Smoking aggravates neovascular age-related macular degeneration via Sema4D-PlexinB1 axis-mediated activation of pericytes [scRNA-seq]
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ABSTRACT:
PROVIDER: PRJNA1215754 | ENA |
REPOSITORIES: ENA
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Project description:Age-related macular degeneration (AMD) is a prevalent neuroinflammation condition and the leading cause of irreversible blindness among the elderly population. Smoking significantly increases AMD risk, yet the mechanisms remain unclear. Here, we investigated the role of Sema4D-PlexinB1 axis in the progression of AMD, in which Sema4D-PlexinB1 is highly activated by smoking. Using patient-derived samples and mouse models, we discovered that smoking increased the presence of Sema4D on the surface of CD8+ T cells that migrated into the choroidal neovascularization (CNV) lesion via CXCL12-CXCR4 axis and interacted with its receptor PlexinB1 on choroidal pericytes. This led to ROR2-mediated PlexinB1 phosphorylation and pericytes activation, hence disrupted vascular homeostasis and promoted neovascularization. Inhibition of Sema4D reduced CNV and improved the benefit of anti-VEGF treatment. In conclusion, this study unveils the molecular mechanisms through which smoking exacerbates AMD pathology, and presents a potential therapeutic strategy by targeting Sema4D to augment current AMD treatments.
2025-01-26 | GSE288036 | GEO
Project description:Age-related macular degeneration (AMD) is a prevalent neuroinflammation condition and the leading cause of irreversible blindness among the elderly population. Smoking significantly increases AMD risk, yet the mechanisms remain unclear. Here, we investigated the role of Sema4D-PlexinB1 axis in the progression of AMD, in which Sema4D-PlexinB1 is highly activated by smoking. Using patient-derived samples and mouse models, we discovered that smoking increased the presence of Sema4D on the surface of CD8+ T cells that migrated into the choroidal neovascularization (CNV) lesion via CXCL12-CXCR4 axis and interacted with its receptor PlexinB1 on choroidal pericytes. This led to ROR2-mediated PlexinB1 phosphorylation and pericytes activation, hence disrupted vascular homeostasis and promoted neovascularization. Inhibition of Sema4D reduced CNV and improved the benefit of anti-VEGF treatment. In conclusion, this study unveils the molecular mechanisms through which smoking exacerbates AMD pathology, and presents a potential therapeutic strategy by targeting Sema4D to augment current AMD treatments.
2025-01-26 | GSE288035 | GEO
Project description:Smoking aggravates neovascular age-related macular degeneration via Sema4D-PlexinB1 axis-mediated activation of pericytes [bulk RNA-seq]
| PRJNA1215752 | ENA
Project description:Age-related macular degeneration (AMD) is a prevalent neuroinflammation condition and the leading cause of irreversible blindness among the elderly population. Smoking significantly increases AMD risk, yet the mechanisms remain unclear. Here, we investigated the role of Sema4D-PlexinB1 axis in the progression of AMD, in which Sema4D-PlexinB1 is highly activated by smoking. Using patient-derived samples and mouse models, we discovered that smoking increased the presence of Sema4D on the surface of CD8+ T cells that migrated into the choroidal neovascularization (CNV) lesion via CXCL12-CXCR4 axis and interacted with its receptor PlexinB1 on choroidal pericytes. This led to ROR2-mediated PlexinB1 phosphorylation and pericytes activation, hence disrupted vascular homeostasis and promoted neovascularization. Inhibition of Sema4D reduced CNV and improved the benefit of anti-VEGF treatment. In conclusion, this study unveils the molecular mechanisms through which smoking exacerbates AMD pathology, and presents a potential therapeutic strategy by targeting Sema4D to augment current AMD treatments.
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Project description:Mononuclear phagocytes (MPs), including monocytes and macrophages, play complex roles in the pathogenesis of age-related macular degeneration (AMD). We aimed to perform global transcriptome analysis on monocytes from AMD patients to obtain additional insight to the role of MPs in AMD. Peripheral blood was taken from treatment-naïve neovascular AMD (nvAMD) patients (n=14), and age-matched controls (n=15). Peripheral blood mononuclear cells (PBMCs) were separated and monocytes were isolated via negative selection. Gene expression was evaluated with Affymetrix Gene1.0 ST microarrays. Statistical/bioinformatics analysis was performed using open sourceware programs.
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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.
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Project description:Retinal pathological angiogenesis (PA) is a common hallmark in proliferative retinopathies, including age-related macular degeneration (AMD), proliferative diabetic retinopathy (PDR), and retinopathy of prematurity (ROP). The mechanisms underlying PA is complex and incompletely understood. Using oxygen-induced retinopathy (OIR) mouse as a model, the role of extracellular matrix (ECM) protein biglycan (BGN) in PA was studied. Significant upregulation of BGN in the retina of OIR mice and in neovascular proliferative membranes of PDR patients was found. The reduction of BGN expression by Bgn-specific small interfering RNA (siRNA) effectively diminished retinal PA in OIR mouse. Subsequent analysis of the mouse OIR retinal single-cell RNA sequencing data from the Gene Expression Omnibus dataset (GSE150703) suggested pericyte as a source of BGN. This was verified using cultured retinal capillary pericytes. BGN expression in pericytes was highly sensitive to hypoxic stimulation. BGN stimulated retinal PA via the upregulation of C-X-C motif chemokine ligand 12 (CXCL12). Inhibition of the CXCL12-CXCR4 axis effectively diminished PA in OIR mouse. In conclusion, this study demonstrated the stimulatory role of BGN in retinal PA, identified the link between BGN and CXCL12 expression, and further highlighted the role of pericytes in retinal PA.
2025-02-10 | GSE259255 | GEO
Project description:Retinal pathological angiogenesis (PA) is a common hallmark in proliferative retinopathies, including age-related macular degeneration (AMD), proliferative diabetic retinopathy (PDR), and retinopathy of prematurity (ROP). The mechanisms underlying PA is complex and incompletely understood. Using oxygen-induced retinopathy (OIR) mouse as a model, the role of extracellular matrix (ECM) protein biglycan (BGN) in PA was studied. Significant upregulation of BGN in the retina of OIR mice and in neovascular proliferative membranes of PDR patients was found. The reduction of BGN expression by Bgn-specific small interfering RNA (siRNA) effectively diminished retinal PA in OIR mouse. Subsequent analysis of the mouse OIR retinal single-cell RNA sequencing data from the Gene Expression Omnibus dataset (GSE150703) suggested pericyte as a source of BGN. This was verified using cultured retinal capillary pericytes. BGN expression in pericytes was highly sensitive to hypoxic stimulation. BGN stimulated retinal PA via the upregulation of C-X-C motif chemokine ligand 12 (CXCL12). Inhibition of the CXCL12-CXCR4 axis effectively diminished PA in OIR mouse. In conclusion, this study demonstrated the stimulatory role of BGN in retinal PA, identified the link between BGN and CXCL12 expression, and further highlighted the role of pericytes in retinal PA.
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