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Single-cell and spatial transcriptomics of vulvar lichen sclerosus reveal multi-compartmental alterations in gene expression and signaling cross-talk

ABSTRACT: Vulvar diseases are a critical but often overlooked issue in women's health, impacting many women and frequently causing long-term physical and emotional challenges. Lichen sclerosus (LS) is a chronic inflammatory skin disease that causes scarring of the vulva and is associated with an increased risk of malignancy. The molecular pathogenesis of vulvar LS (VLS) is not well understood, preventing development of any FDA-approved therapies. Here, we utilize single-cell and spatial transcriptomics to analyze lesional and non-lesional skin from VLS patients, as well as healthy control vulvar skin. Our studies, which reveal histologic, cellular, and molecular heterogeneities within VLS, also identify unifying molecular changes across fibroblasts, immune cells, keratinocytes, and melanocytes in lesional skin. The findings depict a scenario of cellular stress and damage affecting both fibroblasts and keratinocytes, along with a complex immune landscape indicating enhanced CD8+ T cell cytotoxicity but also signs of exhaustion. They further suggest aberrant cell-cell signaling across, and increased activation of IFN, JAK/STAT and p53 pathways in, specific cell types. Using monolayer and organotypic culture models, we demonstrate that the depletion of select genes, which are downregulated in VLS lesional skin keratinocytes, partially recapitulates VLS-like stress-associated changes. Collectively, these data provide novel insights into the pathogenesis of VLS, identifying potential biomarkers and therapeutic targets for future research.

ORGANISM(S): Homo sapiens

PROVIDER: GSE274068 | GEO | 2025/01/27

REPOSITORIES: GEO

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Project description:The autoinflammatory disorder, Neonatal-onset Multisystem Inflammatory Disease (NOMID) is the most severe phenotype of disorders caused by mutations in the CIAS1 gene that result in increased production and secretion of active IL-1≤. NOMID patients present with systemic and organ-specific inflammation of the skin, central nervous system and bony growth plates, and respond dramatically to treatment with IL-1 blocking agents. We compared the cellular infiltrates and transcriptome of skin biopsies from patients with NOMID (n=14) before treatment [lesional (LS) and non-lesional (pre-NL) skin] and after treatment (post-NL) with the IL-1 blocker anakinra (recombinant IL-1 receptor antagonist, Kineret®), to normal skin (n=5). Abundant neutrophils distinguish LS skin from pre-NL and post-NL skin. CD11c+ dermal dendritic cells and CD163+ macrophages expressed activated caspase-1 and are the likely sources of cutaneous IL-1 production. Treatment with anakinra led to the disappearance of neutrophils, but CD3+ T cells and HLA-DR+ cells remained elevated. Among the upregulated genes IL-6, IL-8, TNF, IL-17A, CCL20, and the neutrophil defensins DEFA1 and DEFA3 were differentially regulated in LS tissues (compared to normal skin). Important significantly downregulated pathways included IL-1R/TLR signaling, type I and II cytokine receptor signaling, mitochondrial dysfunction, and antigen presentation. Differential expression and regulation of microRNAs and pathways involved in post-transcriptional modification are indicative of epigenetic modification in the various tissue states. Overall, the dysregulated genes and pathways suggest extensive “adaptive” mechanisms to control inflammation, and maintain tissue homeostasis in the skin of patients with NOMID. To determine the transcsriptome of skin samples in Neonatal-onset Multisystem Inflammatory Disease (NOMID), using pre-treatment non-lesional (pre-NL, n=4); lesional (LS, n=6); post-treatment non-lesional (post-NL, n=8), and normal skin (n=5). Comparison of mean gene expression of each group at baseline, and considering treatment effect

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Single-cell and spatial transcriptomics of vulvar lichen sclerosus reveal multi-compartmental alterations in gene expression and signaling cross-talk

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