Wnt/β-catenin signaling stimulates the self-renewal of conjunctival stem cells and promotes corneal conjunctivalization

Abstract

Limbal stem cell deficiency causes conjunctivalization characterized by the covering of the corneal surface with conjunctival epithelium. However, the driving force for the encroachment of these conjunctival cells is unclear. Conjunctival stem cells are bipotent stem cells that can proliferate and differentiate into conjunctival epithelial cells and goblet cells to maintain regeneration of the conjunctival epithelium. Here, we show a robust proliferative response of conjunctival stem cells and upregulation of Wnt2b and Wnt3a gene expression in the conjunctivae of mice with induced limbal stem cell deficiency. Topical application of the Wnt/β-catenin signaling activator CHIR resulted in increased proliferation of ΔNp63α-positive stem cells in the basal layers of the bulbar and forniceal conjunctivae and enhanced invasion of conjunctival epithelial and goblet cells into the corneal surface. We also found that in cultures of stem cells isolated from the human conjunctiva, Wnt/β-catenin pathway activation improved the expansion of the ΔNp63α/ABCG2 double-positive cell population by promoting the proliferation and preventing the differentiation of these cells. These expanded stem cells formed a stratified epithelium containing goblet cells under airlift culture conditions. Our data reveal that Wnt/β-catenin signaling contributes to the pathological process of limbal stem cell deficiency by promoting the self-renewal of conjunctival stem cells and suggest that these cells are a driving force in corneal conjunctivalization.

Advancements in Ocular Regenerative Therapies

“…This concept has been advanced by Li Q et al; while still in the animal models, supplementation of MLN4924 resulted in faster corneal regeneration by remnant LSCs [66]. Alternatively, a discovery by Jang et al offers an entirely different approach with potentially the same effect [67]. Scientists found that the increased Wnt/-β-catenin signalling in LSCD encourages the self-renewal of conjunctival stem cells and promotes corneal conjunctivalisation in animal models and human conjunctiva that has been removed from the eye [67].…”

“…Alternatively, a discovery by Jang et al offers an entirely different approach with potentially the same effect [67]. Scientists found that the increased Wnt/-β-catenin signalling in LSCD encourages the self-renewal of conjunctival stem cells and promotes corneal conjunctivalisation in animal models and human conjunctiva that has been removed from the eye [67]. Reducing or blocking this signalling could positively affect corneal transparency, leaving the LSC in patients with LSCD or pterygia more time to reconstruct a healthy cornea [67].…”