Ectodysplasin A protein promotes corneal epithelial cell proliferation

Abstract

The gene encodes ectodysplasin A (Eda), which if mutated causes X-linked hypohidrotic ectodermal dysplasia (XLHED) disease in humans. Ocular surface changes occur in XLHED patients whereas its underlying mechanism remains elusive. In this study, we found Eda was highly expressed in meibomian glands, and it was detected in human tears but not serum. Corneal epithelial integrity was defective and the thickness was reduced in the early postnatal stage of mutant mice. Corneal epithelial cell proliferation decreased and the epithelial wound healing was delayed in mice, whereas it was restored by exogenous Eda. Eda exposure promoted mouse corneal epithelial wound healing during organ culture, whereas scratch wound assay showed that it did not affect human corneal epithelial cell line migration. Epidermal growth factor receptor (EGFR), phosphorylated EGFR (p-EGFR), and phosphorylated ERK1/2 (p-ERK) were down-regulated in mice corneal epithelium. Eda treatment up-regulated the expression of Ki67, EGFR,EGFR, and ERK in human corneal epithelial cells in a dose-dependent manner. In conclusion, Eda protein can be secreted from meibomian glands and promotes corneal epithelial cell proliferation through regulation of the EGFR signaling pathway. Eda release into the tears plays an essential role in the maintenance of corneal epithelial homeostasis.

Ectodysplasin-A signaling is a key integrator in the lacrimal gland–cornea feedback loop

“…Previous studies reported decreased cell proliferation in Eda −/− corneas, along with impaired wound healing (Li et al, 2017). As our results indicate a misregulation of the growth factors produced by the LG, we hypothesized a defective response of Eda −/− LG to corneal insult, resulting in an impaired wound healing process.…”

“…Previous work suggested a modulation of tear film composition when reflex tears are produced, to support corneal wound healing (for a review, see Klenkler et al, 2007), and Eda −/− animals were recently shown to have a slower corneal epithelium wound healing (Li et al, 2017). Here, we showed that Cxcl10, Hgf, Fgf7 and Tgfb1, all involved in corneal wound healing (Tervo et al, 1997;Tuominen et al, 2001;Wilson et al, 1999), were misregulated in Eda −/− LGs.…”

“…We recently reported that corneal epithelium is in an active wound-healing process 18 h after abrasion (Kalha et al, 2018b). Moreover, it was shown that Eda −/− animals present high corneal dystrophy, along with impaired corneal epithelium barrier function and delayed cornea wound healing (Li et al, 2018(Li et al, , 2017Wang et al, 2016). Our Eda −/− mouse strain did not exhibit corneal dystrophy in young animals (13 wo), but an epithelial thinning in old ones (52-64 wo) (Fig.…”

“…Finally, Gdf5 increased expression is of interest, as it was shown to inhibit corneal epithelial cell proliferation (You et al, 1999). The increase of Gdf5 expression might partially explain the delayed corneal wound healing in Eda −/− animals (Li et al, 2017) although we expect that a combination of factors is responsible for this delay. Collectively, our results demonstrate that Eda signaling in LGs plays a crucial role in corneal physiology.…”

“…This well-conserved mechanism results in a fully re-stratified corneal epithelium 7 days post-injury in cat (Petznick et al, 2013). Interestingly in mouse, Eda −/− mutants exhibit delayed corneal wound healing in comparison with control animals (Li et al, 2017).…”