Microglia-RPE Cell Communication via the SPP1-ITGAV Axis Drives EMT and Retinal Degeneration in Dry AMD
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE281280 | GEO | 2024/11/12
REPOSITORIES: GEO
Similar Datasets
Project description:Microglia-RPE Cell Communication via the SPP1-ITGAV Axis Drives EMT and Retinal Degeneration in Dry AMD
| PRJNA1183307 | ENA
Project description:Comparing fibroblasts and derived -iPSC and - RPE cells from human AMD and non-AMD donors Retinal pigment epithelium (RPE) generated from skin biopsies of donors with age-related macular degeneration (AMD) exhibit a disease phenotype and a distinct transcriptome compared to age-matched controls. We investigated whether similar differences existed in the skin fibroblasts and induced pluripotent stem cells (iPSCs) derived from them. Hierarchical cluster and principal component analyses revealed significant overlap in the transcriptome of fibroblasts of AMD and non-AMD donors. After reprogramming, iPSCs exhibited slight differences. In contrast, the transcriptome of RPE derived from AMD and normal donors segregated into two distinct clusters. Differences in the expression of specific genes that were evident between normal and AMD-derived RPE were not observed in fibroblasts or iPSCs. Mitochondrial respiration was reduced in RPE from AMD patients but not in fibroblast or iPSCs. RPE derived from AMD patients have a distinct transcriptome and phenotype compared to controls that is not observed in their corresponding skin fibroblasts or iPSCs.
2024-04-23 | GSE149202 | GEO
Project description:Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly. There are two types of AMD: dry AMD and wet AMD. While laser-induced choroidal neovascularization has been used extensively in the studies of wet AMD by presenting the main features of human wet AMD, there was no established mouse model which fully recapitulates the cardinal features of human dry AMD. In this regard, lack of appropriate mouse model for dry AMD hampered the translational research on the pathogenesis and development of therapeutic agents. We recently suggested that 5XFAD mice could be a mouse model of dry AMD with regard to the amyloid beta (Aβ) related pathology. In this study, using transmission electron microscope, we analyzed ultrastructure of retinal pigment epithelium (RPE) of 5XFAD mice. Of importance, aged 5XFAD mice had ultrastructural changes of RPE and Bruchâs membrane compatible with cardinal features of dry AMD, including loss of apical microvilli and basal infolding of RPE, increased thickness of Bruchâs membrane, basal laminar and linear deposits, and accumulation of lipofuscin granules and undigested photoreceptor outer segment-laiden phagosomes. Using a threshold of 1.2 fold difference, we found â564â differentially expressed genes of which â190â were up-regulated and â374â were down-regulated in the RPE complex of aged 5XFAD mice. These altered genes were implicated in the pathogenesis of AMD including inflammation and immune response-related genes and retinol metabolism-related genes. Taken together, we suggest that aged 5XFAD mice can be used for dry AMD mouse model. All 5XFAD mice used were heterozygotes with respect to the transgene, and non-transgenic wild-type littermate (WT) mice served as controls.
2016-08-10 | E-GEOD-85408 | biostudies-arrayexpress
Project description:Non-neovascular or dry age-related macular degeneration (AMD) is a multi-factorial disease with degeneration of the aging retinal-pigmented epithelium (RPE) as a central pathogenic driver. Lysosomes play a crucial role in RPE health due to their involvement in phagocytosis and autophagy, which are regulated by transcription factor EB/E3 (TFEB/E3). Disruption in these processes can accelerate aging disorders, like AMD. Here we tried to ascertain if upregulation of AKT2 in the RPE cells triggers abnormalities lysosomal/autophagy processes and mitochondrial function culminating into an early AMD-like phenotype using mouse and in vitro "disease in a dish" models as tools.
2024-06-14 | GSE269923 | GEO
Project description:Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly. There are two types of AMD: dry AMD and wet AMD. While laser-induced choroidal neovascularization has been used extensively in the studies of wet AMD by presenting the main features of human wet AMD, there was no established mouse model which fully recapitulates the cardinal features of human dry AMD. In this regard, lack of appropriate mouse model for dry AMD hampered the translational research on the pathogenesis and development of therapeutic agents. We recently suggested that 5XFAD mice could be a mouse model of dry AMD with regard to the amyloid beta (Aβ) related pathology. In this study, using transmission electron microscope, we analyzed ultrastructure of retinal pigment epithelium (RPE) of 5XFAD mice. Of importance, aged 5XFAD mice had ultrastructural changes of RPE and Bruch’s membrane compatible with cardinal features of dry AMD, including loss of apical microvilli and basal infolding of RPE, increased thickness of Bruch’s membrane, basal laminar and linear deposits, and accumulation of lipofuscin granules and undigested photoreceptor outer segment-laiden phagosomes. Using a threshold of 1.2 fold difference, we found “564” differentially expressed genes of which “190” were up-regulated and “374” were down-regulated in the RPE complex of aged 5XFAD mice. These altered genes were implicated in the pathogenesis of AMD including inflammation and immune response-related genes and retinol metabolism-related genes. Taken together, we suggest that aged 5XFAD mice can be used for dry AMD mouse model.
2016-08-10 | GSE85408 | GEO
Project description:Comparing iPS derived RPE cells from human AMD and non-AMD donors It has been a challenge to model retinal disorders such as geographic atrophy (GA) in in vivo animals, primarily because several factors, including genetics and aging itself, contribute to disease phenotype of age-related macular degeneration (AMD). We generated retinal pigment epithelial (RPE) cells from patients with advanced AMD and assessed their ability to model disease. We observed alterations in the transcriptome of AMD patients compared to non-diseased controls. RPE cells from AMD patients displayed decreases in mitochondrial function (basal respiration and adenosine triphosphate (ATP) production) compared with non-diseased controls. Using a system of mimicing AMD diseased ECM, we showed RPE cells derived from patients with AMD have a reduced ability to survive and proliferate on nitrite-modified extracellular matrix (ECM) when compared to non-diseased controls. These results demonstrate changes in the cell biology and phenotype of RPE cells from patients with advanced AMD, providing a platform for disease modeling to understand AMD pathophysiology.
2020-02-26 | GSE125564 | GEO
Project description:To explore whether IL-4 could exert a novel protective role for RPE damage and attenuate the pathogenesis of dry age-related macular degeneration (AMD), we established a retinal degeneration model of dry AMD by intravenous injection of NaIO3, and explored the treatment effects of intravitreal IL-4 injection. We found exogenous IL-4 protected against retinal degeneration characterized by well-preserved structures and improved retinal function. The RNA-seq analysis revealed that IL-4 treatment suppressed the essential oxidative and pro-inflammatory pathways in the degenerative retina. IL-4 induced the expression of IL-4Rα and Nrf2 for anti-oxidative defense in vivo and in vitro. Our data provides evidences that IL-4 can be a useful neuroprotective agent against retinal degeneration due to its antioxidant and anti-inflammatory property through Nrf2 activation. The IL-4/IL-4Rα-Nrf2 axis maybe the potential targets for the development of novel therapies for dry AMD.
2022-12-17 | GSE193808 | GEO
Project description:Purpose: Age-related degeneration (AMD) is a major cause of blindness in developed countries. The molecular pathogenesis of early events in AMD is poorly understood. We investigated differential gene expression in samples of human retinal pigment epithelium (RPE)/choroid from early AMD and control maculas using exon-based arrays. Methods: Gene expression levels in nine early AMD and nine control human donor eyes were assessed using Affymetrix Human Exon ST 1.0 arrays. Two controls did not pass quality control and were removed. Differentially expressed genes were annotated using DAVID, and gene set enrichment analysis (GSEA) was performed on RPE-specific and endothelium-associated gene sets. CFH genotype was also assessed and differential expression was analyzed with respect to high AMD risk (YH/HH) and low AMD risk (YY) genotypes. Results: Seventy-five genes were identified as differentially expressed (raw p-value < 0.01; >50% fold change, mean log2 expression level in AMD or control M-bM-^IM-% median of all average gene expression values); however, no genes were significant (adj. p-value < 0.01) after correction for multiple hypothesis testing. Of 52 genes with decreased expression in AMD (fold change < 0.5; raw p-value < 0.01), 18 genes were identified by DAVID analysis as associated with vision or neurological processes. GSEA of RPE-associated and endothelium-associated genes revealed a significant decrease in genes typically expressed by endothelial cells in the early AMD group compared to controls, consistent with previous histologic and proteomic studies. Analysis with respect to CFH genotype indicated decreased expression of ADAMTS9 in eyes with high-risk genotypes (fold change = -2.61; raw p-value = 0.0008). Conclusions: GSEA results suggest that RPE transcripts are preserved or elevated in early AMD, concomitant with loss of endothelial cell marker expression. These results are consistent with the notion that choroidal endothelial cell dropout occurs early in the pathogenesis of AMD. Using AltAnalyze (ver. 2.0.7 beta), we analyzed nine early AMD and nine control eyes using Affymetrix Human Exon ST 1.0 arrays. Following initial processing in AltAnalyze, two control arrays were identified as potential outliers by tests implement in arrayQualityMetrics, a package for R.
2013-12-23 | E-GEOD-50195 | biostudies-arrayexpress
Project description:iPSC-RPE cells derived from a patient with AMD, whom harboured the Y402H mutation were compared to healthy donor RPE cells.
2017-12-19 | GSE91087 | GEO
Project description:Purpose: Age-related degeneration (AMD) is a major cause of blindness in developed countries. The molecular pathogenesis of early events in AMD is poorly understood. We investigated differential gene expression in samples of human retinal pigment epithelium (RPE)/choroid from early AMD and control maculas using exon-based arrays. Methods: Gene expression levels in nine early AMD and nine control human donor eyes were assessed using Affymetrix Human Exon ST 1.0 arrays. Two controls did not pass quality control and were removed. Differentially expressed genes were annotated using DAVID, and gene set enrichment analysis (GSEA) was performed on RPE-specific and endothelium-associated gene sets. CFH genotype was also assessed and differential expression was analyzed with respect to high AMD risk (YH/HH) and low AMD risk (YY) genotypes. Results: Seventy-five genes were identified as differentially expressed (raw p-value < 0.01; >50% fold change, mean log2 expression level in AMD or control ≥ median of all average gene expression values); however, no genes were significant (adj. p-value < 0.01) after correction for multiple hypothesis testing. Of 52 genes with decreased expression in AMD (fold change < 0.5; raw p-value < 0.01), 18 genes were identified by DAVID analysis as associated with vision or neurological processes. GSEA of RPE-associated and endothelium-associated genes revealed a significant decrease in genes typically expressed by endothelial cells in the early AMD group compared to controls, consistent with previous histologic and proteomic studies. Analysis with respect to CFH genotype indicated decreased expression of ADAMTS9 in eyes with high-risk genotypes (fold change = -2.61; raw p-value = 0.0008). Conclusions: GSEA results suggest that RPE transcripts are preserved or elevated in early AMD, concomitant with loss of endothelial cell marker expression. These results are consistent with the notion that choroidal endothelial cell dropout occurs early in the pathogenesis of AMD.
2013-12-23 | GSE50195 | GEO