1. Canonical NF-κB signaling maintains corneal epithelial integrity and prevents corneal aging via retinoic acid.
- Author
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Yu Q, Biswas S, Ma G, Zhao P, Li B, and Li J
- Subjects
- Age Factors, Aldehyde Dehydrogenase 1 Family genetics, Aldehyde Dehydrogenase 1 Family metabolism, Animals, Burns, Chemical etiology, Burns, Chemical metabolism, Burns, Chemical pathology, Cell Differentiation drug effects, Cell Proliferation drug effects, Cells, Cultured, Corneal Neovascularization metabolism, Corneal Neovascularization pathology, Corneal Stroma drug effects, Corneal Stroma metabolism, Corneal Stroma pathology, Disease Models, Animal, Epithelium, Corneal metabolism, Epithelium, Corneal pathology, Eye Burns chemically induced, Eye Burns metabolism, Eye Burns pathology, Mice, Knockout, Retinal Dehydrogenase genetics, Retinal Dehydrogenase metabolism, Signal Transduction, Stem Cells metabolism, Stem Cells pathology, Transcription Factor RelA genetics, Mice, Burns, Chemical drug therapy, Cellular Senescence drug effects, Corneal Neovascularization prevention & control, Epithelium, Corneal drug effects, Eye Burns drug therapy, Regeneration drug effects, Stem Cells drug effects, Transcription Factor RelA metabolism, Tretinoin pharmacology
- Abstract
Disorders of the transparent cornea affect millions of people worldwide. However, how to maintain and/or regenerate this organ remains unclear. Here, we show that Rela (encoding a canonical NF-κB subunit) ablation in K14
+ corneal epithelial stem cells not only disrupts corneal regeneration but also results in age-dependent epithelial deterioration, which triggers aberrant wound-healing processes including stromal remodeling, neovascularization, epithelial metaplasia, and plaque formation at the central cornea. These anomalies are largely recapitulated in normal mice that age naturally. Mechanistically, Rela deletion suppresses expression of Aldh1a1, an enzyme required for retinoic acid synthesis from vitamin A. Retinoic acid administration blocks development of ocular anomalies in Krt14-Cre; Relaf/f mice and naturally aged mice. Moreover, epithelial metaplasia and plaque formation are preventable by inhibition of angiogenesis. This study thus uncovers the major mechanisms governing corneal maintenance, regeneration, and aging and identifies the NF-κB-retinoic acid pathway as a therapeutic target for corneal disorders., Competing Interests: QY, SB, GM, PZ, BL, JL No competing interests declared, (© 2021, Yu et al.)- Published
- 2021
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