GENE EXPRESSION WITHIN A HUMAN CHOROIDAL NEOVASCULAR MEMBRANE USING SPATIAL TRANSCRIPTOMICS
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA979238 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24820380_1.fastq.gz | Fastqsanger.gz | |||
| SRR24820380_2.fastq.gz | Fastqsanger.gz | |||
| SRR24820381_1.fastq.gz | Fastqsanger.gz | |||
| SRR24820381_2.fastq.gz | Fastqsanger.gz | |||
| SRR24820382_1.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: The goals of this study were to identify expression patterns in human macular neovascularization with spatial transcriptomics Methods: Independent libraries were prepared two human donors: one with macular neovascularation (MNV) and one healthy control. Three tissue sections were taken from the MNV donor and two from the control donor. From the right eyes of both donors, a 4 mm diameter macular punch was collected centered on the fovea centralis, as was a 4 mm peripheral punch approximately 12 mm superotemporal from the macula. Both central and peripheral punches (spanning retina, choroid and sclera) were placed in optimal cutting temperature compound (OCT) and were rapidly snap frozen in liquid nitrogen and stored at -80C. Final libraries were sequenced on an Illumina NovaSeq system. Sequenced reads were mapped to the human genome build hg38 with CellRanger(v7.0.0). Feature selection was performed with the variance stabilizing transformation with Seurat (v4). Results: Spots from the MNV and control donor were deconvoluted with CSIDE, which estimated the percent RNA contribution to each spot from different cell types. Differential expression was performed between the MNV and control donors. Within the area of neovascularization, endothelial cells were predicted to increase expression of genes related to Rho family GTPase signaling and integrin signaling. Likewise, VEGF and TGFB1 were identified as potential upstream regulators that could drive the observed gene expression changes produced by endothelial and retinal pigment epithelium cells in the macular neovascularization donor. Conclusions: Overall, this study spatially analyzes gene expression across the retina, retinal pigment epithelium, and choroid in health and describes a set of candidate molecules that become dysregulated in macular neovascularization.
2023-08-07 | GSE234047 | GEO
Project description:Macular neovascularization is a relatively common and potentially visually devastating complication of age-related macular degeneration. In macular neovascularization, pathologic angiogenesis can originate from either the choroid or the retina, but we have limited understanding of how different cell types become dysregulated in this dynamic process. In this study, we performed spatial RNA sequencing on a human donor eye with macular neovascularization as well as a healthy control donor. We identified genes enriched within the area of macular neovascularization and used deconvolution algorithms to predict the originating cell type of these dysregulated genes. Within the area of neovascularization, endothelial cells were predicted to increase expression of genes related to Rho family GTPase signaling and integrin signaling. Likewise, VEGF and TGFB1 were identified as potential upstream regulators that could drive the observed gene expression changes produced by endothelial and retinal pigment epithelium cells in the macular neovascularization donor. These spatial gene expression profiles were compared to previous single-cell gene expression experiments in human age-related macular degeneration as well as a model of laser-induced neovascularization in mice. As a secondary aim, we also investigated spatial gene expression patterns within the macular neural retina and between the macular and peripheral choroid. We recapitulated previously described regional-specific gene expression patterns across both tissues. Overall, this study spatially analyzes gene expression across the retina, retinal pigment epithelium, and choroid in health and describes a set of candidate molecules that become dysregulated in macular neovascularization.
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Project description:Although genome-wide association studies, animal models, and cell culture systems have yielded important insights into the pathogenesis of neovascular age-related macular degeneration (nAMD), the underlying molecular pathways remain ill defined. Recent studies have deciphered the transcriptional profile of choroidal neovascularisation (CNV) of body donor eyes and were thus limited by the time span from death to preservation and the associated rapid 5'-RNA degradation. In this study, CNVs were therefore formalin-fixed immediately after surgical extraction from patients with nAMD and analyzed using a 3’ RNA sequencing approach called Massive Analysis of cDNA Ends (MACE). Age-matched formalin-fixed paraffin-embedded (FFPE) RPE-choroidal specimens obtained from the macular region of enucleated eyes with ciliary body melanoma served as controls. Transcriptome profiles were generated and disease-associated gene signatures were identified using statistical and bioinformatic methods. Calprotectin (S100A8/A9) protein expression was investigated by immunohistochemistry and ELISA.We identified 158 differentially-expressed genes (DEG) that were significantly increased in CNV compared to control tissue. Gene ontology enrichment analysis demonstrated that these DEG contributed to biological processes, such as Blood Vessel Development, Extracellular Structure Organization, Response to Wounding and several immune-related terms. The S100 calcium-binding protein A8 (S100A8) and S100A9 emerged among the top DEG, as confirmed by immunohistochemistry on CNV tissue and protein analysis of vitreous samples from nAMD patients and controls. This study provides a high-resolution RNA-sequencing-based transcriptional signature of choroidal neovascular membranes in AMD patients and reveals S100A8/A9 as a novel biomarker and promising target for AMD-directed therapeutics and diagnostics.
2020-04-09 | GSE146887 | GEO
Project description:Recently, Lodhi SA and colleagues have reported on a patient with choroidal neovascular membrane (CNVM) associated with tubercular granuloma, who responded to intravitreal bevacizumab injections. The available literature regarding CNVM associated with intraocular tuberculosis is briefly discussed. Choroidal neovascular membrane is a possible complication of choroidal tuberculosis and the patients should be informed about this risk. However, patients usually respond well to intravitreal anti-vascular endothelial growth factor agents as evidenced by the case reported by us and the current case reported by Lodhi et al.
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Project description:Neovascular age-related macular degeneration represents the most common cause of blindness in the western world. Alterations of the outer Blood-retina barrier integrity and a localized inflammatory microenvironment lead to sprouting of choroidal neovascularization in intimate contact with surrounding myeloid cells and ultimately lead to visual impairment. The discovery of novel targets interfering with angiogenesis and inflammation is vital for the future treatments in AMD patients. To identify novel potential targets in the local phagocytes of the retina, microglia, we performed a comprehensive RNA-seq analysis in the mouse model of laser-induced choroidal neovascularization (mCNV). Here, we identified the angiogenic factor Osteopontin (Opn), also known as "secreted phosphoprotein 1” (Spp1), to be one of the most highly expressed genes in retinal microglia in the course of CNV formation. We could confirm the presence of SPP1 at the lesion site in recruited retinal microglia of Cx3cr1CreER:Rosa26-Tomato reporter mice using immunohistochemistry and in whole retinal tissue lysates by ELISA compared to controls highlighting a massive local production of SPP1. Inhibition of SPP1 by intravitreal injection of anti-SPP1 antibody significantly increased the lesion size compared to IgG-treated control eyes. In line with the results in rodents, we found an increased SPP1 mRNA expression in surgically extracted human choroidal neovascular (hCNV) membranes by the quantitative RNA-seq approach of massive analysis of cDNA ends (MACE) and found numerous IBA1+SPP1+ myeloid cells in human CNV membranes. Taken together, these results highlight the importance of SPP1 in the formation of CNV and potentially offer new opportunities for therapeutic intervention by inhibiting the SPP1 pathway.
2021-02-16 | GSE160011 | GEO
Project description:The purpose of the study was to investigate the roles and possible functions of the miRNAs and tsRNAs in choroidal neovascularization (CNV).The mouse model of laser-induced CNV was conducted by laser photocoagulation and the samples were collected 7 days after laser treatment. The expression profiles of miRNAs and tsRNAs were accessed by small RNA sequencing in RPE-choroid-sclera complexes of mice in CNV group and controls. Our study identified differential expressions of miRNAs and tsRNAs in CNV model, and these altered miRNAs and tsRNAs might be novel potential targets in treating CNVs in patients with neovascular age-related macular degeneration.
2019-05-23 | GSE131646 | GEO
Project description:Transcriptomic Characterization of Human Choroidal Neovascular Membranes Identifies Calprotectin as a Novel Biomarker for Patients with Age-related Macular Degeneration
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Project description:Patients with neovascular AMD (nAMD) suffer vision loss from destructive angiogenesis, termed choroidal neovascularization (CNV). Macrophages are found in CNV lesions from nAMD patients. Additionally, Ccr2-/- mice, which lack classical monocyte-derived macrophages, show reduced CNV size. However, macrophages are highly diverse cells that can perform multiple functions. We performed single-cell RNA-sequencing on immune cells from wildtype and Ccr2-/- eyes to uncover macrophage heterogeneity during the laser-induced CNV mouse model of nAMD. We identified 12 macrophage subtypes, including Spp1+ macrophages. Spp1+ macrophages were enriched from wildtype lasered eyes and expressed a pro-angiogenic transcriptome via multiple pathways, including vascular endothelial growth factor signaling, endothelial cell sprouting, cytokine signaling, and fibrosis. Additionally, Spp1+ macrophages expressed the marker CD11c, and CD11c+ macrophages were increased by laser and present in CNV lesions. Finally, CD11c+ macrophage depletion reduced CNV size by 40%. These findings broaden our understanding of ocular macrophage heterogeneity and implicate CD11c+ macrophages as a potential therapeutic target for treatment-resistant nAMD patients.
2023-02-27 | GSE222094 | GEO