{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:28:29Z","timestamp":1760059709514,"version":"build-2065373602"},"reference-count":21,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T00:00:00Z","timestamp":1751414400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Gelbert Foundation","award":["F02-10354"],"award-info":[{"award-number":["F02-10354"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>We previously showed that selective suppression of CD44 in the corneal epithelium leads to structural abnormalities in the mouse cornea. Our comparative studies of young and aged ocular biopsies revealed that CD44 expression is downregulated in aged corneas, while leucine-rich repeats and immunoglobulin-like domain 1 (Lrig1+) stem cells remain preserved in the peripheral limbus. These findings suggest an age-related shift in the corneal stem cell compartmentalization, characterized by impaired CD44 expression in the central cornea and preservation of Lrig1+ stem cells in the limbus, which become the main stem cells in the senescent cornea. To investigate this further, we performed topical tamoxifen-inducible, diphtheria toxin-mediated ablation of Lrig1+ stem cells in mouse corneas. We then assessed both activated and non-activated beta-catenin expression in wild-type (WT) and CD44 knockout (CD44KO) mice, given that CD44 modulates the Wingless-related integration site (Wnt) pathway. Our results indicate that two distinct stem cell populations operate in the mouse cornea: Lrig1-derived stem cells and Wnt-activity\/CD44-dependent stem cells. The Lrig1-derived cells act as a reservoir of quiescent stem cells that regenerate the cornea upon injury, whereas under homeostatic conditions, the Wnt-activity\/CD44-dependent stem cells are primarily responsible for corneal renewal. In the aged cornea, the loss of CD44 expression leads to reduced Wnt signaling, making the tissue increasingly dependent on Lrig1+ stem cells for regeneration. In mice, Lrig1+ stem cells are capable of sustaining permanent corneal renewal, even in the absence of CD44.<\/jats:p>","DOI":"10.3390\/ijms26136383","type":"journal-article","created":{"date-parts":[[2025,7,3]],"date-time":"2025-07-03T04:07:17Z","timestamp":1751515637000},"page":"6383","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Identification of Two Distinct Stem Cell Clusters, Lrig1-Derived and Wnt\/CD44-Dependent, in Corneal Epithelium"],"prefix":"10.3390","volume":"26","author":[{"given":"Laurent","family":"Barnes","sequence":"first","affiliation":[{"name":"Department of Dermatology, University Hospital of Geneva, CH-1205 Geneva, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6941-5552","authenticated-orcid":false,"given":"Evangelia","family":"Konstantinou","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Geneva, CH-1206 Geneva, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6668-2337","authenticated-orcid":false,"given":"Jean-Hilaire","family":"Saurat","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Toxicology, University of Geneva, CH-1206 Geneva, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandre","family":"Moulin","sequence":"additional","affiliation":[{"name":"Jules-Gonin Eye Hospital, Lausanne University, CH-1004 Lausanne, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4957-549X","authenticated-orcid":false,"given":"G\u00fcrkan","family":"Kaya","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University Hospital of Geneva, CH-1205 Geneva, Switzerland"},{"name":"Department of Medicine, University of Geneva, CH-1206 Geneva, Switzerland"},{"name":"Department of Clinical Pathology, University Hospital of Geneva, CH-1205 Geneva, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1101\/gad.11.8.996","article-title":"Selective suppression of CD44 in keratinocytes of mice bearing an antisense CD44 transgene driven by a tissue-specific promoter disrupts. hyaluronate metabolism in the skin and impairs keratinocyte proliferation","volume":"11","author":"Kaya","year":"1997","journal-title":"Genes Dev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1159\/000107621","article-title":"Dermatoporosis: A chronic cutaneous insufficiency\/fragility syndrome-Clinicopathological features, mechanisms, prevention and potential treatments","volume":"215","author":"Kaya","year":"2007","journal-title":"Dermatology"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Barnes, L., Saurat, J.H., and Kaya, G. 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