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Single cell RNA sequencing reveals transcriptional changes of human choroid and retinal pigment epithelium cells during development, in healthy adult and intermediate age-related macular degeneration

ABSTRACT: Age related macular degeneration (AMD) is the most prominent cause of blindness in the developed countries. Vision loss in the advanced stages of the disease is caused by atrophy of retinal photoreceptors, overlaying retinal pigment epithelium (RPE) and choroid endothelial cells. The molecular events that underline the development of these cell types from in utero to adult as well as the progression from the asymptomatic, to intermediate and advanced stages AMD are not yet fully understood. We performed single cell RNA-Sequencing (Seq) of human fetal and adult RPE and choroid, profiling in detail all the cell types and elucidating proliferation, differentiation, antigen pathway presentation and immunomodulation events that characterise the first half of human gestation. Our data demonstrate that progression from fetal to adult state is characterised by an increase in expression of genes involved in oxidative stress response and detoxification from heavy metals, suggesting a better defence against oxidative stress in the adult RPE and choroid tissues. Single cell comparative transcriptional analysis between an intermediate AMD patient and unaffected subject revealed specific loss of RPE and melanocytes in the macular region. While the CECs loss was not supported by our single cell RNA-Seq data, pathway enrichment analyses supported the onset of apoptosis in these cells, suggesting that during the course of AMD pathogenesis, endothelial cells are the most likely cell type to atrophy in the macula of AMD patients. Together these finds provide a rich resource for enhancing our understanding the development of RPE and choroid and the role they play in AMD progression and pathogenesis

ORGANISM(S): Homo sapiens

PROVIDER: GSE210543 | GEO | 2023/01/19

REPOSITORIES: GEO

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Project description:Proper spatial differentiation of retinal cell types is necessary for normal human vision. Many retinal diseases, such as Best disease and male germ cell associated kinase (MAK)-associated retinitis pigmentosa, preferentially affect distinct topographic regions of the retina. While much is known about the distribution of cell types in the retina, the distribution of molecular components across the posterior pole of the eye has not been well-studied. To investigate regional difference in molecular composition of ocular tissues, we assessed differential gene expression across the temporal, macular, and nasal retina and retinal pigment epithelium (RPE)/choroid of human eyes using RNA-Seq. RNA from temporal, macular, and nasal retina and RPE/choroid from four human donor eyes was extracted, poly-A selected, fragmented, and sequenced as 100 bp read pairs. Digital read files were mapped to the human genome and analyzed for differential expression using the Tuxedo software suite. Retina and RPE/choroid samples were clearly distinguishable at the transcriptome level. Numerous transcription factors were differentially expressed between regions of the retina and RPE/choroid. Photoreceptor-specific genes were enriched in the peripheral samples, while ganglion cell and amacrine cell genes were enriched in the macula. Within the RPE/choroid, RPE-specific genes were upregulated at the periphery while endothelium associated genes were upregulated in the macula. Consistent with previous studies, BEST1 expression was lower in macular than extramacular regions. The MAK gene was expressed at lower levels in macula than in extramacular regions, but did not exhibit a significant difference between nasal and temporal retina. The regional molecular distinction is greatest between macula and periphery and decreases between different peripheral regions within a tissue. Datasets such as these can be used to prioritize candidate genes for possible involvement in retinal diseases with regional phenotypes. Reprinted from <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=25446321">Whitmore, S.S., Wagner, A.H., DeLuca, A.P., Drack, A.V., Stone, E.M., Tucker, B.A., Zeng, S., Braun, T.A., Mullins, R.F., Scheetz, T.E., 2014. Transcriptomic analysis across nasal, temporal, and macular regions of human neural retina and RPE/choroid by RNA-Seq. Experimental Eye Research</a>. Used under <a href="http://creativecommons.org/licenses/by-nc-sa/3.0/">Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported </a>license. Additional RNA sequencing was performed on temporal, macular, nasal, inferior, and superior retina from a fifth subject and is included in this dataset. See original publication for details.

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Single cell RNA sequencing reveals transcriptional changes of human choroid and retinal pigment epithelium cells during development, in healthy adult and intermediate age-related macular degeneration

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