Transcriptomic Atlas of Human Trabecular Meshwork Uncovers the Cellular Landscape and Provides Insights into Glaucoma Pathophysiology

The trabecular meshwork (TM) is a specialized multicellular tissue that regulates aqueous humor outflow and intraocular pressure (IOP), and its dysfunction is a central driver of glaucoma. However, how cellular states and molecular mechanisms of TM cell populations are altered in human glaucoma remains poorly understood. Here, we present a comprehensive single-nucleus transcriptomic atlas of the human TM across normal and glaucomatous eyes. Analysis of 285,356 nuclei identified 17 distinct cell populations, including multiple TM structural subtypes, endothelial and neural-associated cells, and immune populations. Comparative analysis revealed widespread but cell-type–specific transcriptomic remodeling across TM populations in glaucoma, including dysregulation of metal ion homeostasis, inflammatory and interleukin signaling, disrupted calcium signaling, and activation of autophagy and mitophagy pathways. These changes were accompanied by altered extracellular matrix regulation, impaired endocytic processes, and enhanced stress-response and mechanosensitive signaling across TM populations. Notably, fibroblast- and myofibroblast-like TM populations exhibited transcriptomic signatures consistent with fibrotic remodeling and altered biomechanical responses, suggesting a potential role in increased outflow resistance. Together, these findings define a coordinated multicellular remodeling program linking proteostasis failure, mitochondrial dysfunction, inflammation, and fibrosis to TM failure in glaucoma, and highlight cell-type-specific therapeutic targets for restoring outflow and preventing vision loss.