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Here we demonstrate that glandular Sox9-expressing progenitors capable of SAE repair decline with age in mice. Notably, Sox9-lineage glandular progenitors produced basal and ciliated cells in the SAE, but failed to produce secretory cells. Lef1 was required for glandular Sox9 lineage contribution to SAE repair, and its deletion significantly reduced proliferation following injury. By contrast, in vivo deletion of Sox9 enhanced proliferation of progenitors in both the SAE and SMG shortly following injury, but these progenitors failed to proliferate in vitro in the absence of Sox9, similar to that previously shown for Lef1 deletion. In cystic fibrosis ferret airways, Sox9 expression inversely correlated with Ki67 proliferative marker expression in SMG and the SAE. Using in vitro and ex vivo models, we demonstrate that Sox9 is extinguished as glandular progenitors exit ducts and proliferate on the airway surface and that Sox9 is required for migration and proper differentiation of SMG, but not surface airway, progenitors. We propose a model whereby Wnt\/Lef1 and Sox9 signals differentially regulate the proliferative and migratory behavior of glandular progenitors, respectively.<\/jats:p>","DOI":"10.1093\/stmcls\/sxac038","type":"journal-article","created":{"date-parts":[[2022,5,31]],"date-time":"2022-05-31T20:09:48Z","timestamp":1654027788000},"page":"778-790","source":"Crossref","is-referenced-by-count":15,"title":["Sox9 and Lef1 Regulate the Fate and Behavior of Airway Glandular Progenitors in Response to Injury"],"prefix":"10.1093","volume":"40","author":[{"given":"Vitaly","family":"Ievlev","sequence":"first","affiliation":[{"name":"Department of Anatomy and Cell Biology, University of Iowa , Iowa City, IA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chandler C","family":"Jensen-Cody","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, University of Iowa , Iowa City, IA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas J","family":"Lynch","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, University of Iowa , Iowa City, IA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert C","family":"Pai","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, University of Iowa Hospitals and Clinics , Iowa City, IA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soo","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, University of Iowa , Iowa City, IA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weam","family":"Shahin","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, University of Iowa , Iowa City, IA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, University of Iowa College of Public Health , Iowa City, IA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kalpaj R","family":"Parekh","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, University of Iowa Hospitals and Clinics , Iowa City, IA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2389-9277","authenticated-orcid":false,"given":"John F","family":"Engelhardt","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, University of Iowa , Iowa City, IA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,5,27]]},"reference":[{"issue":"31","key":"2022082514093664600_CIT0001","doi-asserted-by":"crossref","first-page":"12771","DOI":"10.1073\/pnas.0906850106","article-title":"Basal cells as stem cells of the mouse trachea and human airway epithelium","volume":"106","author":"Rock","year":"2009","journal-title":"Proc Natl Acad Sci USA"},{"issue":"5","key":"2022082514093664600_CIT0002","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1016\/j.stem.2018.03.017","article-title":"Submucosal gland myoepithelial cells are reserve stem cells that can regenerate mouse tracheal epithelium","volume":"22","author":"Lynch","year":"2018","journal-title":"Cell Stem Cell"},{"issue":"5","key":"2022082514093664600_CIT0003","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1016\/j.stem.2018.03.018","article-title":"Myoepithelial cells of submucosal glands can function as reserve stem cells to regenerate airways after injury","volume":"22","author":"Tata","year":"2018","journal-title":"Cell Stem Cell"},{"key":"2022082514093664600_CIT0004","first-page":"70","volume-title":"Stem cells of submucosal glands: their function as tissue stem cells and a reserve population for airway repair","author":"Tata","year":"2021"},{"issue":"21","key":"2022082514093664600_CIT0005","doi-asserted-by":"crossref","first-page":"2813","DOI":"10.1101\/gad.1017802","article-title":"The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6","volume":"16","author":"Akiyama","year":"2002","journal-title":"Genes Dev"},{"issue":"1","key":"2022082514093664600_CIT0006","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1095\/biolreprod.105.045930","article-title":"Homozygous inactivation of Sox9 causes complete XY sex reversal in 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