Dissecting the transcriptome landscape of the human fetal neural retina and retinal pigment epithelium by single-cell RNA-seq analysis

Hu, Yuqiong; Wang, Xiaoye; Hu, Boqiang; Mao, Yunuo; Chen, Yidong; Yan, Liying; Yong, Jun; Dong, Ji; Yuan, Wei; Wang, Wei; Wen, Lu; Qiao, Jie; Tang, Fuchou

doi:10.1371/journal.pbio.3000365

Cited by 120 publications

(169 citation statements)

References 71 publications

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“…Spearman correlations were performed between WT cells of each population and published fetal and adult retinal scRNAseq datasets (Supplementary Figs. 7 and 8) 23,24 . This analysis revealed d100 organoids yielded amacrine, horizontal, and retinal ganglion cells more similar to fetal retinal populations.…”

Section: Resultsmentioning

confidence: 99%

“…Dropseq, a single-cell RNA sequencing (scRNAseq) method utilizing microfluidics and barcoded beads to capture the transcriptomes of single cells, has proven powerful for characterizing mouse retinas and identifying subtypes of mouse bipolar cells 21,22 . More recently, scRNAseq studies with developing and adult retinal tissue have offered insight into in vivo human retinal cell populations [23][24][25] . While previous studies have utilized scRNAseq to identify cell types of developing retinal organoids, they have not discerned distinct photoreceptor sub-populations [26][27][28] .…”

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confidence: 99%

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Investigating cone photoreceptor development using patient-derived NRL null retinal organoids

et al. 2020

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Photoreceptor loss is a leading cause of blindness, but mechanisms underlying photoreceptor degeneration are not well understood. Treatment strategies would benefit from improved understanding of gene-expression patterns directing photoreceptor development, as many genes are implicated in both development and degeneration. Neural retina leucine zipper (NRL) is critical for rod photoreceptor genesis and degeneration, with NRL mutations known to cause enhanced S-cone syndrome and retinitis pigmentosa. While murine Nrl loss has been characterized, studies of human NRL can identify important insights for human retinal development and disease. We utilized iPSC organoid models of retinal development to molecularly define developmental alterations in a human model of NRL loss. Consistent with the function of NRL in rod fate specification, human retinal organoids lacking NRL develop Sopsin dominant photoreceptor populations. We report generation of two distinct S-opsin expressing populations in NRL null retinal organoids and identify MEF2C as a candidate regulator of cone development.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Investigating cone photoreceptor development using patient-derived NRL null retinal organoids

et al. 2020

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“…The statistic criteria is less stringent comparing to that of the fovea vs peripheral comparison within human cells (next section) to compensate for the across species differences. DE genes were selected as those satisfying a p <0.001 cutoff according to the 'MAST' test (56). For each shared type i this resuled in two DE lists, one each for human (hDE i ) and macaque (mDE i ) respectively.…”

Section: Comparing Human and Macaque Cell Typesmentioning

confidence: 99%

Cell Atlas of the Human Fovea and Peripheral Retina

Yan¹,

Peng

Zyl

et al. 2020

Preprint

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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 retina of seven adult human donors. Utilizing computational methods, we identified 58 cell types within 6 classes: photoreceptor, horizontal, bipolar, amacrine, retinal ganglion and nonneuronal cells. Nearly all types are shared between the two retinal regions, 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 2 636 genes implicated as causes of or risk factors for blinding diseases. Many are expressed in striking cell class-, type-, or region-specific patterns. Finally, 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 provide a foundation for investigating molecular mechanisms underlying visual processing.

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“…The relevance of animal models for AMD remains unclear since the macula is specific to primates, and most animal models lack regions of high-acuity vision. Although both bulk RNA-Seq analysis and small-scale single-cell RNA-Seq (scRNA-Seq) studies (Hoshino et al, 2017; Hu et al, 2019) have been used to profiled gene expression changes during retinal neurogenesis, these data have not shed light on human-specific mechanisms that regulate retinal development, particularly with respect to cone photoreceptor specification and foveal patterning.…”

Section: Introductionmentioning

confidence: 99%

Single-cell analysis of human retina identifies evolutionarily conserved and species-specific mechanisms controlling development

Lü

Shiau

et al. 2019

Preprint

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SummaryThe development of single-cell RNA-Sequencing (scRNA-Seq) has allowed high resolution analysis of cell type diversity and transcriptional networks controlling cell fate specification. To identify the transcriptional networks governing human retinal development, we performed scRNA-Seq over retinal organoid and in vivo retinal development, across 20 timepoints. Using both pseudotemporal and cross-species analyses, we examined the conservation of gene expression across retinal progenitor maturation and specification of all seven major retinal cell types. Furthermore, we examined gene expression differences between developing macula and periphery and between two distinct populations of horizontal cells. We also identify both shared and species-specific patterns of gene expression during human and mouse retinal development. Finally, we identify an unexpected role for ATOH7 expression in regulation of photoreceptor specification during late retinogenesis. These results provide a roadmap to future studies of human retinal development, and may help guide the design of cell-based therapies for treating retinal dystrophies.

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Dissecting the transcriptome landscape of the human fetal neural retina and retinal pigment epithelium by single-cell RNA-seq analysis

Cited by 120 publications

References 71 publications

Investigating cone photoreceptor development using patient-derived NRL null retinal organoids

Investigating cone photoreceptor development using patient-derived NRL null retinal organoids

Cell Atlas of the Human Fovea and Peripheral Retina

Single-cell analysis of human retina identifies evolutionarily conserved and species-specific mechanisms controlling development

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