Cell Atlas of Aqueous Humor Outflow Pathways in Eyes of Humans and Four Model Species Provides Insights into Glaucoma Pathogenesis

Abstract

<jats:title>ABSTRACT</jats:title><jats:p>Increased intraocular pressure (IOP) represents a major risk factor for glaucoma, a prevalent eye disease characterized by death of retinal ganglion cells that carry information from the eye to the brain; lowering IOP is the only proven treatment strategy to delay disease progression. The main determinant of IOP is the equilibrium between production and drainage of aqueous humor, with compromised drainage generally viewed as the primary contributor to dangerous IOP elevations. Drainage occurs through two pathways in the anterior segment of the eye, called conventional and uveoscleral. To gain insights into the cell types that comprise these pathways, we used high-throughput single cell RNA sequencing (scRNA-seq). From ∼24,000 single cell transcriptomes, we identified 19 cell types with molecular markers for each and used histological methods to localize each type. We then performed similar analyses on four organisms used for experimental studies of IOP dynamics and glaucoma: cynomolgus macaque (<jats:italic>Macaca fascicularis</jats:italic>), rhesus macaque (<jats:italic>Macaca mulatta</jats:italic>), pig (<jats:italic>Sus scrofa</jats:italic>) and mouse (<jats:italic>Mus musculus</jats:italic>). Many human cell types had counterparts in these models, but differences in cell types and gene expression were evident. Finally, we identified the cell types that express genes implicated in glaucoma in all five species. Together, our results provide foundations for investigating the pathogenesis of glaucoma, and for using model systems to assess mechanisms and potential interventions.</jats:p>

Cell Atlas of The Human Fovea and Peripheral Retina

“…S3). Indeed, in a parallel study, we have demonstrated expression of these genes in cells of the aqueous humor outflow pathways 53 .…”

Single cell transcriptome analyses of the developing zebrafish eye— perspectives and applications

“…Not only could we identify cell types of the cornea and AL, but we were also able to follow clusters of these cells throughout the different timepoints and thereby monitor changes in their gene expression profiles. We were able to compare our data to human studies (van Zyl et al, 2020;van Zyl et al, 2022) and found that human marker genes such as krt4, krt5 and myoc are expressed in the zebrafish cornea and AL respectively. Moreover, we found previously unknown markers like hgd and cndp1 expressed in the AL which might also play a role in human TM development (Vöcking and Famulski, 2023).…”

A new gene-scoring method for uncovering novel glaucoma-related genes using non-negative matrix factorization based on RNA-seq data

“…Lo Faro et al (2021 identified an association between POAG and polymorphisms in the mitochondrial genes mt-Nd4 (rs2853496) and mt-Cyb (rs35788393). Atp2a1 encodes one of the Serca Ca (2+)-ATPases, which are intracellular pumps located in the sarcoplasmic or endoplasmic reticula of muscle cells (Odermatt et al, 1996), and Serca1 is also expressed in some non-muscle tissues, including the trabecular meshwork, which is a tissue in the eye that plays a role in regulating intraocular pressure (van Zyl et al, 2020). Thus, Atp2a1 potentially affects the regulation of intraocular pressure and contributes to the development of glaucoma.…”