Oxidative Stress Susceptibility, Complement Dysregulation, and Metabolic Reprogramming in CFH Y402H Patient-Derived Choriocapillaris Endothelial Cells

Abstract

Age-related macular degeneration (AMD) is a leading cause of central vision loss. Immunofluorescence and gene expression studies in human donor eyes have shown that choriocapillaris endothelial cells (CECs) are lost before retinal pigment epithelium (RPE) degeneration, leaving extracellular matrix-filled empty lumens known as "ghost vessels." To investigate disease mechanisms, we generated CECs from patient-specific induced pluripotent stem cells (iPSCs) carrying the high-risk CFH Y402H variant and CRISPR-Cas9-corrected isogenic controls. The iPSC-derived CECs expressed canonical endothelial markers, formed fenestrations, maintained barrier function, and assembled capillary-like structures. Although baseline metabolism was preserved, Y402H CECs showed heightened sensitivity to hydroquinone-induced oxidative stress, with increased cytotoxicity and deposition of the complement membrane attack complex (C5b-9). RNA sequencing revealed oxidative stress-driven upregulation of lipid biosynthesis, mTORC signalling, endothelial-to-mesenchymal transition, and angiogenic pathways, alongside an imbalance in the complement pathway. These findings demonstrate that the CFH Y402H polymorphism increases CEC vulnerability to environmental stress, linking complement dysregulation and metabolic reprogramming to choriocapillaris dysfunction in AMD and highlighting CECs as a potential therapeutic target.