Canonical NF-κB signaling maintains corneal epithelial integrity and prevents corneal aging via retinoic acid

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-kB 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 major mechanisms governing corneal maintenance, regeneration and aging and identifies the NF-kB-retinoic acid pathway as a therapeutic target for corneal disorders.

Notch1 signaling in keratocytes maintains corneal transparency by suppressing VEGF expression

“…We reexamined NOTCH1 expression by western blot and found that NOTCH1 was expressed in mouse cornea samples, which was increased upon alkali-induced injury ( Figure 1 A). In this study, we briefly exposed the mouse cornea to NaOH so that the damage was limited to the epithelial layer with the underlying stroma unscathed ( Ma et al., 2006 ; Yu et al., 2021 ). The injured epithelial layer is recovered within 14 days ( Yu et al., 2021 ).…”

“…In this study, we briefly exposed the mouse cornea to NaOH so that the damage was limited to the epithelial layer with the underlying stroma unscathed ( Ma et al., 2006 ; Yu et al., 2021 ). The injured epithelial layer is recovered within 14 days ( Yu et al., 2021 ). We carried out immunohistochemical staining for Hes1, a downstream target of Notch signaling.…”

“…Another possibility is that limbal stem cells are not sensitive to signals from the newly formed vascularized stroma due to their quiescent nature, since the stroma underneath the limbus region are normally vascularized. While limbal CESCs have been shown to be mostly quiescent ( Altshuler et al., 2021 ; Yu et al., 2021 ), studies have suggested that the transit-amplifying cells at the central cornea have stem cell activities ( Majo et al., 2008 ; Nasser et al., 2018 ). Here, we show that the cells at the central cornea undergo proliferation, express p63, expand further in injury models, and can convert into epidermal-like cells, properties possessed by stem cells but not terminally differentiated epithelial cells.…”

“…The corneal epithelia exhibit a dynamic turnover, driven by corneal epithelial stem cells (CESCs), while keratocytes and endothelial cells remain quiescent in adults ( Funderburgh et al., 2016 ; Kamil and Mohan, 2021 ; Yazdanpanah et al., 2017 ). While limbal CESCs have been established as slow-cycling or quiescent stem cells ( Altshuler et al., 2021 ; Yu et al., 2021 ), a number of studies have shown that transit-amplifying cells at the central cornea have stem cell activities (termed epithelial progenitor cells hereafter) ( Chang et al., 2011 ; Majo et al., 2008 ; Nasser et al., 2018 ). Visual acuity requires corneal transparency, which is attributable to proper organization of the collagen fibrils, expression of crystalline, the lack of keratin, and blood vessels ( Meek and Knupp, 2015 ; Mittal et al., 2016 ).…”

Aldehyde Dehydrogenase Enzyme Functions in Acute Leukemia Stem Cells

“…Consequently, decreased expression of ALDH1A1 has been linked to the development of Parkinsons' disease [56]. Furthermore, the ALDH1A1 protein is a critical enzyme for maintaining clarity in human, rat, and mouse lenses, and corneal integrity; ALDH1A1-null mice grow to adulthood, but develop cataracts later in life (by six to nine months of age) [57][58][59][60]. Hematopoietic cells from ALDH1A1-deficient mice exhibit increased sensitivity to liver metabolites of cyclophosphamide; however, ALDH1A1 deficiency did not affect the basal function of stem cells from the hematopoietic and nervous system [61].…”