Insulin Promotes Corneal Nerve Repair and Wound Healing in Type 1 Diabetic Mice by Enhancing Wnt/β-Catenin Signaling

Yang, Shuo; Zhang, Yangyang; Zhang, Zhaohua; Jing, Dan; Zhou, Qingjun; Wang, Xiaochuan; Li, Weina; Zhou, Li; Yang, Lingling; Xie, Lixin

doi:10.1016/j.ajpath.2020.08.006

Cited by 37 publications

(28 citation statements)

References 45 publications

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“…However, diabetes suppressed Wnt signaling in the skin, contributing to delayed skin wound healing ( 16 ). Recently, a study suggests that Wnt signaling may mediate the beneficial effect of insulin on corneal wound healing ( 17 ). However, the mechanism for the dysregulation of Wnt signaling in the cornea in diabetes is unclear.…”

Section: Introductionmentioning

confidence: 99%

Pathogenic Role of Diabetes-Induced Overexpression of Kallistatin in Corneal Wound Healing Deficiency Through Inhibition of Canonical Wnt Signaling

Liang

Huang

et al. 2022

Diabetes

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It was reported previously that circulation levels of kallistatin, an endogenous Wnt signaling inhibitor, are increased in diabetic patients. The present study was to determine the role of kallistatin in delayed wound healing in diabetic cornea. Immunostaining and Western blot analysis showed kallistatin levels were upregulated in diabetic human and rodent corneas. In murine corneal wound healing models, the canonical Wnt signaling was activated in non-diabetic cornea and suppressed in diabetic cornea, correlating with delayed wound healing. Transgenic expression of kallistatin suppressed the activation of Wnt signaling in the cornea and delayed wound healing. Local inhibition of Wnt signaling in the cornea by kallistatin, an LRP6-blocking antibody, or the soluble VLDLR ectodomain (an endogenous Wnt signaling inhibitor) delayed wound healing. In contrast, ablation of VLDLR resulted in overactivation of Wnt/β-catenin signaling and accelerated corneal wound healing. Activation of Wnt signaling in the cornea accelerated wound healing. Activation of Wnt signaling promoted human corneal epithelial cell migration and proliferation, which was attenuated by kallistatin. Our findings suggested that diabetes-induced overexpression of kallistatin contributes to delayed corneal wound healing by inhibiting the canonical Wnt signaling. Thus, kallistatin and Wnt/β-catenin signaling in the cornea could be potential therapeutic targets for diabetic corneal complications.

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Section: Introductionmentioning

confidence: 99%

Pathogenic Role of Diabetes-Induced Overexpression of Kallistatin in Corneal Wound Healing Deficiency Through Inhibition of Canonical Wnt Signaling

Liang

Huang

et al. 2022

Diabetes

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show abstract

“…The TKE2 cell line has been widely used in the research of corneal epithelial lesions. 7 , 22 , 34 – 36 , 41 , 50 , 51 Naturally, the expression of miR-181a-5p and Rik was verified in both CECs and TKE2 cell lines by qRT–PCR, and the luciferase reporter assay confirmed the interaction between Rik and miR-181a-5p. RNA FISH experiments targeting Rik showed both cytoplasmic and nuclear dots, further suggesting that Rik might perform important functions through the ceRNA mechanism.…”

Section: Discussionmentioning

confidence: 77%

“…By searching the results of 8 studies, 17 DEGs were found to be affected by hyperglycemia on CECs ( Table 3 ). 7 , 33 , 34 , 38 – 42 In light of the lncRNA-miRNA and miRNA-mRNA interactive pairs, a potential ceRNA network was constructed using the TargetScan and miRanda algorithms ( Fig. 4 ).…”

Section: Resultsmentioning

confidence: 99%

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Long Noncoding RNA 3632454L22Rik Contributes to Corneal Epithelial Wound Healing by Sponging miR-181a-5p in Diabetic Mice

Chen

2021

Invest. Ophthalmol. Vis. Sci.

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“…Corneal wound involves a series of complex and dynamic pathological processes, including cell death, inflammatory and immune response, corneal neovascularization (CNV), and limbal stem cell deficiency, which compromise corneal transparency and lead to decreased vision ( Roshandel et al, 2018 ; Ziaei et al, 2018 ). Previous studies have illustrated the effectiveness of inhibiting inflammatory responses and blocking angiogenic signaling pathways in accelerating corneal wound healing, providing potential therapeutic options that target multiple processes in treating corneal wounds ( Ellenberg et al, 2010 ; Chandler et al, 2019 ; Yang J. et al, 2020 , Yang et al, 2020 S. ; Rebibo et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Ocular Wnt/β-Catenin Pathway Inhibitor XAV939-Loaded Liposomes for Treating Alkali-Burned Corneal Wound and Neovascularization

Zhong

Wang

Zhang

et al. 2021

Front. Bioeng. Biotechnol.

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Corneal wound involves a series of complex and coordinated physiological processes, leading to persistent epithelial defects and opacification. An obstacle in the treatment of ocular diseases is poor drug delivery and maintenance. In this study, we constructed a Wnt/β-catenin pathway inhibitor, XAV939-loaded liposome (XAV939 NPs), and revealed its anti-inflammatory and antiangiogenic effects. The XAV939 NPs possessed excellent biocompatibility in corneal epithelial cells and mouse corneas. In vitro corneal wound healing assays demonstrated their antiangiogenic effect, and LPS-induced expressions of pro-inflammatory genes of IL-1β, IL-6, and IL-17α were significantly suppressed by XAV939 NPs. In addition, the XAV939 NPs significantly ameliorated alkali-burned corneas with slight corneal opacity, reduced neovascularization, and faster recovery, which were attributed to the decreased gene expressions of angiogenic and inflammatory cytokines. The findings supported the potential of XAV939 NPs in ameliorating corneal wound and suppressing neovascularization, providing evidence for their clinical application in ocular vascular diseases.

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Insulin Promotes Corneal Nerve Repair and Wound Healing in Type 1 Diabetic Mice by Enhancing Wnt/β-Catenin Signaling

Cited by 37 publications

References 45 publications

Pathogenic Role of Diabetes-Induced Overexpression of Kallistatin in Corneal Wound Healing Deficiency Through Inhibition of Canonical Wnt Signaling

Pathogenic Role of Diabetes-Induced Overexpression of Kallistatin in Corneal Wound Healing Deficiency Through Inhibition of Canonical Wnt Signaling

Long Noncoding RNA 3632454L22Rik Contributes to Corneal Epithelial Wound Healing by Sponging miR-181a-5p in Diabetic Mice

Ocular Wnt/β-Catenin Pathway Inhibitor XAV939-Loaded Liposomes for Treating Alkali-Burned Corneal Wound and Neovascularization

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