Single-cell–resolution map of human retinal pigment epithelium helps discover subpopulations with differential disease sensitivity

Ortolan, Davide; Sharma, Ruchi; Volkov, A. I.; Maminishkis, Arvydas; Hotaling, Nathan; Huryn, Laryssa A.; Cukras, Catherine A; Marco, Stefano Di; Bisti, Silvia; Bharti, Kapil

doi:10.1073/pnas.2117553119

Cited by 51 publications

(70 citation statements)

References 47 publications

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“…Overall, these results confirmed that the ABCA4 LOF does not affect the ability of iPSCs to differentiate into mature and functional RPE cells. A comprehensive single-cell-resolution morphometric analysis of iRPE lines was performed to determine potential changes in iRPE cell shape metrics caused by ABCA4 LOF ( Ortolan et al., 2022 ). STGD1-iRPE did not show any significant differences compared with control-iRPE on four distinct morphometric features that define compact packing of epithelial cells in a sheet—cell area, aspect ratio, hexagonality, and the number of neighbors ( Figures S3 G–S3J).…”

Section: Resultsmentioning

confidence: 99%

Cell-autonomous lipid-handling defects in Stargardt iPSC-derived retinal pigment epithelium cells

et al. 2022

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Section: Resultsmentioning

confidence: 99%

Cell-autonomous lipid-handling defects in Stargardt iPSC-derived retinal pigment epithelium cells

et al. 2022

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“…In addition to existing evidence for topographical differences in hRPE cellular and molecular features (for example, comparing peripheral with macular tissue; see Table S1 ), a recent study revealed regional heterogeneity and cellular mosaicism based on surveying hRPE cell morphology over the entire posterior eye [ 119 ]. The multiple RPE subpopulations identified by scRNA-seq in both the human and mouse raises the possibility that transcriptomic differences underlie this heterogeneity.…”

Section: Discussionmentioning

confidence: 99%

Single-Cell RNA Sequencing Reveals Molecular Features of Heterogeneity in the Murine Retinal Pigment Epithelium

Pandey

Krebs

Bolisetty

et al. 2022

IJMS

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Transcriptomic analysis of the mammalian retinal pigment epithelium (RPE) aims to identify cellular networks that influence ocular development, maintenance, function, and disease. However, available evidence points to RPE cell heterogeneity within native tissue, which adds complexity to global transcriptomic analysis. Here, to assess cell heterogeneity, we performed single-cell RNA sequencing of RPE cells from two young adult male C57BL/6J mice. Following quality control to ensure robust transcript identification limited to cell singlets, we detected 13,858 transcripts among 2667 and 2846 RPE cells. Dimensional reduction by principal component analysis and uniform manifold approximation and projection revealed six distinct cell populations. All clusters expressed transcripts typical of RPE cells; the smallest (C1, containing 1–2% of total cells) exhibited the hallmarks of stem and/or progenitor (SP) cells. Placing C1–6 along a pseudotime axis suggested a relative decrease in melanogenesis and SP gene expression and a corresponding increase in visual cycle gene expression upon RPE maturation. K-means clustering of all detected transcripts identified additional expression patterns that may advance the understanding of RPE SP cell maintenance and the evolution of cellular metabolic networks during development. This work provides new insights into the transcriptome of the mouse RPE and a baseline for identifying experimentally induced transcriptional changes in future studies of this tissue.

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“…The m.3243A>G mutation causes a characteristic macular atrophy (Figure 1A). It has been hypothesized that the unique macular specificity in this disease is caused by region-specific dysfunctional RPE cells (56). Another notable anatomical feature of retinal dystrophy caused by m.3243A>G is the presence of outer retinal tubulations (ORT) (24, 37, 38), indicating outer retinal dysfunction and Müller cell activation (49).…”

Section: Discussionmentioning

confidence: 99%

Multimodal single-cell analysis of non-random heteroplasmy distribution in human retinal mitochondrial disease

Mullin

Voigt

Flamme-Wiese

et al. 2022

Preprint

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Variants within the mitochondrial genome (mtDNA) disrupt organelle function and lead to severe multi-system disease. mtDNA partitioning in complex tissues has implications for how cellular dosing of genetic variants governs pathogenesis. Here, we profiled the transcriptome, chromatin accessibility state, and heteroplasmy of the most common pathogenic mitochondrial mutation, m.3243A>G, in single cells from the retina and choroid of a patient with retinal and systemic disease. We found that the proportion of the pathogenic m.3243G allele was neither evenly nor randomly distributed across ocular cell types. All classes of cells in the neural retinal exhibited a high percentage of the mutant variant. However, endothelial and lymphocyte populations of the choroid were near homoplasmic for the wildtype allele. Gene expression analysis revealed that the presence of m.3243G deranges expression and causes upregulation of MTRNR2L1, a pseudogene of humanin, known to be protective against oxidative damage. We further found by joint multimodal sequencing of the retinal pigment epithelium that a high proportion of 3243G variant was associated with transcriptionally and morphologically abnormal cells. Together, these findings illuminate the non-random nature of mitochondrial variant partitioning and demonstrate that m.3243A>G causes non-cell autonomous dysfunction in the complex and metabolically linked light-sensing tissue of the eye.

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Single-cell–resolution map of human retinal pigment epithelium helps discover subpopulations with differential disease sensitivity

Cited by 51 publications

References 47 publications

Cell-autonomous lipid-handling defects in Stargardt iPSC-derived retinal pigment epithelium cells

Cell-autonomous lipid-handling defects in Stargardt iPSC-derived retinal pigment epithelium cells

Single-Cell RNA Sequencing Reveals Molecular Features of Heterogeneity in the Murine Retinal Pigment Epithelium

Multimodal single-cell analysis of non-random heteroplasmy distribution in human retinal mitochondrial disease

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