Abstract
Type VIII collagen, a member of the short-chain collagen family, plays essential roles in structural support, functional regulation, and mechanobiology across multiple organ systems. Although early studies suggested ubiquitous expression, emerging single-cell transcriptomic and proteomic analyses have refined this view, demonstrating selective enrichment in corneal endothelial cells, vascular smooth muscle cells, activated fibroblasts, and tumor-associated extracellular matrix (ECM) compartments. These findings establish type VIII collagen as both a structural constituent of the ECM and a dynamic regulator of cell behavior. Functionally, type VIII collagen is critical for endothelial cell stability, angiogenesis, ECM remodeling, and mechanosignaling. Dysregulation of Col8a1 and Col8a2 is implicated in a broad spectrum of disorders, including vascular remodeling, tissue fibrosis, diabetic nephropathy, cancer progression, and corneal endothelial dystrophies. With growing mechanistic insight, translational applications are rapidly expanding. Current directions include gene-editing strategies targeting Col8a2 for Fuchs' endothelial corneal dystrophy, RNA-based approaches to dissect Col8a1and Col8a2 regulation in fibrotic and vascular disease, and the development of biomaterials incorporating type VIII collagen-derived motifs to promote endothelial repair and guide angiogenesis. Moreover, its restricted expression profile supports its potential utility as a diagnostic and prognostic biomarker. Collectively, these advances position type VIII collagen as a multifunctional ECM regulator with substantial promise for disease diagnostics, therapeutic innovation, and biomaterial engineering.