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Macrophage elastase (MMP12) critically contributes to the development of subretinal fibrosis

ABSTRACT: Macular subretinal fibrosis is the end-stage complication of neovascular age-related macular degeneration (nAMD). RPE/Choroid from control and subretinal fibrosis mice were collected and processed for RNA sequencing (RNA-seq) analysis to investigate the molecular mechanism of subretinal fibrosis.

ORGANISM(S): Mus musculus

PROVIDER: GSE189555 | GEO | 2022/04/13

REPOSITORIES: GEO

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A novel ocular fibrosis signature for AMD using transcriptomic profiling of the two-stage laser-induced subretinal fibrosis mouse model.

Project description:Subretinal fibrosis is a major cause of irreversible vision loss in neovascular age-related macular degeneration (nAMD), yet conserved molecular signatures remain to be fully elucidated. Using RNA-seq on RPE/Choroid from a two-stage laser-induced subretinal fibrosis mouse model, we identified a novel core ocular fibrosis signature of 88 persistently upregulated genes across acute-to-chronic phases (days 3–10 post-injury). This signature, enriched in epithelial-mesenchymal transition, complement activation, and inflammatory pathways, showed choroid-specific expression with minimal retinal involvement. Cross-validation in independent chronic mouse data and multiple human AMD datasets (peripheral retina, surgically extracted CNV membranes, and macular RPE/choroid) confirmed progressive enrichment in advanced disease stages. Immunofluorescence in human fibrotic tissue validated key genes (Tenascin C, Tissue Inhibitor of Metalloproteinases-1, and Apelin receptor) with co-localization to myofibroblast-like cells and microglia. This persistent, cross-species-validated signature potentially highlights conserved fibrogenic drivers and offers a translational tool for biomarker development and targeted antifibrotic therapies in nAMD.

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Dysregulated Proline Metabolism Contributes to Subretinal Fibrosis in Neovascular AMD: Therapeutic Potential of Prolyl-4-Hydroxylase Inhibition

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Macrophage elastase (MMP12) critically contributes to the development of subretinal fibrosis

Project description:Macrophage elastase (MMP12) critically contributes to the development of subretinal fibrosis

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Glypican-1 modulates TGF-β signaling to drive subretinal fibrosis through a non-canonical AKT-Cyclin A2 cell cycle axis and its inhibition alleviates fibrosis progression

Project description:Subretinal fibrosis (SRF) is a major cause of irreversible vision loss in neovascular age-related macular degeneration (nAMD) and remains poorly responsive to current anti-vascular endothelial growth factor (anti-VEGF) therapies, with effective therapeutic targets still lacking. Here, using unbiased proteomic profiling of aqueous humor samples from patients with nAMD together with transcriptomic analysis of human choroidal neovascular membranes, we performed cross-omics integration and identified glypican-1 (GPC1) as the only overlapping candidate that was markedly elevated in the aqueous humor of patients with SRF. ELISA validation confirmed significantly increased GPC1 levels in the aqueous humor of patients with SRF, and experimental analyses localized GPC1 expression to retinal pigment epithelial (RPE) cells in vivo. GPC1 expression was markedly upregulated in fibrosis-induced human retinal pigment epithelial cells (ARPE-19) and in mouse models of SRF. Gain- and loss-of-function studies demonstrated that GPC1 promotes fibrotic responses in vitro and in vivo. Mechanistically, GPC1 amplified transforming growth factor-β (TGF-β)-driven fibrotic activation through a non-canonical AKT–Cyclin A2 (CCNA2)-mediated cell cycle axis, thereby enhancing the proliferative and migratory capacities of RPE cells. Importantly, intravitreal administration of a GPC1-neutralizing antibody attenuated SRF in vivo. Collectively, these findings provide mechanistic insight into SRF pathogenesis and support the translational potential of targeting GPC1 to mitigate fibrosis-associated vision loss in nAMD.

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Macrophage elastase (MMP12) critically contributes to the development of subretinal fibrosis.

Project description: Not available

| S-EPMC8985356 | biostudies-literature

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