{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T14:53:44Z","timestamp":1784213624705,"version":"3.55.0"},"reference-count":38,"publisher":"National Academy of Sciences","issue":"48","license":[{"start":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T00:00:00Z","timestamp":1764028800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000055","name":"NIDCD","doi-asserted-by":"crossref","award":["DC4336"],"award-info":[{"award-number":["DC4336"]}],"id":[{"id":"10.13039\/100000055","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000055","name":"NIDCD","doi-asserted-by":"crossref","award":["DC20734"],"award-info":[{"award-number":["DC20734"]}],"id":[{"id":"10.13039\/100000055","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000057","name":"NIGMS","doi-asserted-by":"crossref","award":["GM102756"],"award-info":[{"award-number":["GM102756"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,12,2]]},"abstract":"<jats:p>\n                    Identifying progenitor cells in laryngeal and vocal fold (VF) mucosa is essential for advancing stem cell\u2013based therapies for VF diseases. In this study, we used\n                    <jats:italic toggle=\"yes\">Lrig1<\/jats:italic>\n                    (leucine-rich repeats and immunoglobulin-like domains 1) gene to label tissue-resident stem cells within laryngeal and VF mucosa, aiming to investigate cellular networks underlying VF homeostasis and regeneration.\n                    <jats:italic toggle=\"yes\">Lrig1<\/jats:italic>\n                    <jats:sup>+<\/jats:sup>\n                    cells exhibited hallmark features of quiescent stem cells\u2014including slow cycling, long-term persistence, and differentiation potential\u2014and contributed to sustained VF regeneration and repair after naphthalene injury. By one week post injury\n                    <jats:italic toggle=\"yes\">Lrig1<\/jats:italic>\n                    <jats:sup>+<\/jats:sup>\n                    progeny restored the damaged VF epithelium. Transcriptionally, these cells suppressed cell type specific genes and proliferation while activating programs related to RNA metabolism, epigenetic regulation, and protein ubiquitination, consistent with quiescence and readiness for activation.\n                    <jats:italic toggle=\"yes\">Lrig1<\/jats:italic>\n                    <jats:sup>+<\/jats:sup>\n                    cells were enriched in basal, parabasal, and immature secretory populations within surface epithelium and submucosal glands, residing in niches characterized by transcriptional flexibility and spatial shielding from direct stress\u2014features that likely prevent premature or chronic mobilization. Notably, analogous LRIG1 expressing cells were identified in human laryngeal and VF tissues, highlighting the translational relevance of our findings. To explore regulation of\n                    <jats:italic toggle=\"yes\">Lrig1<\/jats:italic>\n                    <jats:sup>+<\/jats:sup>\n                    cell quiescence, we conditionally deleted\n                    <jats:italic toggle=\"yes\">Notch1,<\/jats:italic>\n                    which led to epithelial hyperplasia, expansion of secretory populations, and mucus hyperproduction. In summary,\n                    <jats:italic toggle=\"yes\">Lrig1<\/jats:italic>\n                    marks a conserved, quiescent stem cell population in the larynx and VFs that supports long-term tissue homeostasis and repair, with quiescence maintained via\n                    <jats:italic toggle=\"yes\">Notch1<\/jats:italic>\n                    signaling.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2513590122","type":"journal-article","created":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T19:02:44Z","timestamp":1764097364000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":4,"title":["<i>Lrig1<\/i>\n                    -expressing quiescent stem cells maintain vocal fold mucosal homeostasis via\n                    <i>Notch<\/i>\n                    signaling"],"prefix":"10.1073","volume":"122","author":[{"given":"Vlasta","family":"Lungova","sequence":"first","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery, University of Wisconsin Madison","place":["Madison"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica M.","family":"Fernandez","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery, University of Wisconsin Madison","place":["Madison"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3919-7993","authenticated-orcid":false,"given":"Yujia","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Medical Informatics, University of Wisconsin Madison","place":["Madison"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Kendziorski","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Medical Informatics, University of Wisconsin Madison","place":["Madison"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9046-4356","authenticated-orcid":false,"given":"Susan L.","family":"Thibeault","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery, University of Wisconsin Madison","place":["Madison"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,11,25]]},"reference":[{"key":"e_1_3_4_1_2","first-page":"641","article-title":"Spatiotemporal analysis of normal and pathological human vocal fold vibrations","volume":"33","author":"Krausert C. 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Lungova J. M. Fernandez Y. Cai C. Kendzioski S. L. Thibeault Lrig1-expressing quiescent stem cells maintain vocal fold mucosal homeostasis via Notch signaling. Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE298629. Deposited 30 May 2025."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2513590122","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T19:02:51Z","timestamp":1764097371000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2513590122"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,25]]},"references-count":38,"journal-issue":{"issue":"48","published-print":{"date-parts":[[2025,12,2]]}},"alternative-id":["10.1073\/pnas.2513590122"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2513590122","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,25]]},"assertion":[{"value":"2025-05-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-13","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-25","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2513590122"}}