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Cell atlas of the human fovea and peripheral retina

ABSTRACT: Most irreversible blindness results from retinal disease. To advance our understanding of the etiology of blinding diseases, we used single-cell RNA-sequencing (scRNA-seq) to analyze the transcriptomes of ~85,000 cells from the fovea and peripheral reti-na of seven adult human donors. Utilizing computational methods, we identified 58 cell types within 6 classes: photoreceptor, horizontal, bipolar, amacrine, retinal gangli-on and non-neuronal cells. Nearly all types are shared between the two retinal re-gions, but there are notable differences in gene expression and proportions between foveal and peripheral cohorts of shared types. We then used the human retinal atlas to map expression of 636 genes implicated as causes of or risk factors for blinding dis-eases. Many are expressed in striking cell class-, type-, or region-specific patterns. Fi-nally, we compared gene expression signatures of cell types between human and the cynomolgus macaque monkey, Macaca fascicularis. We show that over 90% of human types correspond transcriptomically to those previously identified in macaque, and that expression of disease-related genes is largely conserved between the two species. These results validate the use of the macaque for modeling blinding disease, and pro-vide a foundation for investigating molecular mechanisms underlying visual pro-cessing.

ORGANISM(S): Homo sapiens

PROVIDER: GSE148077 | GEO | 2020/06/22

REPOSITORIES: GEO

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Project description:Purpose: The goals of this study were to identify cell specific expression patterns from a donor with a presumed diagnosis of autoimmune retinopathy (AIR). A particular focus of this study was to identify expression signatures of Müller glia and astrocytes in AIR. Methods: Independent libraries were prepared for foveal and peripheral retina from five human donors in two experiments. Foveal and peripheral samples in donors 1-3 were acquired, analyzed, and uploaded in a previous experiment (GSE130636). In donors 4-5, new reads were acquired from a 2-mm fovea-centered punch and an 8-mm peripheral punch from the inferotemporal region in each donor. Donor 4 had no documented history of retinal disease. Donor 5 was followed for 19 years at the University of Iowa Hospitals and Clinics for progressive visual field loss and pigmentary changes and was given a presumptive diagnosis of autoimmune retinopathy. Foveal and peripheral retinal tissue were gently dissociated in papain for 1.25 hours before cryopreservation. In both experiments, libraries were sequenced on a HiSeq4000. Sequenced reads were mapped to the human genome build hg19 with CellRanger(v3.0.1) and filtered to remove cells likely to be doublets or cells with a high proportion of mitochondrial reads. Libraries from all five donors were aggregated to the same effective sequencing depth, and log-normalization of aggregated reads was performed with Seurat (v2.3.4) using a scale factor of 10,000. Results: A total of 23,429 cells were recovered after filtering with 117,885,744 corresponding reads. A total of 9,801 cells were recovered from the fovea while 13,628 cells were recovered from the periphery. A total of 7,189 cells were recovered from the donor with presumed AIR. In total, 23 clusters were identified and corresponded to all retinal cell types. The proportion of recovered cells was compared between the control (donors 1-4) and AIR (donor 5) patients. In addition, differential expression analysis identified genes enriched in each population of cells originating from the AIR donor. Particular emphasis was given to the expression profiles of glial cells (Müller cells and astrocytes) that originated from the AIR donor. Conclusions: This study provides a complementary clinical and molecular interrogation of the retina in a blinding inflammatory condition. Glial cells from the AIR donor were enriched in genes implicated in reactive gliosis, including ANXA1. Clinical, histologic, and transcriptomic evidence identify the loss of cone and rod photoreceptor cells with relative preservation of inner retinal cell types.

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Cell atlas of the human fovea and peripheral retina

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