Early Transcriptomic and Pathologic Changes of Col8a2 Mutant Fuchs Endothelial Corneal Dystrophy

The purpose of this study was to characterize the early transcriptomic and pathologic changes of Fuchs endothelial corneal dystrophy (FECD) using the Col8a2Q455K/Q455K mutant mouse model.

The Col8a2Q455K/Q455K mutant mice were divided into the early-stage (≤2-month-old) group and the late-stage (≥8-month-old) group, based on corneal endothelial changes evaluated by slit-lamp microscopy, optical coherence tomography (OCT), and confocal microscopy. The corneal endothelial cells from early-stage mutant and age-matched wild-type (WT) mice were collected for transcriptomic analysis and validated by quantitative PCR and immunofluorescence staining.

The Col8a2Q455K/Q455K mutant mice showed no observable corneal abnormality before 2 months of age. Morphological changes of the corneal endothelium appeared at 4 months and aggravated continuously with apparent corneal edema. However, when analyzing transcriptomic changes of the corneal endothelium, we found that the early-stage mutant mice exhibited 221 upregulated and 55 downregulated genes compared with age-matched WT mice; these differences were even more pronounced in the late-stage mutant mice. The upregulated genes predominantly enriched three signaling processes, including extracellular matrix (ECM) remodeling (e.g. Lgals3, Timp1, and Mmp3), endoplasmic reticulum (ER) stress (e.g. Hspa5, Dnajb9, and Atf3), and early activation of immune-related pathways (e.g. Icam1, Bpifb1, and C1q). Moreover, the qPCR and immunofluorescence staining further validated changes in gene and protein expressions prior to the morphological abnormalities in the mutant mice.

The Col8a2Q455K/Q455K mutant mice exhibit aberrant activation of ECM remodeling, ER stress. and immune responses in the corneal endothelium prior to observable pathogenic changes, providing the first in vivo evidence of potential early biomarkers and therapeutic treatments for FECD.