PEDF Prevents Corneal Endothelial Dysfunction of Fuchs Endothelial Corneal Dystrophy

Purpose: The purpose of this study was to explore the protection of pigment epithelium-derived factor (PEDF) on the corneal endothelium in Fuchs endothelial corneal dystrophy (FECD). Methods: PEDF levels in aqueous humor of FECD patients were quantified by enzyme-linked immunosorbent assay. PEDF receptor expression of corneal endothelium was validated by immunofluorescence staining and single-cell RNA sequencing datasets. In vitro cultured human corneal endothelial cells (HCECs) were treated with menadione (MN) alone or in combination with PEDF. Cellular viability, oxidative stress, mitochondrial membrane potential, adenosine triphosphate (ATP) production, mitochondrial DNA copy number, and mitochondrial bioenergetics were evaluated. The ultraviolet A (UVA)-induced FECD mouse model was employed to assess the protective effects of PEDF on corneal thickness and endothelial cell density, morphology, and functions. In addition, RNA sequencing, quantitative PCR, immunofluorescence staining, and automated simple western assay were performed to analyze the downstream signaling pathways of PEDF-treated HCECs. Results: Human and mouse corneal endothelial cells express PEDF receptor, but PEDF levels were significantly reduced in the aqueous humor of FECD patients. In cultured human corneal endothelial cells exposed to MN, PEDF effectively enhanced cellular viability, attenuated oxidative stress, and improved mitochondria-related functions. In the UVA-induced FECD mouse model, PEDF pretreatment prevented the decline of corneal endothelial cells and promoted the recovery of endothelial cell density, morphology, and functions. Mechanistically, the protective effects of PEDF were associated with the suppression of p53, TGF-β, and Hippo signaling pathways elevated in FECD. Conclusions: PEDF effectively prevents corneal endothelial dysfunction in FECD mouse and cellular models, highlighting its preclinical promise as a protective and therapeutic approach.