{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T18:18:56Z","timestamp":1792174736180,"version":"4.4.0"},"reference-count":123,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2023,10,16]],"date-time":"2023-10-16T00:00:00Z","timestamp":1697414400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["APP1156944"],"award-info":[{"award-number":["APP1156944"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Continuous replenishment of the corneal epithelium is pivotal for maintaining optical transparency and achieving optimal visual perception. This dynamic process is driven by limbal epithelial stem cells (LESCs) located at the junction between the cornea and conjunctiva, which is otherwise known as the limbus. In patients afflicted with diabetes, hyperglycemia-induced impairments in corneal epithelial regeneration results in persistent epithelial and other defects on the ocular surface, termed diabetic keratopathy (DK), which progressively diminish vision and quality of life. Reports of delayed corneal wound healing and the reduced expression of putative stem cell markers in diabetic relative to healthy eyes suggest that the pathogenesis of DK may be associated with the abnormal activity of LESCs. However, the precise role of these cells in diabetic corneal disease is poorly understood and yet to be comprehensively explored. Herein, we review existing literature highlighting aberrant LESC activity in diabetes, focusing on factors that influence their form and function, and emerging therapies to correct these defects. The consequences of malfunctioning or depleted LESC stocks in DK and limbal stem cell deficiency (LSCD) are also discussed. These insights could be exploited to identify novel targets for improving the management of ocular surface complications that manifest in patients with diabetes.<\/jats:p>","DOI":"10.3390\/cells12202458","type":"journal-article","created":{"date-parts":[[2023,10,16]],"date-time":"2023-10-16T01:31:22Z","timestamp":1697419882000},"page":"2458","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Limbal Epithelial Stem Cells in the Diabetic Cornea"],"prefix":"10.3390","volume":"12","author":[{"given":"Lamia","family":"Nureen","sequence":"first","affiliation":[{"name":"School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW 2052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nick","family":"Di Girolamo","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW 2052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"American Diabetes Association (2015). 2. Classification and Diagnosis of Diabetes. Diabetes Care, 38, S8\u2013S16.","DOI":"10.2337\/dc15-S005"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1038\/s41574-022-00690-7","article-title":"The burden and risks of emerging complications of diabetes mellitus","volume":"18","author":"Tomic","year":"2022","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_3","unstructured":"International Diabetes Federation (2021). IDF Diabetes Atlas, International Diabetes Federation. [10th ed.]."},{"key":"ref_4","unstructured":"Klein, R., and Klein, B.E.K. (2018). Chapter 21: Epidemiology of Ocular Functions and Diseases in Persons with Diabetes, National Institute of Diabetes and Digestive and Kidney Diseases (US)."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1580","DOI":"10.1016\/j.ophtha.2021.04.027","article-title":"Global Prevalence of Diabetic Retinopathy and Projection of Burden through 2045: Systematic Review and Meta-analysis","volume":"128","author":"Teo","year":"2021","journal-title":"Ophthalmology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.visres.2017.04.003","article-title":"The pathology associated with diabetic retinopathy","volume":"139","author":"Lechner","year":"2017","journal-title":"Vision. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"E2655","DOI":"10.1073\/pnas.1522014113","article-title":"Retinal neurodegeneration may precede microvascular changes characteristic of diabetic retinopathy in diabetes mellitus","volume":"113","author":"Sohn","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Vieira-Potter, V.J., Karamichos, D., and Lee, D.J. (2016). Ocular Complications of Diabetes and Therapeutic Approaches. Biomed. Res. Int., 2016.","DOI":"10.1155\/2016\/3801570"},{"key":"ref_9","first-page":"180","article-title":"Diabetic keratopathy","volume":"79","author":"Schultz","year":"1981","journal-title":"Trans. Am. Ophthalmol. Soc."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"53","DOI":"10.2147\/CIA.S190713","article-title":"Influence of diabetes mellitus on anterior segment of the eye","volume":"14","author":"Han","year":"2018","journal-title":"Clin. Interv. Aging"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e251","DOI":"10.1038\/nutd.2017.4","article-title":"A systematic review on the impact of diabetes mellitus on the ocular surface","volume":"7","author":"Shih","year":"2017","journal-title":"Nutr. Diabetes"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1586\/eop.10.44","article-title":"Comprehensive Review of the Effects of Diabetes on Ocular Health","volume":"5","author":"Skarbez","year":"2010","journal-title":"Expert. Rev. Ophthalmol."},{"key":"ref_13","first-page":"1531","article-title":"Evaluation of the corneal endothelium in patients with diabetes mellitus type I and II","volume":"25","author":"Szalai","year":"2010","journal-title":"Histol. Histopathol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1016\/j.survophthal.2020.02.005","article-title":"Diabetic keratopathy: Insights and challenges","volume":"65","author":"Priyadarsini","year":"2020","journal-title":"Surv. Ophthalmol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"108455","DOI":"10.1016\/j.exer.2021.108455","article-title":"Systemic diseases and the cornea","volume":"204","author":"Shah","year":"2021","journal-title":"Exp. Eye Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.visres.2017.03.002","article-title":"Diabetic complications in the cornea","volume":"139","author":"Ljubimov","year":"2017","journal-title":"Vision. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1111\/j.1442-9071.2010.02435.x","article-title":"New therapeutic approaches in the treatment of diabetic keratopathy: A review","volume":"39","author":"Abdelkader","year":"2011","journal-title":"Clin. Exp. Ophthalmol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"154402","DOI":"10.1016\/j.metabol.2020.154402","article-title":"Hyperglycemia-reduced NAD(+) biosynthesis impairs corneal epithelial wound healing in diabetic mice","volume":"114","author":"Li","year":"2021","journal-title":"Metabolism"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.2337\/db08-0997","article-title":"High glucose suppresses epidermal growth factor receptor\/phosphatidylinositol 3-kinase\/Akt signaling pathway and attenuates corneal epithelial wound healing","volume":"58","author":"Xu","year":"2009","journal-title":"Diabetes"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1076\/ceyr.27.4.197.16598","article-title":"Prolonged exposure to high glucose impaired cellular behavior of normal human corneal epithelial cells","volume":"27","author":"Fujita","year":"2003","journal-title":"Curr. Eye Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/S0014-4835(03)00111-8","article-title":"Human diabetic corneas preserve wound healing, basement membrane, integrin and MMP-10 differences from normal corneas in organ culture","volume":"77","author":"Kabosova","year":"2003","journal-title":"Exp. Eye Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1016\/j.ophtha.2009.01.002","article-title":"In vivo confocal microscopic findings of corneal wound healing after corneal epithelial debridement in diabetic vitrectomy","volume":"116","author":"Chen","year":"2009","journal-title":"Ophthalmology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1097\/ICO.0000000000000262","article-title":"Diabetes mellitus increases risk of unsuccessful graft preparation in Descemet membrane endothelial keratoplasty: A multicenter study","volume":"33","author":"Greiner","year":"2014","journal-title":"Cornea"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"329","DOI":"10.3109\/08820538.2014.959197","article-title":"Cataract surgery and its complications in diabetic patients","volume":"29","author":"Haddad","year":"2014","journal-title":"Semin. Ophthalmol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1097\/00003226-200204000-00002","article-title":"Laser-assisted in situ keratomileusis complications in diabetes mellitus","volume":"21","author":"Fraunfelder","year":"2002","journal-title":"Cornea"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1905","DOI":"10.2337\/dc08-0342","article-title":"Ocular associations of diabetes other than diabetic retinopathy","volume":"31","author":"Jeganathan","year":"2008","journal-title":"Diabetes Care"},{"key":"ref_27","unstructured":"GBD 2019 Blindness and Vision Impairment Collaborators, and Vision Loss Expert Group of the Global Burden of Disease Study (2021). Causes of blindness and vision impairment in 2020 and trends over 30 years, and prevalence of avoidable blindness in relation to VISION 2020: The Right to Sight: An analysis for the Global Burden of Disease Study. Lancet Glob. Health, 9, e144\u2013e160."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.preteyeres.2015.04.002","article-title":"Moving epithelia: Tracking the fate of mammalian limbal epithelial stem cells","volume":"48","year":"2015","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"12388","DOI":"10.1038\/ncomms12388","article-title":"Self-organized centripetal movement of corneal epithelium in the absence of external cues","volume":"7","author":"Lobo","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"26633","DOI":"10.1073\/pnas.1912260116","article-title":"Peripheral (not central) corneal epithelia contribute to the closure of an annular debridement injury","volume":"116","author":"Park","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"441","DOI":"10.5650\/jos.59.441","article-title":"Kinetic analysis of the rate of corneal wound healing in Otsuka long-evans Tokushima Fatty rats, a model of type 2 diabetes mellitus","volume":"59","author":"Nagai","year":"2010","journal-title":"J. Oleo Sci."},{"key":"ref_32","first-page":"1357","article-title":"Persistence of reduced expression of putative stem cell markers and slow wound healing in cultured diabetic limbal epithelial cells","volume":"21","author":"Kramerov","year":"2015","journal-title":"Mol. Vis."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"312401","DOI":"10.1155\/2014\/312401","article-title":"Alterations in the corneal nerve and stem\/progenitor cells in diabetes: Preventive effects of insulin-like growth factor-1 treatment","volume":"2014","author":"Ueno","year":"2014","journal-title":"Int. J. Endocrinol."},{"key":"ref_34","first-page":"2177","article-title":"Alterations of epithelial stem cell marker patterns in human diabetic corneas and effects of c-met gene therapy","volume":"17","author":"Saghizadeh","year":"2011","journal-title":"Mol. Vis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"101039","DOI":"10.1016\/j.preteyeres.2021.101039","article-title":"The impact of sensory neuropathy and inflammation on epithelial wound healing in diabetic corneas","volume":"89","author":"Yu","year":"2022","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.2337\/db19-0870","article-title":"Role of VIP and Sonic Hedgehog Signaling Pathways in Mediating Epithelial Wound Healing, Sensory Nerve Regeneration, and Their Defects in Diabetic Corneas","volume":"69","author":"Zhang","year":"2020","journal-title":"Diabetes"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2058","DOI":"10.1016\/j.ajpath.2012.08.029","article-title":"Reduced innervation and delayed re-innervation after epithelial wounding in type 2 diabetic Goto-Kakizaki rats","volume":"181","author":"Wang","year":"2012","journal-title":"Am. J. Pathol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"4344","DOI":"10.1167\/iovs.17-21506","article-title":"Mesenchymal Stem Cells Promote Diabetic Corneal Epithelial Wound Healing Through TSG-6-Dependent Stem Cell Activation and Macrophage Switch","volume":"58","author":"Di","year":"2017","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"57","DOI":"10.15283\/ijsc.2012.5.1.57","article-title":"Effect of stem cell therapy on induced diabetic keratopathy in albino rat","volume":"5","author":"Zickri","year":"2012","journal-title":"Int. J. Stem Cells"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/eye.1989.16","article-title":"The anatomy of the limbus","volume":"3","year":"1989","journal-title":"Eye"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1369\/jhc.2008.952390","article-title":"Distribution of label-retaining cells in the limbal epithelium of a mouse eye","volume":"57","author":"Zhao","year":"2009","journal-title":"J. Histochem. Cytochem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/0092-8674(89)90958-6","article-title":"Existence of slow-cycling limbal epithelial basal cells that can be preferentially stimulated to proliferate: Implications on epithelial stem cells","volume":"57","author":"Cotsarelis","year":"1989","journal-title":"Cell"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1093\/bmb\/ldr026","article-title":"Stem cells of the human cornea","volume":"100","year":"2011","journal-title":"Br. Med. Bull."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2867","DOI":"10.1242\/jcs.111.19.2867","article-title":"Strategies of epithelial repair: Modulation of stem cell and transit amplifying cell proliferation","volume":"111","author":"Lehrer","year":"1998","journal-title":"J. Cell Sci."},{"key":"ref_45","first-page":"1864","article-title":"Relative proliferative rates of limbal and corneal epithelia. Implications of corneal epithelial migration, circadian rhythm, and suprabasally located DNA-synthesizing keratinocytes","volume":"32","author":"Lavker","year":"1991","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1016\/j.stem.2021.04.003","article-title":"Discrete limbal epithelial stem cell populations mediate corneal homeostasis and wound healing","volume":"28","author":"Altshuler","year":"2021","journal-title":"Cell Stem Cell"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1016\/j.stem.2021.02.022","article-title":"Two-photon live imaging of single corneal stem cells reveals compartmentalized organization of the limbal niche","volume":"28","author":"Farrelly","year":"2021","journal-title":"Cell Stem Cell"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1016\/j.stem.2021.06.001","article-title":"\u201cEyeing\u201d corneal stem cell identity, dynamics, and compartmentalization","volume":"28","year":"2021","journal-title":"Cell Stem Cell"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"101981","DOI":"10.1016\/j.gde.2022.101981","article-title":"Corneal regeneration: Insights in epithelial stem cell heterogeneity and dynamics","volume":"77","author":"Lee","year":"2022","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/S1542-0124(12)70119-2","article-title":"The corneal epithelial stem cell niche","volume":"3","author":"Stepp","year":"2005","journal-title":"Ocul. Surf."},{"key":"ref_51","first-page":"155","article-title":"Limbal palisades of Vogt","volume":"80","author":"Goldberg","year":"1982","journal-title":"Trans. Am. Ophthalmol. Soc."},{"key":"ref_52","first-page":"721","article-title":"The limbal palisades of Vogt","volume":"89","author":"Townsend","year":"1991","journal-title":"Trans. Am. Ophthalmol. Soc."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1634\/stemcells.22-3-355","article-title":"Characterization of putative stem cell phenotype in human limbal epithelia","volume":"22","author":"Chen","year":"2004","journal-title":"Stem Cells"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1136\/bjo.2004.049742","article-title":"Limbal epithelial crypts: A novel anatomical structure and a putative limbal stem cell niche","volume":"89","author":"Dua","year":"2005","journal-title":"Br. J. Ophthalmol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1136\/bjo.2006.102640","article-title":"Morphological characteristics of the limbal epithelial crypt","volume":"91","author":"Shanmuganathan","year":"2007","journal-title":"Br. J. Ophthalmol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1126\/science.287.5457.1427","article-title":"Out of Eden: Stem cells and their niches","volume":"287","author":"Watt","year":"2000","journal-title":"Science"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1038\/nrm3620","article-title":"Role of the extracellular matrix in regulating stem cell fate","volume":"14","author":"Watt","year":"2013","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"107665","DOI":"10.1016\/j.exer.2019.05.005","article-title":"Inflammation, vascularization and goblet cell differences in LSCD: Validating animal models of corneal alkali burns","volume":"185","author":"Kethiri","year":"2019","journal-title":"Exp. Eye Res."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Sprogyte, L., Park, M., and Di Girolamo, N. (2023). Pathogenesis of Alkali Injury-Induced Limbal Stem Cell Deficiency: A Literature Survey of Animal Models. Cells, 12.","DOI":"10.3390\/cells12091294"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1016\/j.scr.2015.10.008","article-title":"Short-term uvb-irradiation leads to putative limbal stem cell damage and niche cell-mediated upregulation of macrophage recruiting cytokines","volume":"15","author":"Notara","year":"2015","journal-title":"Stem Cell Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1097\/ICO.0000000000001820","article-title":"Global Consensus on Definition, Classification, Diagnosis, and Staging of Limbal Stem Cell Deficiency","volume":"38","author":"Deng","year":"2019","journal-title":"Cornea"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Chen, D., Wang, L., Guo, X., Zhang, Z., Xu, X., Jin, Z., and Liang, Q. (2023). Evaluation of Limbal Stem Cells in Patients with Type 2 Diabetes: An In Vivo Confocal Microscopy Study. Cornea.","DOI":"10.1097\/ICO.0000000000003334"},{"key":"ref_63","first-page":"e54058","article-title":"Adenoviral Gene Therapy for Diabetic Keratopathy: Effects on Wound Healing and Stem Cell Marker Expression in Human Organ-cultured Corneas and Limbal Epithelial Cells","volume":"110","author":"Kramerov","year":"2016","journal-title":"J. Vis. Exp."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"8172","DOI":"10.1167\/iovs.13-13233","article-title":"Enhanced wound healing, kinase and stem cell marker expression in diabetic organ-cultured human corneas upon MMP-10 and cathepsin F gene silencing","volume":"54","author":"Saghizadeh","year":"2013","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.exer.2014.10.022","article-title":"Normalization of wound healing and stem cell marker patterns in organ-cultured human diabetic corneas by gene therapy of limbal cells","volume":"129","author":"Saghizadeh","year":"2014","journal-title":"Exp. Eye Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.jtos.2021.04.006","article-title":"Inducing dry eye disease using a custom engineered desiccation system: Impact on the ocular surface including keratin-14-positive limbal epithelial stem cells","volume":"21","author":"Zhang","year":"2021","journal-title":"Ocul. Surf."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Zhang, Z., Yang, L., Li, Y., Sun, D., Chen, R., Dou, S., Liu, T., Zhang, S., Zhou, Q., and Xie, L. (2023). Interference of sympathetic overactivation restores limbal stem\/progenitor cells function and accelerates corneal epithelial wound healing in diabetic mice. Biomed. Pharmacother., 161.","DOI":"10.1016\/j.biopha.2023.114523"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"3604","DOI":"10.1167\/iovs.04-1507","article-title":"Proteinase and growth factor alterations revealed by gene microarray analysis of human diabetic corneas","volume":"46","author":"Saghizadeh","year":"2005","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"102332","DOI":"10.1016\/j.nano.2020.102332","article-title":"Novel nanopolymer RNA therapeutics normalize human diabetic corneal wound healing and epithelial stem cells","volume":"32","author":"Kramerov","year":"2021","journal-title":"Nanomedicine"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"e2204134120","DOI":"10.1073\/pnas.2204134120","article-title":"Dry eye disease in mice activates adaptive corneal epithelial regeneration distinct from constitutive renewal in homeostasis","volume":"120","author":"Lin","year":"2023","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1943","DOI":"10.1007\/s00125-023-05960-1","article-title":"Reversal of dual epigenetic repression of non-canonical Wnt-5a normalises diabetic corneal epithelial wound healing and stem cells","volume":"66","author":"Shah","year":"2023","journal-title":"Diabetologia"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"835","DOI":"10.3109\/02713683.2013.780625","article-title":"Limbal dermoid epithelium shares phenotypic characteristics common to both hair epidermal and limbal epithelial stem cells","volume":"38","author":"Watson","year":"2013","journal-title":"Curr. Eye Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"101149","DOI":"10.1016\/j.preteyeres.2022.101149","article-title":"Non-canonical Wnt signaling in the eye","volume":"95","author":"Shah","year":"2022","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1007\/978-3-642-30406-4_19","article-title":"Stem cells and corneal epithelial maintenance: Insights from the mouse and other animal models","volume":"55","author":"Mort","year":"2012","journal-title":"Results Probl. Cell Differ."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1167\/iovs.11-8438","article-title":"Dependence of corneal stem\/progenitor cells on ocular surface innervation","volume":"53","author":"Ueno","year":"2012","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/j.jtos.2021.04.010","article-title":"Molecular identity of human limbal heterogeneity involved in corneal homeostasis and privilege","volume":"21","author":"Dou","year":"2021","journal-title":"Ocul. Surf."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"e2217795120","DOI":"10.1073\/pnas.2217795120","article-title":"Redefining the human corneal immune compartment using dynamic intravital imaging","volume":"120","author":"Downie","year":"2023","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Hargrave, A., Courson, J.A., Pham, V., Landry, P., Magadi, S., Shankar, P., Hanlon, S., Das, A., Rumbaut, R.E., and Smith, C.W. (2020). Corneal dysfunction precedes the onset of hyperglycemia in a mouse model of diet-induced obesity. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0238750"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1566","DOI":"10.1002\/stem.1942","article-title":"Ciliary neurotrophic factor promotes the activation of corneal epithelial stem\/progenitor cells and accelerates corneal epithelial wound healing","volume":"33","author":"Zhou","year":"2015","journal-title":"Stem Cells"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1038\/nrg1379","article-title":"MicroRNAs: Small RNAs with a big role in gene regulation","volume":"5","author":"He","year":"2004","journal-title":"Nat. Rev. Genet."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"5451","DOI":"10.1002\/jcp.27486","article-title":"An overview of microRNAs: Biology, functions, therapeutics, and analysis methods","volume":"234","author":"Saliminejad","year":"2019","journal-title":"J. Cell Physiol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1038\/nrm3838","article-title":"Regulation of microRNA biogenesis","volume":"15","author":"Ha","year":"2014","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Tribolet, L., Kerr, E., Cowled, C., Bean, A.G.D., Stewart, C.R., Dearnley, M., and Farr, R.J. (2020). MicroRNA Biomarkers for Infectious Diseases: From Basic Research to Biosensing. Front. Microbiol., 11.","DOI":"10.3389\/fmicb.2020.01197"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"e398","DOI":"10.1038\/cddis.2012.134","article-title":"MicroRNA-10b pleiotropically regulates invasion, angiogenicity and apoptosis of tumor cells resembling mesenchymal subtype of glioblastoma multiforme","volume":"3","author":"Lin","year":"2012","journal-title":"Cell Death Dis."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1002\/emmm.201100209","article-title":"MicroRNA dysregulation in cancer: Diagnostics, monitoring and therapeutics. A comprehensive review","volume":"4","author":"Iorio","year":"2012","journal-title":"EMBO Mol. Med."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1161\/ATVBAHA.112.300144","article-title":"MicroRNAs in metabolic disease","volume":"33","author":"Goedeke","year":"2013","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1016\/j.tig.2022.02.006","article-title":"Emerging concepts of miRNA therapeutics: From cells to clinic","volume":"38","author":"Diener","year":"2022","journal-title":"Trends Genet."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Lee, S.K., Teng, Y., Wong, H.K., Ng, T.K., Huang, L., Lei, P., Choy, K.W., Liu, Y., Zhang, M., and Lam, D.S. (2011). MicroRNA-145 regulates human corneal epithelial differentiation. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0021249"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"4133","DOI":"10.3892\/mmr.2017.7083","article-title":"MicroRNA-494 inhibits nerve growth factor-induced cell proliferation by targeting cyclin D1 in human corneal epithelial cells","volume":"16","author":"Wu","year":"2017","journal-title":"Mol. Med. Rep."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"3673","DOI":"10.1167\/iovs.15-16467","article-title":"MicroRNA Expression Profile and the Role of miR-204 in Corneal Wound Healing","volume":"56","author":"An","year":"2015","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"11692","DOI":"10.1002\/jcp.27837","article-title":"Inhibition of microRNA-129-5p expression ameliorates ultraviolet ray-induced corneal epithelial cell injury via upregulation of EGFR","volume":"234","author":"Yang","year":"2019","journal-title":"J. Cell Physiol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1252557","DOI":"10.1155\/2022\/1252557","article-title":"Umbilical Cord Mesenchymal Stem Cell-Derived Small Extracellular Vesicles Deliver miR-21 to Promote Corneal Epithelial Wound Healing through PTEN\/PI3K\/Akt Pathway","volume":"2022","author":"Liu","year":"2022","journal-title":"Stem Cells Int."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"7418","DOI":"10.1038\/s41598-020-64273-0","article-title":"MicroRNA Profiling of Highly Enriched Human Corneal Epithelial Stem Cells by Small RNA Sequencing","volume":"10","author":"Kalaimani","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1186\/s40662-020-00202-6","article-title":"MicroRNA-184 negatively regulates corneal epithelial wound healing via targeting CDC25A, CARM1, and LASP1","volume":"7","author":"Cao","year":"2020","journal-title":"Eye Vis."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"6167","DOI":"10.1167\/iovs.12-11577","article-title":"Inhibition of miR-205 impairs the wound-healing process in human corneal epithelial cells by targeting KIR4.1 (KCNJ10)","volume":"54","author":"Lin","year":"2013","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Qian, J., Yu, J., Zhu, X., and Liang, S. (2022). MiR-335 promotes corneal neovascularization by Targeting EGFR. BMC Ophthalmol., 22.","DOI":"10.1186\/s12886-022-02481-0"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1398","DOI":"10.1167\/iovs.15-17417","article-title":"Down-Regulation of MicroRNA-184 Is Associated with Corneal Neovascularization","volume":"57","author":"Zong","year":"2016","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1167\/iovs.63.1.41","article-title":"MiR-223-3p Regulates Autophagy and Inflammation by Targeting ATG16L1 in Fusarium solani-Induced Keratitis","volume":"63","author":"Tang","year":"2022","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"729","DOI":"10.4049\/immunohorizons.2000091","article-title":"The miR-183\/96\/182 Cluster Regulates the Functions of Corneal Resident Macrophages","volume":"4","author":"Coku","year":"2020","journal-title":"Immunohorizons"},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Mun, J., Tam, C., Chan, G., Kim, J.H., Evans, D., and Fleiszig, S. (2013). MicroRNA-762 is upregulated in human corneal epithelial cells in response to tear fluid and Pseudomonas aeruginosa antigens and negatively regulates the expression of host defense genes encoding RNase7 and ST2. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0057850"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1007\/s10142-014-0417-9","article-title":"Signature microRNAs in human cornea limbal epithelium","volume":"15","author":"Teng","year":"2015","journal-title":"Funct. Integr. Genomics"},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Karali, M., Peluso, I., Gennarino, V.A., Bilio, M., Verde, R., Lago, G., Doll\u00e9, P., and Banfi, S. (2010). miRNeye: A microRNA expression atlas of the mouse eye. BMC Genom., 11.","DOI":"10.1186\/1471-2164-11-715"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.preteyeres.2008.11.003","article-title":"microRNA expression in the eyes and their significance in relation to functions","volume":"28","author":"Xu","year":"2009","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1083\/jcb.201604032","article-title":"MicroRNAs-103\/107 coordinately regulate macropinocytosis and autophagy","volume":"215","author":"Park","year":"2016","journal-title":"J. Cell Biol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1167\/iovs.64.12.42","article-title":"Extracellular Vesicle MicroRNAs from Corneal Stromal Stem Cell Enhance Stemness of Limbal Epithelial Stem Cells by Targeting the Notch Pathway","volume":"64","author":"Wang","year":"2023","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Funari, V.A., Winkler, M., Brown, J., Dimitrijevich, S.D., Ljubimov, A.V., and Saghizadeh, M. (2013). Differentially expressed wound healing-related microRNAs in the human diabetic cornea. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0084425"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"3448","DOI":"10.1038\/s41598-017-03449-7","article-title":"Genome-wide analysis suggests a differential microRNA signature associated with normal and diabetic human corneal limbus","volume":"7","author":"Kulkarni","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1152\/physiolgenomics.00160.2010","article-title":"MiRNA in innate immune responses: Novel players in wound inflammation","volume":"43","author":"Roy","year":"2011","journal-title":"Physiol. Genom."},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Winkler, M.A., Dib, C., Ljubimov, A.V., and Saghizadeh, M. (2014). Targeting miR-146a to treat delayed wound healing in human diabetic organ-cultured corneas. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0114692"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.jtos.2022.06.001","article-title":"Regulatory role of miR-146a in corneal epithelial wound healing via its inflammatory targets in human diabetic cornea","volume":"25","author":"Poe","year":"2022","journal-title":"Ocul. Surf."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1739","DOI":"10.3892\/ijo.2017.3947","article-title":"MicroRNA-10b mediates TGF-\u03b21-regulated glioblastoma proliferation, migration and epithelial-mesenchymal transition","volume":"50","author":"Ma","year":"2017","journal-title":"Int. J. Oncol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.3892\/mmr.2013.1615","article-title":"MicroRNA-10b promotes the migration of mouse bone marrow-derived mesenchymal stem cells and downregulates the expression of E-cadherin","volume":"8","author":"Zhang","year":"2013","journal-title":"Mol. Med. Rep."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"337","DOI":"10.2337\/dc15-1111","article-title":"A Type 1 Diabetes Genetic Risk Score Can Aid Discrimination Between Type 1 and Type 2 Diabetes in Young Adults","volume":"39","author":"Oram","year":"2016","journal-title":"Diabetes Care"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"6478","DOI":"10.1126\/science.aau6977","article-title":"The biology, function, and biomedical applications of exosomes","volume":"367","author":"Kalluri","year":"2020","journal-title":"Science"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"108794","DOI":"10.1016\/j.exer.2021.108794","article-title":"Plasma exosomal proteomic studies of corneal epithelial injury in diabetic and non-diabetic group","volume":"212","author":"Chen","year":"2021","journal-title":"Exp. Eye Res."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"15173","DOI":"10.1038\/s41598-018-33169-5","article-title":"Exosomes from normal and diabetic human corneolimbal keratocytes differentially regulate migration, proliferation and marker expression of limbal epithelial cells","volume":"8","author":"Leszczynska","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"167","DOI":"10.21037\/atm-22-6644","article-title":"Effect of PKH-26-labeled exosomes derived from bone marrow mesenchymal stem cells on corneal epithelium regeneration in diabetic mice","volume":"11","author":"Wu","year":"2023","journal-title":"Ann. Transl. Med."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"109484","DOI":"10.1016\/j.exer.2023.109484","article-title":"Extracellular vesicles derived from mouse adipose-derived mesenchymal stem cells promote diabetic corneal epithelial wound healing through NGF\/TrkA pathway activation involving dendritic cells","volume":"231","author":"Wang","year":"2023","journal-title":"Exp. Eye Res."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.exer.2007.09.003","article-title":"Nerve growth factor and its receptor TrkA serve as potential markers for human corneal epithelial progenitor cells","volume":"86","author":"Qi","year":"2008","journal-title":"Exp. Eye Res."},{"key":"ref_120","doi-asserted-by":"crossref","unstructured":"Singer, M., O\u2019Brien, P., and Mein, L. (2023). Corneal sensitivity is inversely correlated with severity of diabetic retinopathy in a predominantly underrepresented population. Am. J. Ophthalmol.","DOI":"10.1016\/j.ajo.2023.08.010"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1097\/ICB.0000000000000832","article-title":"Neurotrophic keratopathy after retinal detachment surgery combined with endolaser photocoagulation","volume":"15","author":"Kurt","year":"2021","journal-title":"Retin. Cases Brief. Rep."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1038\/sj.eye.6700004","article-title":"Dilated pupils and loss of accommodation following diode panretinal photocoagulation with sub-tenon local anaesthetic in four cases","volume":"16","author":"Patel","year":"2002","journal-title":"Eye"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1097\/IIO.0000000000000423","article-title":"Complications in Retinal Surgery: A Review of Corneal Changes Following Vitreoretinal Procedures","volume":"62","author":"Levine","year":"2022","journal-title":"Int. Ophthalmol. Clin."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/20\/2458\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:07:21Z","timestamp":1760130441000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/20\/2458"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,16]]},"references-count":123,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2023,10]]}},"alternative-id":["cells12202458"],"URL":"https:\/\/doi.org\/10.3390\/cells12202458","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,16]]}}}