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

Ophthalmology: conjunctivalization of the cornea linked to stem cell activity A major signaling pathway that regulates stem cell function acts as a key mediator of conjunctival invasion into the cornea following eye injuries. Using human tissue and mouse models, a team from South Korea led by Chang Rae Rho of Daejeon St. Mary's Hospital and Jungmook Lyu of Konyang University, Daejon, showed how insults to the eye can spur the proliferation of stem cells found in the conjunctiva, the thin membrane covering the white part of the eyeball. This cell growth and self-renewal is driven by increased activity of the Wnt/beta-catenin signaling pathway, leading to conjunctivalization of the cornea, the transparent outer layer of the eye, resulting in corneal opacity and loss of vision. Therapies that manipulate this signaling pathway could help improve vision for people with certain corneal diseases. 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/beta-catenin signaling activator CHIR resulted in increased proliferation of Delta Np63 alpha-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/beta-catenin pathway activation improved the expansion of the Delta Np63 alpha/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/beta-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.