinsically independent of its role in canonical WNT transcription, while embedding, osmotic compression, or fibroblast wrapping elevate CMT extrinsically. Combined intrinsic and extrinsic tension traps alveolar epithelial cells in a KRT8\u207a transitional state seen in fibrotic lungs. Membrane tension thus integrates physical and molecular cues linking morphogenesis to fibrosis.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Graphical Abstract<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"708749v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>In Brief<\/jats:title>\n                  <jats:p>We identify a conserved drop in cell membrane tension (CMT) that gates epithelial fate transitions across mouse and human lungs. In bipotent progenitors, reduced CMT promotes Alveolar Type 2 (AT2) fate via FGFR2 endocytosis and ERK signaling, as well as Alveolar Type 1 (AT1) fate by enabling architectural remodeling required for YAP\/TAZ nuclear entry. We further show that intrinsic \u03b2-catenin and extrinsic confinement cues, including mesenchymal contact, converge to elevate CMT, restricting differentiation and\u2014in adult AT2s\u2014inducing a KRT8\u207a transitional state associated with fibrosis.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Highlights<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>Cell membrane tension drops before differentiation and is required for AT1 and AT2 fate acquisition.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Reduced tension enhances FGFR2 endocytosis and ERK signaling to drive AT2 specification.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Reduced tension permits architectural remodeling and YAP\/TAZ nuclear entry required for AT1 maturation.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Intrinsic \u03b2-catenin and extrinsic confinement elevate CMT to restrict differentiation and together strongly induce a KRT8\u207a transitional state associated with fibrosis.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.64898\/2026.03.04.708749","type":"posted-content","created":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T14:35:26Z","timestamp":1772721326000},"source":"Crossref","is-referenced-by-count":0,"title":["Membrane Tension Integrates Physical and Signaling Cues to Gate Cell Fate Transitions"],"prefix":"10.64898","author":[{"given":"Gibran","family":"Ali","sequence":"first","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Gibbard","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Ghelfi","sequence":"additional","affiliation":[{"name":"Molecular and Integrative Physiological Sciences Program, Harvard T.H. Chan School of Public Health, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron","family":"Olson","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junming","family":"Cai","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aidan","family":"Balagtas","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isaiah","family":"Klein","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Maccoux","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yulong","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Mechanical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiro","family":"Miura","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Mechanical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Glass","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Washington, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Munemasa","family":"Mori","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4769-1518","authenticated-orcid":false,"given":"Douglas G","family":"Brownfield","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA"},{"name":"Molecular and Integrative Physiological Sciences Program, Harvard T.H. 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