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Multiple lung stem cell populations have been implicated in the pathogenesis of lung fibrosis, and more progenitor cell populations continue to be discovered and characterized. In this review, we summarize the functions and differentiation pathways of various cells that constitute the lung epithelium. We then focus on two subpopulations of KRT5+ or KRT8+ transitional cells that both originate from alveolar type II cells but experience different cell fates and play important roles in lung regeneration and repair. We address these transitional cells\u2019 potential role in fibrosis and bronchiolization of the alveoli, as they are correlated to aggregate near fibrotic foci in both in vivo models and in human fibrotic lung disease. We conclude by discussing recent advances in cell and organoid therapy to replace aberrant transitional cells and treat lung fibrosis. Namely, we focus on strategies to minimize immune clearance of transplanted cells and to optimize engraftment by transplanting cells precultured as three-dimensional organoids.<\/jats:p>","DOI":"10.1165\/rcmb.2024-0372tr","type":"journal-article","created":{"date-parts":[[2024,12,6]],"date-time":"2024-12-06T16:47:58Z","timestamp":1733503678000},"page":"472-483","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":17,"title":["From Epithelium to Therapy: Transitional Cells in Lung Fibrosis"],"prefix":"10.1093","volume":"72","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2367-7623","authenticated-orcid":false,"given":"Sarah Y.","family":"Shin","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology and"},{"name":"Department of Diagnostic and Biomedical Sciences, School of Dentistry, UTHealth Houston, Houston, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jichao","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Cincinnati Children\u2019s Hospital, Cincinnati, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irit","family":"Milman Krentsis","sequence":"additional","affiliation":[{"name":"Department of Stem Cell Transplantation and Cell Therapy, MD Anderson Cancer Center, Houston, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yair","family":"Reisner","sequence":"additional","affiliation":[{"name":"Department of Stem Cell Transplantation and Cell Therapy, MD Anderson Cancer Center, Houston, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodeo","family":"Abrencillo","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, McGovern Medical School, Houston, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rahat","family":"Hussain","sequence":"additional","affiliation":[{"name":"Center for Advanced Cardiopulmonary Therapies and Transplantation, University of Texas Health Science Center at Houston, Houston, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Diagnostic and Biomedical Sciences, School of Dentistry, UTHealth Houston, Houston, Texas"},{"name":"Department of Bioengineering, George R. Brown School of Engineering, Rice University, Houston, Texas; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4753-9823","authenticated-orcid":false,"given":"Harry","family":"Karmouty-Quintana","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology and"},{"name":"Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, McGovern Medical School, Houston, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,5,1]]},"reference":[{"key":"2026012204172943100_bib1","first-page":"110","article-title":"Idiopathic pulmonary fibrosis: epidemiology, natural history, phenotypes","volume":"6","author":"Sauleda","year":"2018","journal-title":"Med Sci (Basel)"},{"key":"2026012204172943100_bib2","doi-asserted-by":"crossref","first-page":"2071","DOI":"10.1056\/NEJMoa1402584","article-title":"Efficacy and safety of 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