Human photoreceptor cells from different macular subregions have distinct transcriptional profiles

Voigt, Andrew P.; Mullin, Nathaniel K.; Whitmore, S. Scott; DeLuca, Adam P.; Burnight, Erin R; Liu, Xiuying; Tucker, Budd A.; Scheetz, Todd E.; Stone, Edwin M; Mullins, Robert F.

doi:10.1093/hmg/ddab140

Cited by 23 publications

(22 citation statements)

References 56 publications

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“…6 ) ( 46 ), we calculated the expression level in each choroidal cell population (using data from the current study), each retinal cell population (using data from Voigt et al. ( 65 )), and in the RPE (using data from Voigt et al. (19 )).…”

Section: Methodsmentioning

confidence: 99%

Choroidal endothelial and macrophage gene expression in atrophic and neovascular macular degeneration

Voigt

Mullin

Mulfaul

et al. 2022

Human Molecular Genetics

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The human choroid is a heterogeneous, highly vascular connective tissue that dysfunctions in age-related macular degeneration (AMD). In this study, we performed single-cell RNA sequencing on twenty-one human choroids, eleven of which were derived from donors with early atrophic or neovascular AMD. Using this large donor cohort, we identified new gene expression signatures and immunohistochemically characterized discrete populations of resident macrophages, monocytes/inflammatory macrophages, and dendritic cells. These three immune populations demonstrated unique expression patterns for AMD genetic risk factors, with dendritic cells possessing the highest expression of the neovascular AMD-associated MMP9 gene. Additionally, we performed trajectory analysis to model transcriptomic changes across the choroidal vasculature, and we identified expression signatures for endothelial cells from choroidal arterioles and venules. Finally, we performed differential expression analysis between control, early atrophic AMD, and neovascular AMD samples, and we observed that early atrophic AMD samples had high expression of SPARCL1, a gene that has been shown to increase in response to endothelial damage. Likewise, neovascular endothelial cells harbored gene expression changes consistent with endothelial cell damage and demonstrated increased expression of the sialomucins CD34 and ENCM, which were also observed at the protein level within neovascular membranes. Overall, this study characterizes the molecular features of new populations of choroidal endothelial cells and mononuclear phagocytes in a large cohort of AMD and control human donors.

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Section: Methodsmentioning

confidence: 99%

Choroidal endothelial and macrophage gene expression in atrophic and neovascular macular degeneration

Voigt

Mullin

Mulfaul

et al. 2022

Human Molecular Genetics

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“…Differences in the function, distribution and morphology of retinal cells between fovea and peripheral retina are associated with marked differences in gene expression (Peng et al, 2019;Voigt et al, 2019bVoigt et al, , 2021Yan et al, 2020). Using unstructured statistical methods that assessed how close transcription profiles from a large number of cells are, foveal cones were found to form clusters that were distinct from their peripheral counterparts (Voigt et al, 2019b).…”

Section: Retinal Neuronsmentioning

confidence: 99%

Variability in Retinal Neuron Populations and Associated Variations in Mass Transport Systems of the Retina in Health and Aging

Zouache

2022

Front. Aging Neurosci.

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Aging is associated with a broad range of visual impairments that can have dramatic consequences on the quality of life of those impacted. These changes are driven by a complex series of alterations affecting interactions between multiple cellular and extracellular elements. The resilience of many of these interactions may be key to minimal loss of visual function in aging; yet many of them remain poorly understood. In this review, we focus on the relation between retinal neurons and their respective mass transport systems. These metabolite delivery systems include the retinal vasculature, which lies within the inner portion of the retina, and the choroidal vasculature located externally to the retinal tissue. A framework for investigation is proposed and applied to identify the structures and processes determining retinal mass transport at the cellular and tissue levels. Spatial variability in the structure of the retina and changes observed in aging are then harnessed to explore the relation between variations in neuron populations and those seen among retinal metabolite delivery systems. Existing data demonstrate that the relation between inner retinal neurons and their mass transport systems is different in nature from that observed between the outer retina and choroid. The most prominent structural changes observed across the eye and in aging are seen in Bruch’s membrane, which forms a selective barrier to mass transfers at the interface between the choroidal vasculature and the outer retina.

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“…Patterns of retinal atrophy in inherited retinal disease can be traced to specific cell types. We and others (55) have previously demonstrated that different retinal and choroidal cell types express unique gene expression profiles, and such profiles can vary regionally even within a single cell type. The m.3243A>G mutation causes a characteristic macular atrophy (Figure 1A).…”

Section: Discussionmentioning

confidence: 86%

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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Human photoreceptor cells from different macular subregions have distinct transcriptional profiles

Cited by 23 publications

References 56 publications

Choroidal endothelial and macrophage gene expression in atrophic and neovascular macular degeneration

Choroidal endothelial and macrophage gene expression in atrophic and neovascular macular degeneration

Variability in Retinal Neuron Populations and Associated Variations in Mass Transport Systems of the Retina in Health and Aging

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

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