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.
Highlights
The cornea is a transparent organ composed of the epithelial, stromal, and endothelial layers (Yazdanpanah et al, 2017; Nowell and Radtke, 2017; Collinson et al, 2004), with the epithelial basement membrane separating the epithelial and the stroma layers and the Descemet’s basement membrane separating the stroma and endothelial layers (Wilson, 2020; Medeiros et al, 2018)
While the epithelial layer undergoes constant turnover driven by corneal epithelial stem cells (CESCs), the stromal and endothelial layers are relatively quiescent in adults (Castro-Munozledo, 2013; Majo et al, 2008; Schlotzer-Schrehardt and Kruse, 2005)
NF-kB activation was increased in both epithelial and stromal cells after alkaline burn (Figure 1A, B and Figure 1—figure supplement 1). This finding is consistent with the notion that the basal activity of NF-kB is low but activated during wound healing (Zhang et al, 2017) and suggests that NF-kB is involved in corneal regeneration
Summary
The cornea is a transparent organ composed of the epithelial, stromal, and endothelial layers (Yazdanpanah et al, 2017; Nowell and Radtke, 2017; Collinson et al, 2004), with the epithelial basement membrane separating the epithelial and the stroma layers and the Descemet’s basement membrane separating the stroma and endothelial layers (Wilson, 2020; Medeiros et al, 2018). While Rela ablation in keratocytes did not affect corneal homeostasis or regeneration, Krt14-Cre; Relaf/f mice showed age-dependent deterioration in the epithelial layer at the central cornea, which triggered an aberrant repair response that led to inflammation, neovascularization, epithelial metaplasia, and plaque formation at the central cornea. These corneal phenotypes were largely recapitulated in naturally aged mice, associated with decreased NF-kB activation and RelA expression. While vitamin A deficiency is known to cause night blindness, corneal ulcers, and eye development defects, mainly in children (Smith et al, 2018; Fares-Taie et al, 2013; Srour et al, 2013; Yahyavi et al, 2013; Verhoeven et al, 2013), we show for the first time that RA, the metabolic product of vitamin A, is critical in corneal regeneration and aging in mice, implying that RA has the potential to improve corneal health in adult and aged individuals
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