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Single-cell RNA-sequencing reveals the heterogeneity of microglia in fibrous membrane derived from proliferative diabetic retinopathy and proliferative vitreoretinopathy

ABSTRACT: Fibrous membrane (FM), the hallmark for proliferative diabetic retinopathy (PDR) and proliferative vitreoretinopathy (PVR), can cause hemorrhages and retinal detachment, which may lead to blindness if not properly treated. However, little is known about the pathophysiology of FM. In this study, we successfully employed single-cell RNA sequencing on the small-sized vitreous FMs, and generated a comprehensive cell atlas of FMs derived from PVR and PDR. Distinct cell compositions were identified in the FMs, with microglia as the major cell population. Additionally, our analysis revealed a spectrum of microglia activation states with distinct molecular signatures and intercellular interactions in disease-specific microenvironment. This description of microglia phenotypes in the FM of PVR and PDR may offer insight into the activation of microglia in the FM pathogenesis, as well as potential signaling pathways amenable to disease-specific intervention.

ORGANISM(S): Homo sapiens

PROVIDER: GSE165784 | GEO | 2022/01/27

REPOSITORIES: GEO

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Project description:Purpose: The development of vitreoretinal scars remains an unsolved challenge in clinical practice and often leads to repeated revision surgery and blindness due to lack of efficient therapy. The aim of this study was to characterize the cellular and molecular environment in vitreoretinal scar tissue from patients with proliferative vitreoretinopathy (PVR) in comparison to membranes of the vitreoretinal junction, in order to subsequently identify potential drug treatment options using bioinformatics techniques. Methods: A total of 23 patients undergoing vitrectomy for retinal detachment due to proliferative vitreoretinopathy (PVR, n = 15), idiopathic macular hole (MH, n = 10) or idiopathic macular pucker (MP, n = 8), were included in this study. Vitreoretinal samples were analysed by RNA sequencing, MS-CyTOF proteomic and by conventional immunohistochemistry. The cellular microenvironment was assessed by bioinformatics cell type enrichment analysis. Drug target screening was performed by using a transcriptome-based drug-repurposing approach using drug-exposure transcriptome data from public available databases. Results: RNA sequencing of vitreoretinal tissue samples showed distinct transcriptional differences of PVR, ERM and ILM samples allowing an accurate clustering according to the tissue types. The cellular microenvironment of PVR membranes was characterized by the enrichment of melanocytes, astrocytes and various immune cell types, such as M2 macrophages. Differential gene expression (DEG) analysis revealed XX up- and XX downregulated genes in PVR compared to ILM. Among them, FN1 (fibronectin1), SPARC (osteonectin) and various collagens were among the most upregulated factors in PVR, contributing to biological processes such as the organization of extracellular structures, the regulation of cell adhesion and the morphogenesis of blood vessels. Finally, we identified 13 drugs that induce a gene expression profile complementary to the PVR signature and thus represent potential therapeutic options for PVR, including aminocaproic acid and various topoisomerase 2A inhibitors such as doxorubicin, etoposide and mitoxantrone. Conclusion: The present study reveals significant differences in the transcriptional signature of vitreoretinal scar tissue including PVR, MP and ILM tissue. Among a plethora of differentially expressed genes, FN1 and SPARC appeared to be central mediators underlying PVR development. Based on the transcriptome analyses, aminocaproic acid and topoisomerase-2 inhibitors, such as doxorubicin, etoposide and mitoxantrone, were identified as compatible drugs for the treatment of PVR.

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Single-cell RNA-sequencing reveals the heterogeneity of microglia in fibrous membrane derived from proliferative diabetic retinopathy and proliferative vitreoretinopathy

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