{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:02:39Z","timestamp":1790740959174,"version":"4.1.0"},"reference-count":167,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2024,2,25]],"date-time":"2024-02-25T00:00:00Z","timestamp":1708819200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>The corneal epithelium, comprising three layers of cells, represents the outermost portion of the eye and functions as a vital protective barrier while concurrently serving as a critical refractive structure. Maintaining its homeostasis involves a complex regenerative process facilitated by the functions of the lacrimal gland, tear film, and corneal nerves. Crucially, limbal epithelial stem cells located in the limbus (transitional zone between the cornea and the conjunctiva) are instrumental for the corneal epithelium integrity by replenishing and renewing cells. Re-epithelialization failure results in persistent defects, often associated with various ocular conditions including diabetic keratopathy. The insulin-like growth factor (IGF) system is a sophisticated network of insulin and other proteins essential for numerous physiological processes. This review examines its role in maintaining the corneal epithelium homeostasis, with a special focus on the interplay with corneal limbal stem cells and the potential therapeutic applications of the system components.<\/jats:p>","DOI":"10.3390\/biology13030144","type":"journal-article","created":{"date-parts":[[2024,2,26]],"date-time":"2024-02-26T03:34:04Z","timestamp":1708918444000},"page":"144","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["The Role of Insulin-like Growth Factor (IGF) System in the Corneal Epithelium Homeostasis\u2014From Limbal Epithelial Stem Cells to Therapeutic Applications"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0545-9764","authenticated-orcid":false,"given":"Ma\u0142gorzata","family":"Woronkowicz","sequence":"first","affiliation":[{"name":"NDDH, Royal Devon University Healthcare NHS Foundation Trust, Barnstaple EX31 4JB, UK"},{"name":"Moorfields Eye Hospital NHS Foundation Trust, 162 City Road, London EC1V 2PD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3590-0856","authenticated-orcid":false,"given":"Harry","family":"Roberts","sequence":"additional","affiliation":[{"name":"West of England Eye Unit, Royal Devon University Healthcare NHS Foundation Trust, Exeter EX2 5DW, UK"},{"name":"University of Exeter Medical School, Exeter EX1 2HZ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5794-9346","authenticated-orcid":false,"given":"Piotr","family":"Skopi\u0144ski","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, SPKSO Ophthalmic University Hospital, Medical University of Warsaw, 00-576 Warsaw, Poland"},{"name":"Department of Histology and Embryology, Medical University of Warsaw, 02-004 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,25]]},"reference":[{"key":"ref_1","first-page":"163","article-title":"Persistent Corneal Epithelial Defects: A Review Article","volume":"8","author":"Vaidyanathan","year":"2019","journal-title":"Med. Hypothesis Discov. Innov. Ophthalmol. J."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Tarvestad-Laise, K.E., and Ceresa, B.P. (2023). Modulating Growth Factor Receptor Signaling to Promote Corneal Epithelial Homeostasis. Cells, 12.","DOI":"10.3390\/cells12232730"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Stuard, W.L., Titone, R., and Robertson, D.M. (2022). IGFBP-3 Functions as a Molecular Switch That Mediates Mitochondrial and Metabolic Homeostasis. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol., 36.","DOI":"10.1096\/fj.202100710RR"},{"key":"ref_4","first-page":"1442","article-title":"The X, Y, Z Hypothesis of Corneal Epithelial Maintenance","volume":"24","author":"Thoft","year":"1983","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1038\/nature07406","article-title":"Oligopotent Stem Cells Are Distributed throughout the Mammalian Ocular Surface","volume":"456","author":"Majo","year":"2008","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"5279","DOI":"10.1167\/iovs.07-1260","article-title":"Acute Wound Healing in the Human Central Corneal Epithelium Appears to Be Independent of Limbal Stem Cell Influence","volume":"49","author":"Chang","year":"2008","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/j.jtos.2014.12.005","article-title":"Novel Therapy to Treat Corneal Epithelial Defects: A Hypothesis with Growth Hormone","volume":"13","author":"Wirostko","year":"2015","journal-title":"Ocul. Surf."},{"key":"ref_8","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_9","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_10","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1136\/bjo.28.1.26","article-title":"A Study of Epithelial Regeneration in the Living Eye","volume":"28","author":"Mann","year":"1944","journal-title":"Br. J. Ophthalmol."},{"key":"ref_11","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_12","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_13","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_14","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_15","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_16","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_17","first-page":"155","article-title":"Limbal Palisades of Vogt","volume":"80","author":"Goldberg","year":"1982","journal-title":"Trans. Am. Ophthalmol. Soc."},{"key":"ref_18","first-page":"721","article-title":"The Limbal Palisades of Vogt","volume":"89","author":"Townsend","year":"1991","journal-title":"Trans. Am. Ophthalmol. Soc."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"24","DOI":"10.3389\/fendo.2020.00024","article-title":"The IGF\/Insulin-IGFBP Axis in Corneal Development, Wound Healing, and Disease","volume":"11","author":"Stuard","year":"2020","journal-title":"Front. Endocrinol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1167\/iovs.03-1064","article-title":"Insulin, Not Leptin, Promotes in Vitro Cell Migration to Heal Monolayer Wounds in Human Corneal Epithelium","volume":"45","author":"Shanley","year":"2004","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_21","first-page":"1403","article-title":"Transactivation of EGFR Mediates Insulin-Stimulated ERK1\/2 Activation and Enhanced Cell Migration in Human Corneal Epithelial Cells","volume":"12","author":"Lyu","year":"2006","journal-title":"Mol. Vis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1096\/fj.201901316RR","article-title":"Insulin Receptor Preserves Mitochondrial Function by Binding VDAC1 in Insulin Insensitive Mucosal Epithelial Cells","volume":"34","author":"Titone","year":"2020","journal-title":"FASEB J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"32871","DOI":"10.1038\/srep32871","article-title":"Insulin Restores an Altered Corneal Epithelium Circadian Rhythm in Mice with Streptozotocin-Induced Type 1 Diabetes","volume":"6","author":"Song","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Nureen, L., and Di Girolamo, N. (2023). Limbal Epithelial Stem Cells in the Diabetic Cornea. Cells, 12.","DOI":"10.3390\/cells12202458"},{"key":"ref_25","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_26","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_27","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_28","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_29","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_30","doi-asserted-by":"crossref","first-page":"2416","DOI":"10.1002\/stem.2023","article-title":"IGF-1 Signaling Plays an Important Role in the Formation of Three-Dimensional Laminated Neural Retina and Other Ocular Structures from Human Embryonic Stem Cells","volume":"33","author":"Mellough","year":"2015","journal-title":"Stem Cells"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3341","DOI":"10.1089\/scd.2012.0180","article-title":"The Key Role of Insulin-like Growth Factor I in Limbal Stem Cell Differentiation and the Corneal Wound-Healing Process","volume":"21","author":"Trosan","year":"2012","journal-title":"Stem Cells Dev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1505","DOI":"10.1016\/j.exer.2006.08.012","article-title":"Vitronectin Supports Migratory Responses of Corneal Epithelial Cells to Substrate Bound IGF-I and HGF, and Facilitates Serum-Free Cultivation","volume":"83","author":"Ainscough","year":"2006","journal-title":"Exp. Eye Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1167\/iovs.05-0826","article-title":"Insulin-like Growth Factor-1 Induces Migration and Expression of Laminin-5 in Cultured Human Corneal Epithelial Cells","volume":"47","author":"Hyung","year":"2006","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_34","first-page":"10185","article-title":"Effects of Insulin-like Growth Factor 2 and Its Receptor Expressions on Corneal Repair","volume":"8","author":"Jiang","year":"2015","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"7697","DOI":"10.1167\/iovs.14-15179","article-title":"Expression of Insulin-like Growth Factor 2 Receptor in Corneal Keratocytes during Differentiation and in Response to Wound Healing","volume":"55","author":"Bohnsack","year":"2014","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_36","first-page":"2652","article-title":"Differential Temporal and Spatial Expression of Insulin-like Growth Factor Binding Protein-2 in Developing Chick Ocular Tissues","volume":"36","author":"Schoen","year":"1995","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1076\/ceyr.16.3.256.15405","article-title":"Localization Studies of IGFBP-2 and IGFBP-5 in the Anterior Compartment of the Eye","volume":"16","author":"Burren","year":"1997","journal-title":"Curr. Eye Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1426","DOI":"10.1002\/jcp.26948","article-title":"Mutual Regulation between IGF-1R and IGFBP-3 in Human Corneal Epithelial Cells","volume":"234","author":"Titone","year":"2019","journal-title":"J. Cell. Physiol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Nakagawa, A., Nakajima, T., and Azuma, M. (2021). Tear MiRNA Expression Analysis Reveals MiR-203 as a Potential Regulator of Corneal Epithelial Cells. BMC Ophthalmol., 21.","DOI":"10.1186\/s12886-021-02141-9"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/j.jtos.2019.05.005","article-title":"Insulin-like Growth Factor Binding Protein-7: A Marker of Conjunctivalization in an Animal Model of Limbal Stem Cell Deficiency","volume":"17","author":"Park","year":"2019","journal-title":"Ocul. Surf."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"35","DOI":"10.3109\/03009739709178930","article-title":"Insulin Receptors in Human Ocular Tissues. Immunohistochemical Demonstration in Normal and Diabetic Eyes","volume":"102","author":"Naeser","year":"1997","journal-title":"Ups. J. Med. Sci."},{"key":"ref_42","first-page":"963","article-title":"Identification of Insulin in the Tear Film and Insulin Receptor and IGF-1 Receptor on the Human Ocular Surface","volume":"43","author":"Rocha","year":"2002","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.exer.2011.12.006","article-title":"Cellular Distribution of the IGF-1R in Corneal Epithelial Cells","volume":"94","author":"Robertson","year":"2012","journal-title":"Exp. Eye Res."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Wu, Y.-C., Zhu, M., and Robertson, D.M. (2012). Novel Nuclear Localization and Potential Function of Insulin-like Growth Factor-1 Receptor\/Insulin Receptor Hybrid in Corneal Epithelial Cells. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0042483"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"S8","DOI":"10.2337\/dc15-S005","article-title":"2. Classification and Diagnosis of Diabetes","volume":"38","author":"Tests","year":"2015","journal-title":"Diabetes Care"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1016\/S0021-5155(00)00222-7","article-title":"Glucose Transporter 1 Expression in Corneal Wound Repair under High Serum Glucose Level","volume":"44","author":"Takahashi","year":"2000","journal-title":"Jpn. J. Ophthalmol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"111611","DOI":"10.1016\/j.mce.2022.111611","article-title":"Insulin Facilitates Corneal Wound Healing in the Diabetic Environment through the RTK-PI3K\/Akt\/MTOR Axis in Vitro","volume":"548","author":"Peterson","year":"2022","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1097\/ICO.0000000000001533","article-title":"Reduction in Histone H3 Acetylation and Chromatin Remodeling in Corneas of Alloxan-Induced Diabetic Rats","volume":"37","author":"Aldrovani","year":"2018","journal-title":"Cornea"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1590\/S0004-27492008000700018","article-title":"Tear Film and Ocular Surface Changes in Diabetes Mellitus","volume":"71","author":"Carvalheira","year":"2008","journal-title":"Arq. Bras. Oftalmol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1007\/s12020-009-9208-9","article-title":"Influence of Insulin Treatment on the Lacrimal Gland and Ocular Surface of Diabetic Rats","volume":"36","author":"Jorge","year":"2009","journal-title":"Endocrine"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.1016\/j.bbagen.2007.05.002","article-title":"Extra-Pancreatic Insulin Production in RAt Lachrymal Gland after Streptozotocin-Induced Islet Beta-Cells Destruction","volume":"1770","author":"Cunha","year":"2007","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1076\/ceyr.21.5.833.5535","article-title":"Characterization of the Insulin-Signaling Pathway in Lacrimal and Salivary Glands of Rats","volume":"21","author":"Rocha","year":"2000","journal-title":"Curr. Eye Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.jtos.2020.09.006","article-title":"Ocular Surface Diabetic Disease: A Neurogenic Condition?","volume":"19","author":"Coassin","year":"2021","journal-title":"Ocul. Surf."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"156","DOI":"10.4103\/tjo.tjo_56_20","article-title":"Ocular Surface Disorder among Adult Patients with Type II Diabetes Mellitus and Its Correlation with Tear Film Markers: A Pilot Study","volume":"11","author":"Manchikanti","year":"2021","journal-title":"Taiwan J. Ophthalmol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"303","DOI":"10.5301\/ejo.5000710","article-title":"Ocular Surface Changes in Patients Treated with Oral Antidiabetic Drugs or Insulin","volume":"26","author":"Duman","year":"2016","journal-title":"Eur. J. Ophthalmol."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Purushothaman, I., Zagon, I.S., Sassani, J.W., and McLaughlin, P.J. (2021). Ocular Surface Complications in Diabetes: The Interrelationship between Insulin and Enkephalin. Biochem. Pharmacol., 192.","DOI":"10.1016\/j.bcp.2021.114712"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1097\/01.ico.0000224635.49439.d1","article-title":"Diabetes and Corneal Cell Densities in Humans by in Vivo Confocal Microscopy","volume":"25","author":"Quadrado","year":"2006","journal-title":"Cornea"},{"key":"ref_58","first-page":"548","article-title":"Corneal Epithelial Basement Membrane Changes in Diabetes","volume":"20","author":"Taylor","year":"1981","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Qu, J.H., Li, L., Tian, L., Zhang, X.Y., Thomas, R., and Sun, X.G. (2018). Epithelial Changes with Corneal Punctate Epitheliopathy in Type 2 Diabetes Mellitus and Their Correlation with Time to Healing. BMC Ophthalmol., 18.","DOI":"10.1186\/s12886-017-0645-6"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1167\/tvst.2.2.3","article-title":"Multimodal Highlighting of Structural Abnormalities in Diabetic Rat and Human Corneas","volume":"2","author":"Kowalczuk","year":"2013","journal-title":"Transl. Vis. Sci. Technol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1111\/jdi.12083","article-title":"Morphometric Features of Corneal Epithelial Basal Cells, and Their Relationship with Corneal Nerve Pathology and Clinical Factors in Patients with Type 2 Diabetes","volume":"4","author":"Ishibashi","year":"2013","journal-title":"J. Diabetes Investig."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1177\/1535370220972060","article-title":"Blockade of OGFr Delays the Onset and Reduces the Severity of Diabetic Ocular Surface Complications","volume":"246","author":"Zagon","year":"2021","journal-title":"Exp. Biol. Med."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1414","DOI":"10.1177\/1535370220940273","article-title":"Dysregulation of the OGF\u2013OGFr Pathway Correlates with Elevated Serum OGF and Ocular Surface Complications in the Diabetic Rat","volume":"245","author":"Zagon","year":"2020","journal-title":"Exp. Biol. Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"113436","DOI":"10.1016\/j.physbeh.2021.113436","article-title":"Sex Differences in the Magnitude of Diabetic Ocular Surface Complications: Role of Serum OGF","volume":"237","author":"Purushothaman","year":"2021","journal-title":"Physiol. Behav."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1097\/ICO.0000000000003334","article-title":"Evaluation of Limbal Stem Cells in Patients With Type 2 Diabetes: An In Vivo Confocal Microscopy Study","volume":"43","author":"Chen","year":"2024","journal-title":"Cornea"},{"key":"ref_66","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_67","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_68","doi-asserted-by":"crossref","first-page":"1642","DOI":"10.1111\/jdi.13544","article-title":"Painful Diabetic Neuropathy Is Associated with Increased Nerve Regeneration in Patients with Type 2 Diabetes Undergoing Intensive Glycemic Control","volume":"12","author":"Ponirakis","year":"2021","journal-title":"J. Diabetes Investig."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"3800","DOI":"10.1167\/iovs.18-24265","article-title":"Higher Total Insulin Dose Has Positive Effect on Corneal Nerve Fibers in DM1 Patients","volume":"59","year":"2018","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.1111\/dme.14306","article-title":"V Associations between Acute Glucose Control and Peripheral Nerve Structure and Function in Type 1 Diabetes","volume":"37","author":"Issar","year":"2020","journal-title":"Diabet. Med."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1016\/j.ophtha.2011.10.036","article-title":"Mapping the Nerve Architecture of Diabetic Human Corneas","volume":"119","author":"He","year":"2012","journal-title":"Ophthalmology"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1167\/tvst.11.1.17","article-title":"Corneal Confocal Microscopy in Type 1 Diabetes Mellitus: A Six-Year Longitudinal Study","volume":"11","author":"Misra","year":"2022","journal-title":"Transl. Vis. Sci. Technol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1111\/jns.12111","article-title":"Effect of Diet-Induced Obesity or Type 1 or Type 2 Diabetes on Corneal Nerves and Peripheral Neuropathy in C57Bl\/6J Mice","volume":"20","author":"Yorek","year":"2015","journal-title":"J. Peripher. Nerv. Syst."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1111\/jns.12086","article-title":"Effect of Glycemic Control on Corneal Nerves and Peripheral Neuropathy in Streptozotocin-Induced Diabetic C57Bl\/6J Mice","volume":"19","author":"Yorek","year":"2014","journal-title":"J. Peripher. Nerv. Syst."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1222","DOI":"10.1167\/iovs.13-13794","article-title":"Differences and Similarities in Development of Corneal Nerve Damage and Peripheral Neuropathy and in Diet-Induced Obesity and Type 2 Diabetic Rats","volume":"55","author":"Davidson","year":"2014","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1111\/jns5.12044","article-title":"Repeated Monitoring of Corneal Nerves by Confocal Microscopy as an Index of Peripheral Neuropathy in Type-1 Diabetic Rodents and the Effects of Topical Insulin","volume":"18","author":"Chen","year":"2013","journal-title":"J. Peripher. Nerv. Syst."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1111\/vop.13076","article-title":"Decreased Corneal Subbasal Nerve Fiber Length and Density in Diabetic Dogs with Cataracts Using in Vivo Confocal Microscopy","volume":"26","author":"Chan","year":"2023","journal-title":"Vet. Ophthalmol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1111\/jdi.13974","article-title":"Type 2 Diabetes Influences Intraepithelial Corneal Nerve Parameters and Corneal Stromal-Epithelial Nerve Penetration Sites","volume":"14","author":"Machet","year":"2023","journal-title":"J. Diabetes Investig."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.jtos.2017.10.006","article-title":"The Impact of Diabetes on Corneal Nerve Morphology and Ocular Surface Integrity","volume":"16","author":"Markoulli","year":"2018","journal-title":"Ocul. Surf."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"816062","DOI":"10.3389\/fphar.2022.816062","article-title":"Diabetic Corneal Neuropathy: Pathogenic Mechanisms and Therapeutic Strategies","volume":"13","author":"Zhou","year":"2022","journal-title":"Front. Pharmacol."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Cosmo, E., Midena, G., Frizziero, L., Bruno, M., Cecere, M., and Midena, E. (2022). Corneal Confocal Microscopy as a Quantitative Imaging Biomarker of Diabetic Peripheral Neuropathy: A Review. J. Clin. Med., 11.","DOI":"10.3390\/jcm11175130"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"17294","DOI":"10.1038\/s41598-018-35917-z","article-title":"Modeling Diabetic Corneal Neuropathy in a 3D In Vitro Cornea System","volume":"8","author":"Deardorff","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"e5084","DOI":"10.1097\/MD.0000000000005084","article-title":"Increased Membrane Localization of Pannexin1 in Human Corneal Synaptosomes Causes Enhanced Stimulated ATP Release in Chronic Diabetes Mellitus","volume":"95","author":"Cui","year":"2016","journal-title":"Medicine"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"2237","DOI":"10.1016\/j.ajpath.2020.08.006","article-title":"Insulin Promotes Corneal Nerve Repair and Wound Healing in Type 1 Diabetic Mice by Enhancing Wnt\/\u03b2-Catenin Signaling","volume":"190","author":"Yang","year":"2020","journal-title":"Am. J. Pathol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"2002","DOI":"10.1111\/jdi.13582","article-title":"Insulin Resistance Limits Corneal Nerve Regeneration in Patients with Type 2 Diabetes Undergoing Intensive Glycemic Control","volume":"12","author":"Ponirakis","year":"2021","journal-title":"J. Diabetes Investig."},{"key":"ref_86","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 Wayne Smith, C. (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_87","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_88","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_89","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_90","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_91","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_92","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_93","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_94","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: MiR-146a Inflammatory Role in Diabetic Corneal Epithelial Wound Healing","volume":"25","author":"Poe","year":"2022","journal-title":"Ocul. Surf."},{"key":"ref_95","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_96","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_97","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1016\/j.exer.2009.06.010","article-title":"Naltrexone and Insulin Are Independently Effective but Not Additive in Accelerating Corneal Epithelial Healing in Type I Diabetic Rats","volume":"89","author":"Klocek","year":"2009","journal-title":"Exp. Eye Res."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.2337\/diabetes.55.04.06.db05-1581","article-title":"Insulin Treatment Ameliorates Impaired Corneal Reepithelialization in Diabetic Rats","volume":"55","author":"Zagon","year":"2006","journal-title":"Diabetes"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1136\/bjo.29.7.361","article-title":"The use of insulin in the treatment of corneal ulcers","volume":"29","author":"Aynsley","year":"1945","journal-title":"Br. J. Ophthalmol."},{"key":"ref_100","first-page":"418","article-title":"Randomized Controlled Trial of Topical Insulin for Healing Corneal Epithelial Defects Induced During Vitreoretinal Surgery in Diabetics","volume":"6","author":"Fai","year":"2017","journal-title":"Asia-Pac. J. Ophthalmol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1097\/ICO.0000000000003308","article-title":"Randomized Clinical Trial of Topical Insulin Versus Artificial Tears for Healing Rates of Iatrogenic Corneal Epithelial Defects Induced During Vitreoretinal Surgery in Diabetics","volume":"42","author":"Dasrilsyah","year":"2023","journal-title":"Cornea"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1097\/ICO.0000000000003145","article-title":"Healing of Chemical Injury-Related Persistent Corneal Epithelial Defects With Topical Insulin","volume":"42","author":"Balal","year":"2022","journal-title":"Cornea"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"2280","DOI":"10.1177\/1120672120958307","article-title":"Topical Insulin for Refractory Persistent Corneal Epithelial Defects","volume":"31","year":"2021","journal-title":"Eur. J. Ophthalmol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"3117","DOI":"10.1007\/s11845-023-03373-y","article-title":"Efficacy of Topical Insulin for Recurrent Epithelial Corneal Erosions","volume":"192","author":"Esmail","year":"2023","journal-title":"Ir. J. Med. Sci."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"990","DOI":"10.1097\/ICO.0000000000002858","article-title":"Topical Insulin-Utility and Results in Refractory Neurotrophic Keratopathy in Stages 2 and 3","volume":"41","author":"Soares","year":"2022","journal-title":"Cornea"},{"key":"ref_106","first-page":"e912","article-title":"Comparison of the Efficacy of Topical Insulin with Autologous Serum Eye Drops in Persistent Epithelial Defects of the Cornea","volume":"100","year":"2022","journal-title":"Acta Ophthalmol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1426","DOI":"10.1097\/ICO.0000000000001297","article-title":"Use of Topical Insulin to Treat Refractory Neurotrophic Corneal Ulcers","volume":"36","author":"Wang","year":"2017","journal-title":"Cornea"},{"key":"ref_108","first-page":"208","article-title":"Topical Insulin for Healing of Diabetic Epithelial Defects?: A Retrospective Review of Corneal Debridement during Vitreoretinal Surgery in Malaysian Patients","volume":"68","author":"Bastion","year":"2013","journal-title":"Med. J. Malays."},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Burgos-Blasco, B., Diaz-Valle, D., Rego-Lorca, D., Perez-Garcia, P., Puebla-Garcia, V., Fernandez-Vigo, J.I., Benitez-Del-Castillo, J.M., and Gegundez-Fernandez, J.A. (2023). Topical Insulin, a Novel Corneal Epithelial Regeneration Agent in Dry Eye Disease. Eur. J. Ophthalmol., 11206721231206790.","DOI":"10.1177\/11206721231206790"},{"key":"ref_110","first-page":"297","article-title":"Insulina T\u00f3pica En El Tratamiento de \u00dalcera Corneal Refractaria En Un Paciente No Diab\u00e9tico: A Prop\u00f3sito de Un Caso","volume":"44","year":"2020","journal-title":"Farm. Hosp."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"e170","DOI":"10.1016\/j.jcjo.2020.04.001","article-title":"Topical Insulin for Neurotrophic Corneal Ulcers","volume":"55","author":"Tong","year":"2020","journal-title":"Can. J. Ophthalmol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.oftal.2018.06.003","article-title":"Topical Insulin in Neurotrophic Keratopathy after Resection of Acoustic Neuroma","volume":"94","author":"Galvis","year":"2019","journal-title":"Arch. Soc. Esp. Oftalmol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1097\/ICO.0000000000003361","article-title":"Combined Use of Therapeutic Hyper-CL Soft Contact Lens and Insulin Eye Drops for the Treatment of Recalcitrant Neurotrophic Keratopathy","volume":"43","author":"Giannaccare","year":"2023","journal-title":"Cornea"},{"key":"ref_114","first-page":"7","article-title":"Neurotrophic Keratopathy and Topical Insulin Therapy: A Case Report","volume":"15","author":"Khilji","year":"2023","journal-title":"Cureus"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1080\/02713683.2023.2173237","article-title":"Beneficial Effects of Plasma Rich in Growth Factors (PRGF) Versus Autologous Serum and Topical Insulin in Ocular Surface Cells","volume":"48","author":"Anitua","year":"2023","journal-title":"Curr. Eye Res."},{"key":"ref_116","first-page":"220","article-title":"Effectiveness of Topical Insulin for the Treatment of Surface Corneal Pathologies","volume":"98","year":"2023","journal-title":"Arch. La Soc. Espa\u00f1ola Oftalmol."},{"key":"ref_117","doi-asserted-by":"crossref","unstructured":"Jaworski, M., Lorenc, A., Leszczy\u0144ski, R., and Mrukwa-Kominek, E. (2023). Topical Insulin in Neurotrophic Keratopathy: A Review of Current Understanding of the Mechanism of Action and Therapeutic Approach. Pharmaceutics, 16.","DOI":"10.3390\/pharmaceutics16010015"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ejpb.2019.04.014","article-title":"V Prospective Insulin-Based Ophthalmic Delivery Systems for the Treatment of Dry Eye Syndrome and Corneal Injuries","volume":"140","author":"Cazarim","year":"2019","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1021\/acsabm.1c01161","article-title":"Photothermal Activatable Mucoadhesive Fiber Mats for On-Demand Delivery of Insulin via Buccal and Corneal Mucosa","volume":"5","author":"Voronova","year":"2022","journal-title":"ACS Appl. Bio. Mater."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1169438","DOI":"10.1155\/2022\/1169438","article-title":"Using Convolutional Neural Network as a Statistical Algorithm to Explore the Therapeutic Effect of Insulin Liposomes on Corneal Inflammation","volume":"2022","author":"Liao","year":"2022","journal-title":"Comput. Intell. Neurosci."},{"key":"ref_121","doi-asserted-by":"crossref","unstructured":"Xiong, X., Jiang, H., Liao, Y., Du, Y., Zhang, Y., Wang, Z., Zheng, M., and Du, Z. (2023). Liposome\u2013Trimethyl Chitosan Nanoparticles Codeliver Insulin and SiVEGF to Treat Corneal Alkali Burns by Inhibiting Ferroptosis. Bioeng. Transl. Med., 8.","DOI":"10.1002\/btm2.10499"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1097\/IOP.0000000000002146","article-title":"The Role of Insulin-like Growth Factor-1 and Its Receptor in the Eye: A Review and Implications for IGF-1R Inhibition","volume":"39","author":"Truong","year":"2023","journal-title":"Ophthal. Plast. Reconstr. Surg."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1006\/exer.1999.0775","article-title":"Characterization of Insulin-like Growth Factor-1 Receptors in Rabbit Corneal Epithelial Cells","volume":"70","author":"Nakamura","year":"2000","journal-title":"Exp. Eye Res."},{"key":"ref_124","doi-asserted-by":"crossref","unstructured":"McKay, T.B., Priyadarsini, S., and Karamichos, D. (2022). Sex Hormones, Growth Hormone, and the Cornea. Cells, 11.","DOI":"10.3390\/cells11020224"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"117","DOI":"10.3389\/fendo.2018.00117","article-title":"IGF-Binding Proteins: Why Do They Exist and Why Are There So Many?","volume":"9","author":"Allard","year":"2018","journal-title":"Front. Endocrinol."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.ghir.2018.02.001","article-title":"Shifting the IGF-Axis: An Age-Related Decline in Human Tear IGF-1 Correlates with Clinical Signs of Dry Eye","volume":"40","author":"Patel","year":"2018","journal-title":"Growth Horm. IGF Res."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"1063069","DOI":"10.3389\/fimmu.2023.1063069","article-title":"The Association between Altered Intestinal Microbiome, Impaired Systemic and Ocular Surface Immunity, and Impaired Wound Healing Response after Corneal Alkaline-Chemical Injury in Diabetic Mice","volume":"14","author":"Bu","year":"2023","journal-title":"Front. Immunol."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1089\/scd.2016.0030","article-title":"The Supportive Role of Insulin-Like Growth Factor-I in the Differentiation of Murine Mesenchymal Stem Cells into Corneal-Like Cells","volume":"25","author":"Trosan","year":"2016","journal-title":"Stem Cells Dev."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1167\/iovs.05-0596","article-title":"Induced Expression of Insulin-like Growth Factor-1 by Amniotic Membrane-Conditioned Medium in Cultured Human Corneal Epithelial Cells","volume":"47","author":"Lee","year":"2006","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1002\/jcp.21850","article-title":"IGF-1 Released by Corneal Epithelial Cells Induces up-Regulation of N-Cadherin in Corneal Fibroblasts","volume":"221","author":"Ko","year":"2009","journal-title":"J. Cell. Physiol."},{"key":"ref_131","first-page":"679","article-title":"Protective Effect of Histatin 1 against Ultraviolet-Induced Damage to Human Corneal Epithelial Cells","volume":"15","author":"Huang","year":"2018","journal-title":"Exp. Ther. Med."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.neulet.2013.10.063","article-title":"Effect of Insulin-like Growth Factor-1 on Corneal Surface Ultrastructure and Nerve Regeneration of Rabbit Eyes after Laser in Situ Keratomileusis","volume":"558","author":"Wang","year":"2014","journal-title":"Neurosci. Lett."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"2454","DOI":"10.1016\/j.ymthe.2023.05.002","article-title":"Enhanced Adipose-Derived Stem Cells with IGF-1-Modified MRNA Promote Wound Healing Following Corneal Injury","volume":"31","author":"Yu","year":"2023","journal-title":"Mol. Ther."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"4378","DOI":"10.1038\/s41598-018-21031-7","article-title":"Insulin Mediates de Novo Nuclear Accumulation of the IGF-1\/Insulin Hybrid Receptor in Corneal Epithelial Cells","volume":"8","author":"Titone","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1002\/(SICI)1097-4652(199610)169:1<159::AID-JCP16>3.0.CO;2-8","article-title":"Synergistic Effects of Substance P with Insulin-like Growth Factor-1 on Epithelial Migration of the Cornea","volume":"169","author":"Nishida","year":"1996","journal-title":"J. Cell. Physiol."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1076\/ceyr.16.3.275.15409","article-title":"Combined Effects of Substance P and Insulin-like Growth Factor-1 on Corneal Epithelial Wound Closure of Rabbit in Vivo","volume":"16","author":"Nakamura","year":"1997","journal-title":"Curr. Eye Res."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0021-5155(99)00168-9","article-title":"Signaling Regulation for Synergistic Effects of Substance P and Insulin-like Growth Factor-1 or Epidermal Growth Factor on Corneal Epithelial Migration","volume":"44","author":"Ofuji","year":"2000","journal-title":"Jpn. J. Ophthalmol."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1167\/iovs.04-0775","article-title":"Sensitizing Effect of Substance P on Corneal Epithelial Migration Induced by IGF-1, Fibronectin, or Interleukin-6","volume":"46","author":"Yamada","year":"2005","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1038\/sj.bjp.0702550","article-title":"Synergistic Effect with Phe-Gly-Leu-Met-NH2 of the C-Terminal of Substance P and Insulin-like Growth Factor-1 on Epithelial Wound Healing of Rabbit Cornea","volume":"127","author":"Nakamura","year":"1999","journal-title":"Br. J. Pharmacol."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1038\/sj.bjp.0700923","article-title":"The NK1 Receptor and Its Participation in the Synergistic Enhancement of Corneal Epithelial Migration by Substance P and Insulin-like Growth Factor-1","volume":"120","author":"Nakamura","year":"1997","journal-title":"Br. J. Pharmacol."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1080\/02713680591006129","article-title":"Participation of P38 MAP Kinase, but Not P44\/42 MAP Kinase, in Stimulation of Corneal Epithelial Migration by Substance P and IGF-1","volume":"30","author":"Nakamura","year":"2005","journal-title":"Curr. Eye Res."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1007\/s10384-009-0693-4","article-title":"Efficacy of Substance P and Insulin-like Growth Factor-1 Peptides for Preventing Postsurgical Superficial Punctate Keratopathy in Diabetic Patients","volume":"53","author":"Chikamoto","year":"2009","journal-title":"Jpn. J. Ophthalmol."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1136\/bjo.2007.130013","article-title":"Open Clinical Study of Eye-Drops Containing Tetrapeptides Derived from Substance P and Insulin-like Growth Factor-1 for Treatment of Persistent Corneal Epithelial Defects Associated with Neurotrophic Keratopathy","volume":"92","author":"Yamada","year":"2008","journal-title":"Br. J. Ophthalmol."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1007\/s10384-007-0480-z","article-title":"Persistent Epithelial Defects Due to Neurotrophic Keratopathy Treated with a Substance P-Derived Peptide and Insulin-like Growth Factor 1","volume":"51","author":"Nishida","year":"2007","journal-title":"Jpn. J. Ophthalmol."},{"key":"ref_145","first-page":"409","article-title":"A Clinicopathologic Reports, Case Reports, and Small Case Series","volume":"119","author":"Chalam","year":"2006","journal-title":"Arch. Ophthalmol."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1001\/archopht.123.10.1445","article-title":"Treatment of Recurrent Corneal Erosion with Substance P-Derived Peptide and Insulin-like Growth Factor I","volume":"123","year":"2005","journal-title":"Arch. Ophthalmol."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1167\/tvst.7.1.12","article-title":"The Effect of Topical Substance-P Plus Insulin-like Growth Factor-1 (IGF-1) on Epithelial Healing After Photorefractive Keratectomy in Rabbits","volume":"7","author":"Ghiasi","year":"2018","journal-title":"Transl. Vis. Sci. Technol."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"2937","DOI":"10.1167\/iovs.02-0868","article-title":"Restoration of Corneal Epithelial Barrier Function and Wound Healing by Substance P and IGF-1 in Rats with Capsaicin-Induced Neurotrophic Keratopathy","volume":"44","author":"Nakamura","year":"2003","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1007\/s00125-003-1105-9","article-title":"Promotion of Corneal Epithelial Wound Healing in Diabetic Rats by the Combination of a Substance P-Derived Peptide (FGLM-NH2) and Insulin-like Growth Factor-1","volume":"46","author":"Nakamura","year":"2003","journal-title":"Diabetologia"},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"3810","DOI":"10.1167\/iovs.03-0189","article-title":"Effects of Substance P and IGF-1 in Corneal Epithelial Barrier Function and Wound Healing in a Rat Model of Neurotrophic Keratopathy","volume":"44","author":"Nagano","year":"2003","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_151","first-page":"2252","article-title":"Spontaneous Chronic Corneal Epithelial Defects (SCCED) in Dogs: Clinical Features, Innervation, and Effect of Topical SP, with or without IGF-1","volume":"42","author":"Murphy","year":"2001","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.preteyeres.2015.01.004","article-title":"Peptide Therapies for Ocular Surface Disturbances Based on Fibronectin-Integrin Interactions","volume":"47","author":"Nishida","year":"2015","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_153","first-page":"e30","article-title":"Update on Overview of Pterygium and Its Surgical Management","volume":"29","author":"Akbari","year":"2022","journal-title":"J. Popul. Ther. Clin. Pharmacol."},{"key":"ref_154","doi-asserted-by":"crossref","unstructured":"Maxia, C., Isola, M., Grecu, E., Cuccu, A., Scano, A., Orr\u00f9, G., Di Girolamo, N., Diana, A., and Murtas, D. (2023). Synergic Action of Insulin-like Growth Factor-2 and MiRNA-483 in Pterygium Pathogenesis. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24054329"},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"11","DOI":"10.3803\/EnM.2017.32.1.11","article-title":"Recent Insights into Insulin-Like Growth Factor Binding Protein 2 Transcriptional Regulation","volume":"32","author":"Shin","year":"2017","journal-title":"Endocrinol. Metab."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1006\/exer.1993.1069","article-title":"Distribution of IGF-I and -II, IGF Binding Proteins (IGFBPs) and IGFBP MRNA in Ocular Fluids and Tissues: Potential Sites of Synthesis of IGFBPs in Aqueous and Vitreous","volume":"56","author":"Arnold","year":"1993","journal-title":"Exp. Eye Res."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1016\/j.exer.2007.06.015","article-title":"Insulin-like Growth Factor Binding Protein-3 Expression in the Human Corneal Epithelium","volume":"85","author":"Robertson","year":"2007","journal-title":"Exp. Eye Res."},{"key":"ref_158","doi-asserted-by":"crossref","unstructured":"Stuard, W.L., Guner, M.K., and Robertson, D.M. (2022). IGFBP-3 Regulates Mitochondrial Hyperfusion and Metabolic Activity in Ocular Surface Epithelia during Hyperosmolar Stress. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23074066"},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1167\/iovs.62.7.11","article-title":"IGFBP-3 Mediates Metabolic Homeostasis During Hyperosmolar Stress in the Corneal Epithelium","volume":"62","author":"Bogdan","year":"2021","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"3806","DOI":"10.1167\/iovs.13-12091","article-title":"Overexpression of SIRT1 Promotes High Glucose-Attenuated Corneal Epithelial Wound Healing via P53 Regulation of the IGFBP3\/IGF-1R\/AKT Pathway","volume":"54","author":"Wang","year":"2013","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1097\/ICL.0000000000000700","article-title":"Tear Levels of IGFBP-3: A Potential Biomarker for Diabetic Nerve Changes in the Cornea","volume":"46","author":"Stuard","year":"2020","journal-title":"Eye Contact Lens"},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"6105","DOI":"10.1167\/iovs.17-22425","article-title":"Tear Levels of Insulin-Like Growth Factor Binding Protein 3 Correlate With Subbasal Nerve Plexus Changes in Patients With Type 2 Diabetes Mellitus","volume":"58","author":"Stuard","year":"2017","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.jtos.2012.01.004","article-title":"Elevated IGFBP3 Levels in Diabetic Tears: A Negative Regulator of IGF-1 Signaling in the Corneal Epithelium","volume":"10","author":"Wu","year":"2012","journal-title":"Ocul. Surf."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1167\/iovs.61.2.46","article-title":"Role of Insulin-like Growth Factor Binding Protein-3 in the Pathogenesis of Herpes Stromal Keratitis","volume":"61","author":"Rao","year":"2020","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"2708","DOI":"10.1167\/iovs.04-0921","article-title":"Expression of the IGF System in Normal and Diabetic Transgenic (MRen-2)27 Rat Eye","volume":"46","author":"Bergman","year":"2005","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"30322","DOI":"10.1074\/jbc.271.48.30322","article-title":"Synthesis and Characterization of Insulin-like Growth Factor-Binding Protein (IGFBP)-7. Recombinant Human Mac25 Protein Specifically Binds IGF-I and -II","volume":"271","author":"Oh","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"6834","DOI":"10.1038\/onc.2008.287","article-title":"Glioblastoma-Secreted Factors Induce IGFBP7 and Angiogenesis by Modulating Smad-2-Dependent TGF-Beta Signaling","volume":"27","author":"Pen","year":"2008","journal-title":"Oncogene"}],"container-title":["Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-7737\/13\/3\/144\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:04:31Z","timestamp":1760105071000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-7737\/13\/3\/144"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,25]]},"references-count":167,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2024,3]]}},"alternative-id":["biology13030144"],"URL":"https:\/\/doi.org\/10.3390\/biology13030144","relation":{},"ISSN":["2079-7737"],"issn-type":[{"value":"2079-7737","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,25]]}}}