Wnt activation as a potential therapeutic approach to treat partial limbal stem cell deficiency.
Publication Year:
2023
PubMed ID:
37735479
Funding Grants:
Public Summary:
Limbal stem cell deficiency (LSCD) is a blinding corneal disease characterized by the loss of deficiency of the stem cell population. Moreover, Wnt signaling is a molecular pathway involved in the stem cell maintenance in many systems. In this study, we recreated LSCD in rabbit by creating a chemical injury with sodium hydroxide. We observed that after generating the injury and treating with small molecules that activate this Wnt pathway, the normal characteristics of the stem cell population can be reversed and improve the disease.
Scientific Abstract:
Limbal epithelial stem/progenitor cells (LSCs) are adult stem cells located at the limbus, tightly regulated by their niche involving numerous signaling pathways, such as Wnt. Wnt proteins are secreted morphogens that play critical roles in embryonic development, stem cell proliferation, self-renewal, tissue regeneration, and remodeling in adults. It has been shown that a small molecule Wnt mimic could improve LSCs expansion ex vivo. Damage to the LSCs and/or their niche can lead to limbal stem cell deficiency (LSCD), a condition that can cause corneal blindness and is difficult to treat. This study explored if repopulating residual LSCs in partial LSCD through Wnt activation could be a novel therapeutic approach. To mimic LSCD due to a chemical injury, single cultured LSCs were exposed to various concentrations of sodium hydroxide. A progressive loss of the LSCs phenotype was observed: the percentage of p63(bright) cells and cytokeratin (K)14(+) cells decreased while the percentage of K12(+) increased. Wnt activation was attained by treating the LSCs with lithium chloride (LiCl) and a small-molecule Wnt mimic, respectively. After 18 h of treatment, LSCs proliferation was increased, and the LSCs phenotype was recovered, while the untreated cells did not proliferate and lost their phenotype. The percentage of p63(bright) cells was significantly higher in the Wnt mimic-treated cells compared with untreated cells, while the percentage of K12(+) cells was significantly lower. These findings suggest that local Wnt activation may rescue LSCs upon alkaline injury.