Exploring a peptidomimetic approach of N‐cadherin in modulating fibroblast growth factor receptor signaling for corneal endothelial regeneration

Abstract

Endothelial rejection and a critical shortage of corneal transplants present an unmet medical need in corneal regeneration research area. Although basic fibroblast growth factor (bFGF) is a potent mitogenic factor for corneal ex vivo expansion, it is also a morphogen eliciting unfavorable endothelial‐mesenchymal transition (EnMT) of corneal endothelial cells. A pharmacological reagent that retains the beneficial proliferative effect while lacking the EnMT effect of bFGF would be of great potential in corneal regeneration. In present study, we demonstrated that bFGF not only activated the canonical fibroblast growth factor receptor 1 (FGFR1) tyrosine kinase pathway, but also further upregulated matrix metalloproteinase activity to cleave N‐cadherin into N‐terminus and C‐terminus fragments, which activated the classical FGFR1 tyrosine kinase pathway and a cryptic β‐catenin pathway to affect corneal proliferation and EnMT, respectively. We generated the synthetic peptides resembling a critical motif in the ectodomain of N‐cadherin and found these peptides enhanced downstream proliferative signaling of FGFR1 but without seemingly EnMT effect. The potential of these peptides can be demonstrated on both ex vivo cell culture and in vivo rat cryo‐injury model. Our study indicated this peptidomimetic approach of N‐cadherin can stimulate corneal regeneration and offer a promising therapeutic option to treat corneal endothelial dysfunction.

Characteristic tetraspanin expression patterns mark various tissues during early Xenopus development

“…It is known that secretion of FGF from the lens equator zone is involved in lens development (Lovicu & McAvoy, 2005), and research to identify lens‐specific miRNAs has been conducted (Tanaka et al, 2019). Tspan15 promotes N‐cadherin digestion by ADAM10 (Noy et al, 2016), and the N‐cadherin fragment can activate FGF receptor signaling (Su et al, 2020). Therefore, these molecular interactions together with Exo may promote lens development.…”