Choroidal endothelial and macrophage gene expression in atrophic and neovascular macular degeneration

Author:

Voigt Andrew P12ORCID,Mullin Nathaniel K12ORCID,Mulfaul Kelly12,Lozano Lola P12,Wiley Luke A12,Flamme-Wiese Miles J12,Boese Erin A12,Han Ian C12,Scheetz Todd E12,Stone Edwin M12,Tucker Budd A12,Mullins Robert F12

Affiliation:

1. Department of Ophthalmology and Visual Sciences, The University of Iowa Carver College of Medicine , Iowa City, IA 52242, USA

2. Institute for Vision Research, The University of Iowa , Iowa City, IA 52242, USA

Abstract

Abstract The human choroid is a heterogeneous, highly vascular connective tissue that dysfunctions in age-related macular degeneration (AMD). In this study, we performed single-cell RNA sequencing on 21 human choroids, 11 of which were derived from donors with early atrophic or neovascular AMD. Using this large donor cohort, we identified new gene expression signatures and immunohistochemically characterized discrete populations of resident macrophages, monocytes/inflammatory macrophages and dendritic cells. These three immune populations demonstrated unique expression patterns for AMD genetic risk factors, with dendritic cells possessing the highest expression of the neovascular AMD-associated MMP9 gene. Additionally, we performed trajectory analysis to model transcriptomic changes across the choroidal vasculature, and we identified expression signatures for endothelial cells from choroidal arterioles and venules. Finally, we performed differential expression analysis between control, early atrophic AMD, and neovascular AMD samples, and we observed that early atrophic AMD samples had high expression of SPARCL1, a gene that has been shown to increase in response to endothelial damage. Likewise, neovascular endothelial cells harbored gene expression changes consistent with endothelial cell damage and demonstrated increased expression of the sialomucins CD34 and ENCM, which were also observed at the protein level within neovascular membranes. Overall, this study characterizes the molecular features of new populations of choroidal endothelial cells and mononuclear phagocytes in a large cohort of AMD and control human donors.

Funder

National Institute of Health

Elmer and Sylvia Sramek Charitable Trust

Publisher

Oxford University Press (OUP)

Subject

Genetics (clinical),Genetics,Molecular Biology,General Medicine

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