Losartan Alleviates Chemical Burn-Induced Limbal Stem Cell Deficiency: Repurposing a Venerable Anti-Hypertension Drug.

Abstract

PURPOSE: Currently, treatment for limbal stem cell deficiency (LSCD) involves limbal stem cell transplantation using either autologous or allogeneic tissue to restore the corneal surface. However, limitations such as donor shortages, immune rejection, and variable outcomes highlight a crucial need for more effective and safer therapeutic options. METHODS: We utilized a nitrogen mustard (NM)-induced corneal injury model to create LSCD, characterized by conjunctivalization. Mice exposed to NM were intraperitoneally injected with losartan. Single cell RNA sequencing (scRNA-seq) was conducted using a 10X Genomics platform. RESULTS: Previously, we demonstrated that corneal inflammation can be reversed by treatment with losartan, a widely used anti-hypertension drug with established long-term safety. Here, we demonstrate that systemic treatment with losartan markedly decreased corneal haze and inflammation during the acute and delayed phases of NM corneal injury. In the delayed phase, losartan treatment reduced NM-induced neovascularization in the cornea. Goblet cells detected within the corneal epithelium (conjunctivalization) during the delayed phase were significantly reduced following losartan treatment, indicating that losartan significantly resolves this classical hallmark of LSCD. The scRNA-seq showed that NM injury induced a dramatic increase in monocytes/macrophages in the cornea and that such an increase was attenuated by losartan treatment. Flow cytometry analysis confirmed that losartan attenuated corneal inflammation via reducing the monocytes/macrophages in the cornea. CONCLUSIONS: Our findings strongly support a new therapeutic use for losartan in blunting LSCD, which is a consequence associated with numerous corneal inflammatory conditions (e.g. diabetic keratopathy and tear gland insufficiency).