Multi-scale analysis of histological, ultrastructural and proteomic regional differences in the Descemet’s membrane-endothelium of Fuchs endothelial corneal dystrophy

Late-onset Fuchs endothelial corneal dystrophy (FECD) is marked by progressive thickening of Descemet’s membrane (DM), accumulation of guttae, and endothelial dysfunction, primarily affecting the central cornea. However, the centro-peripheral differences in FECD’s structural and molecular changes remain unexplored. We studied the regional variability of FECD specimens using multiscale electron and surface imaging, along with shotgun proteomics. The central surface showed large, coalescent guttae within curly fibers and amorphous matrix with low roughness, while the deeper layer had buried guttae in a multilaminar matrix. Conversely, the paracentral surface had fewer, small round guttae on a thin matrix enriched with wide-spaced collagens and higher surface roughness. Molecular analysis revealed overexpression of fibril-forming collagens and key regulators of collagen organization and fibrillogenesis in the centre compared to the paracentral region, correlating with structural differences. These findings provide insight into FECD’s regional molecular dynamics and may help to develop biomarkers and therapies.