Molecular characterization of foveal versus peripheral human retina by single-cell RNA sequencing

Voigt, Andrew P.; Whitmore, S. Scott; Flamme-Wiese, Miles J.; Riker, Megan; Wiley, Luke A; Tucker, Budd A.; Stone, Edwin M.; Mullins, Robert F.; Scheetz, Todd E.

doi:10.1016/j.exer.2019.05.001

Cited by 115 publications

(139 citation statements)

References 30 publications

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“…12) 40 . We checked published adult human scRNAseq data and confirmed significant enrichment of MAP4, MYL4, MCF2, and KIF2A in cones, and CABP5 and IRX6 in rods (p < 0.05, one-sided T-test) 24 . We performed similar trajectory analyses using adult photoreceptor data to compare the organoid trajectory to in vivo photoreceptors ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 82%

“…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%

“…We performed similar trajectory analyses using adult photoreceptor data to compare the organoid trajectory to in vivo photoreceptors ( Supplementary Fig. 13) 24 . The resulting trajectory separated rods and cones, and the top 100 non-ribosomal differentially expressed genes between the state 1 rods and state 4 cones were used to create a heatmap for comparison to organoid development.…”

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: 82%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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

et al. 2020

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“…The emergence of single-cell RNA sequencing (scRNA-Seq) technologies provides a powerful tool to comprehensively classify cell types of the central nervous system and the gene regulatory networks that control their development (Fan et al, 2018; Farrell et al, 2018; Liu et al, 2017; Tasic et al, 2018; Wagner et al, 2018; Zeisel et al, 2018; Zhong et al, 2018). Studies in both macaque and human have examined the diversity of cellular subtypes within the mature retina (Cowan et al, 2019; Lukowski et al, 2019; Peng et al, 2019; Voigt et al, 2019). Furthermore, recent studies in mouse using scRNA-Seq analysis have identified changes in gene expression across retinal development, including progenitor maturation and specification/differentiation of each of the major classes of retinal cell types (Buenaventura et al, 2019; Clark et al, 2019; Lo Giudice et al, 2019).…”

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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Overlap of Genetic Loci for Central Serous Chorioretinopathy With Age-Related Macular Degeneration

et al. 2023

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ImportanceCentral serous chorioretinopathy (CSC) is a serous maculopathy of unknown etiology. Two of 3 previously reported CSC genetic risk loci are also associated with AMD. Improved understanding of CSC genetics may broaden our understanding of this genetic overlap and unveil mechanisms in both diseases.ObjectiveTo identify novel genetic risk factors for CSC and compare genetic risk factors for CSC and AMD.Design, Setting, and ParticipantsUsing International Classification of Diseases, Ninth (ICD-9) and Tenth (ICD-10) Revision code-based inclusion and exclusion criteria, patients with CSC and controls were identified in both the FinnGen study and the Estonian Biobank (EstBB). Also included in a meta-analysis were previously reported patients with chronic CSC and controls. Data were analyzed from March 1 to September 31, 2022.Main Outcomes and MeasuresGenome-wide association studies (GWASs) were performed in the biobank-based cohorts followed by a meta-analysis of all cohorts. The expression of genes prioritized by the polygenic priority score and nearest-gene methods were assessed in cultured choroidal endothelial cells and public ocular single-cell RNA sequencing data sets. The predictive utility of polygenic scores (PGSs) for CSC and AMD were evaluated in the FinnGen study.ResultsA total of 1176 patients with CSC and 526 787 controls (312 162 female [59.3%]) were included in this analysis: 552 patients with CSC and 343 461 controls were identified in the FinnGen study, 103 patients with CSC and 178 573 controls were identified in the EstBB, and 521 patients with chronic CSC and 3577 controls were included in a meta-analysis. Two previously reported CSC risk loci were replicated (near CFH and GATA5) and 3 novel loci were identified (near CD34/46, NOTCH4, and PREX1). The CFH and NOTCH4 loci were associated with AMD but in the opposite direction. Prioritized genes showed increased expression in cultured choroidal endothelial cells compared with other genes in the loci (median [IQR] of log 2 [counts per million], 7.3 [0.6] vs 4.7 [3.7]; P = .004) and were differentially expressed in choroidal vascular endothelial cells in single-cell RNA sequencing data (mean [SD] fold change, 2.05 [0.38] compared with other cell types; P &lt; 7.1 × 10−20). A PGS for AMD was predictive of reduced CSC risk (odds ratio, 0.76; 95% CI, 0.70-0.83 per +1 SD in AMD-PGS; P = 7.4 × 10−10). This association may have been mediated by loci containing complement genes.Conclusions and RelevanceIn this 3-cohort genetic association study, 5 genetic risk loci for CSC were identified, highlighting a likely role for genes involved in choroidal vascular function and complement regulation. Results suggest that polygenic AMD risk was associated with reduced risk of CSC and that this genetic overlap was largely due to loci containing complement genes.

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Molecular characterization of foveal versus peripheral human retina by single-cell RNA sequencing

Cited by 115 publications

References 30 publications

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

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

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

Overlap of Genetic Loci for Central Serous Chorioretinopathy With Age-Related Macular Degeneration

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