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Editors Selection IGR 21-2

Basic Science: Cross-species cell types implicated in glaucoma

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86822 Cell atlas of aqueous humor outflow pathways in eyes of humans and four model species provides insight into glaucoma pathogenesis, van Zyl T; Yan W; McAdams A et al., Proceedings of the National Academy of Sciences of the United States of America, 2020; 117: 10339-10349

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Single-cell transcriptomic studies are powerful methods of identifying the unique messenger RNA composition of complex tissue. In Cell Atlas of Aqueous Humor Flow, van Zyl et al. used a high-throughput single-cell RNA sequencing approach to identify the cell types involved in aqueous outflow. They examined the genes that are expressed in the major cell types in humans and in four model species, including cynomolgus macaque, rhesus macaque, pig, and mouse. Prior to this study, trabecular outflow studies had not detailed the cell types implicated in aqueous outflow, including both conventional and uveoscleral outflow tracts. Using the human tissues derived from normal postmortem eyes, the investigators dissected the trabecular meshwork and subjected these cells for high-throughput single-cell transcriptomic analyses.

The major findings of the study include the identification of 19 major cell types. Eight cell types belonged to the conventional outflow pathway, seven to the uveal scleral pathway, and four immune cell types. High expression levels of MYOC, MGP, and PDPN were found as markers for TM cells. The authors further distinguished two populations of beam cells (Beam A and Beam B) with preferential expression of FABP4 and TMEFF2, respectively. Beam B cells were closer in proximity to juxtacanalicular tissue (JCT). Histological analysis suggests that Beam A and B are intermingled layers of uveal and corneoscleral tissue rather than separated into discrete layers.

A key finding of the study is the conservation of gene expression across humans and macaques, with a surprising note that lymphatic markers are reduced in primates as compared to pigs and mice.

A key finding of the study is the conservation of gene expression across humans and macaques, with a surprising note that lymphatic markers are reduced in primates as compared to pigs and mice. Detailed analysis of the cell type-specific analysis of glaucoma- associated Mendelian genes (MYOC, FOXC1, PITX2, CYP1B1) showed strong expression within Beam A, Beam B, and JCT cells. Surprisingly, cells in the uveoscleral pathway also express a number of these genes. Finally, genes encoding the complement factors were selectively expressed in the conventional outflow pathway, including C1Q, suggesting an immunological 'sink' for resident antigen presenting cells that may egress via the SC and venous system.

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