Transcriptomic and Chromatin Accessibility Analysis of the Human Macular and Peripheral Retinal Pigment Epithelium at the Single-Cell Level

Mullin, Nathaniel K.; Voigt, Andrew P.; Boese, Erin A.; Liu, Xiuying; Stone, Edwin M; Tucker, Budd A.; Mullins, Robert F.

doi:10.1016/j.ajpath.2023.01.012

Cited by 10 publications

(6 citation statements)

References 33 publications

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“…The RPE dataset included >10,000 single nucleus transcriptomes from peripheral samples. Their transcriptomes generally resembled those reported in recent single-cell studies ( 15 , 17 – 19 , 55 – 57 ), although our dataset is substantially larger. Along with known markers, we found several previously unreported markers that are selectively expressed by RPE even when compared to all known ocular cell types ( SI Appendix , Fig.…”

Section: Resultssupporting

confidence: 80%

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Transcriptomic analysis of the ocular posterior segment completes a cell atlas of the human eye

Monavarfeshani

Yan

Pappas

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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Although the visual system extends through the brain, most vision loss originates from defects in the eye. Its central element is the neural retina, which senses light, processes visual signals, and transmits them to the rest of the brain through the optic nerve (ON). Surrounding the retina are numerous other structures, conventionally divided into anterior and posterior segments. Here, we used high-throughput single-nucleus RNA sequencing (snRNA-seq) to classify and characterize cells in six extraretinal components of the posterior segment: ON, optic nerve head (ONH), peripheral sclera, peripapillary sclera (PPS), choroid, and retinal pigment epithelium (RPE). Defects in each of these tissues are associated with blinding diseases—for example, glaucoma (ONH and PPS), optic neuritis (ON), retinitis pigmentosa (RPE), and age-related macular degeneration (RPE and choroid). From ~151,000 single nuclei, we identified 37 transcriptomically distinct cell types, including multiple types of astrocytes, oligodendrocytes, fibroblasts, and vascular endothelial cells. Our analyses revealed a differential distribution of many cell types among distinct structures. Together with our previous analyses of the anterior segment and retina, the data presented here complete a “Version 1” cell atlas of the human eye. We used this atlas to map the expression of >180 genes associated with the risk of developing glaucoma, which is known to involve ocular tissues in both anterior and posterior segments as well as the neural retina. Similar methods can be used to investigate numerous additional ocular diseases, many of which are currently untreatable.

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Section: Resultssupporting

confidence: 80%

“…They include WFDC1 , CXCL14 , and CALCB enriched in macular RPE and PMEL and IGFBP5 enriched in peripheral RPE. Many of these genes were also reported to be differentially expressed in previous studies ( 15 , 17 – 19 , 55 – 58 ).…”

Section: Resultssupporting

confidence: 57%

Transcriptomic analysis of the ocular posterior segment completes a cell atlas of the human eye

Monavarfeshani

Yan

Pappas

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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show abstract

“…The RPE dataset included >10,000 single nucleus transcriptomes from peripheral samples. Their transcriptomes generally resembled those reported in recent single cell studies (15,(17)(18)(19)(55)(56)(57), although our dataset is currently the largest. Along with known markers, we found several novel markers that are selectively expressed by RPE even when compared to all known ocular cell types (Fig.…”

Section: Pigmented Cellssupporting

confidence: 76%

“…They include WFDC1, CXCL14, and CALCB enriched in macular RPE, and PMEL and IGFBP5 enriched in peripheral RPE. Many of these genes were also reported to be differentially expressed in previous studies (15,(17)(18)(19)(55)(56)(57)(58).…”

Section: Pigmented Cellsmentioning

confidence: 58%

Transcriptomic Analysis of the Ocular Posterior Segment Completes a Cell Atlas of the Human Eye

Monaverfeshani

Yan

Pappas

et al. 2023

Preprint

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Although the visual system extends through the brain, most vision loss originates from defects in the eye. Its central element is the neural retina, which senses light, processes visual signals, and transmits them to the rest of the brain through the optic nerve (ON). Surrounding the retina are numerous other structures, conventionally divided into anterior and posterior segments. Here we used high-throughput single nucleus RNA sequencing (snRNA-seq) to classify and characterize cells in the extraretinal components of the posterior segment: ON, optic nerve head (ONH), peripheral sclera, peripapillary sclera (PPS), choroid, and retinal pigment epithelium (RPE). Defects in each of these tissues are associated with blinding diseases, for example, glaucoma (ONH and PPS), optic neuritis (ON), retinitis pigmentosa (RPE), and age-related macular degeneration (RPE and choroid). From ~151,000 single nuclei, we identified 37 transcriptomically distinct cell types, including multiple types of astrocytes, oligodendrocytes, fibroblasts, and vascular endothelial cells. Our analyses revealed a differential distribution of many cell types among distinct structures. Together with our previous analyses of the anterior segment and retina, the new data complete a Version 1 cell atlas of the human eye. We used this atlas to map the expression of >180 genes associated with the risk of developing glaucoma, which is known to involve ocular tissues in both anterior and posterior segments as well as neural retina. Similar methods can be used to investigate numerous additional ocular diseases, many of which are currently untreatable.

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“…These data sets are freely available in Spectacle (a free viewer of single-cell RNA data from retinas; ). Data from the different groups indicated that most retinal cells in different species have transcripts for all three isoforms [ 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 ]. However, we found that the data are very noisy and inconsistent between groups, making it difficult to draw more specific conclusions.…”

Section: Vdac Expression In Healthy Retinamentioning

confidence: 99%

VDAC in Retinal Health and Disease

Xu,

Tummala,

Chen

et al. 2024

Biomolecules

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The retina, a tissue of the central nervous system, is vital for vision as its photoreceptors capture light and transform it into electrical signals, which are further processed before they are sent to the brain to be interpreted as images. The retina is unique in that it is continuously exposed to light and has the highest metabolic rate and demand for energy amongst all the tissues in the body. Consequently, the retina is very susceptible to oxidative stress. VDAC, a pore in the outer membrane of mitochondria, shuttles metabolites between mitochondria and the cytosol and normally protects cells from oxidative damage, but when a cell’s integrity is greatly compromised it initiates cell death. There are three isoforms of VDAC, and existing evidence indicates that all three are expressed in the retina. However, their precise localization and function in each cell type is unknown. It appears that most retinal cells express substantial amounts of VDAC2 and VDAC3, presumably to protect them from oxidative stress. Photoreceptors express VDAC2, HK2, and PKM2—key proteins in the Warburg pathway that also protect these cells. Consistent with its role in initiating cell death, VDAC is overexpressed in the retinal degenerative diseases retinitis pigmentosa, age related macular degeneration (AMD), and glaucoma. Treatment with antioxidants or inhibiting VDAC oligomerization reduced its expression and improved cell survival. Thus, VDAC may be a promising therapeutic candidate for the treatment of these diseases.

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Transcriptomic and Chromatin Accessibility Analysis of the Human Macular and Peripheral Retinal Pigment Epithelium at the Single-Cell Level

Cited by 10 publications

References 33 publications

Transcriptomic analysis of the ocular posterior segment completes a cell atlas of the human eye

Transcriptomic analysis of the ocular posterior segment completes a cell atlas of the human eye

Transcriptomic Analysis of the Ocular Posterior Segment Completes a Cell Atlas of the Human Eye

VDAC in Retinal Health and Disease

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