Fibroblast heterogeneity and FN1-mediated signaling in endometriosis revealed by single-cell and spatial transcriptomics

Wenwen Shao, Hongmei Ju, Zhikai Xiahou, Sheng Fang, Rugen Yan, Chunyan Li, Yuan Xu, Pingping Cai
Frontiers in immunology · 2025 · vol. 16 , pp. 1680849 · doi:10.3389/fimmu.2025.1680849 · PMID:41159025 · W4415097769
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⚙ AI-generated summary by claude@2026-06, 2026-06-07 ⓘ

This study used single-cell and spatial transcriptomics to reveal fibroblast heterogeneity in endometriosis, identifying a C2 CXCR4+ subpopulation that drives fibrosis and immune responses via FN1 signaling.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-07 ⓘ

The paper studied fibroblast heterogeneity and cell–cell communication in endometriosis lesions by integrating single-cell RNA-seq from 15 patients with spatial transcriptomics from two ectopic lesions, using clustering to identify fibroblast subpopulations and CellChat plus spatial deconvolution to map ligand–receptor interactions in situ. It found five fibroblast subtypes among 35 clusters, with the C2 CXCR4+ fibroblast subset showing high proliferative capacity and stemness characteristics and mediating immune- and fibrosis-related signaling via FN1. Functional enrichment, trajectory and stemness analyses, and in vitro experiments involving CXCR4 siRNA and measurements of proliferation and migration supported aspects of CXCR4/FN1-linked behavior in endometriosis-associated fibroblast models. The main limitation explicitly implied by the design is that results rely on transcriptional inference and on validation in cell lines rather than direct in vivo functional confirmation at lesion sites. This paper is centrally about endometriosis — it identifies CXCR4+ FN1-mediated fibroblast signaling and spatial enrichment as potential drivers of fibrotic and immune remodeling in endometriotic lesions.

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Abstract

Background Endometriosis (EM) is a chronic gynecological disorder that affects 5% to 10% of women of childbearing age, often causing pelvic pain and infertility. Fibrosis is a hallmark of EM progression, yet its underlying molecular drivers remain poorly understood. Emerging progress in single-cell and spatial transcriptomic technologies offer new opportunities to unravel the cellular heterogeneity and intercellular interactions driving fibrotic and immune remodeling in EM lesions. Methods We performed an integrative multi-omics analysis combining single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics to dissect fibroblast heterogeneity and cell–cell communication networks in EM. ScRNA-seq data from 15 EM patients (GSE213216) were processed to identify transcriptionally distinct fibroblast subpopulations. Functional enrichment (GO, GSEA), stemness estimation (CytoTRACE), and trajectory inference were applied to reveal lineage plasticity. CellChat was used to infer intercellular signaling networks, and spatial transcriptomic data from two ectopic lesions (GSM6690475, GSM6690476) were analyzed to validate the spatial distribution of key ligand–receptor interactions. Results We identified 35 cell clusters across EM lesions, with Fibroblast and T/NK cells as dominant populations. Fibroblast were divided into five subtypes, which were associated with extracellular matrix remodeling, immune interactions, and metabolic regulation. Notably, the C2 CXCR4 + Fibroblast subpopulation exhibited high proliferative capacity and stemness characteristics, and mediated signaling pathways involved in immune and fibrotic responses through FN1. Spatial transcriptomic analysis confirmed the local enrichment of these Fibroblast in ectopic lesions, where they were associated with regions of active signaling. Conclusion This study revealed the transcriptional and spatial heterogeneity of Fibroblast in EM syndrome, and identified the C2 CXCR4 + Fibroblast subpopulation as a may represent key driver of fibrosis and immune regulation. Our integrated omics approach provided new mechanistic insights into the pathogenesis of EM and pointed out new targets for therapeutic intervention.

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Condition tags

mesh:D004715endometriosisinfertility

MeSH descriptors

Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis

Citation neighborhood

Papers in the corpus that this work cites (lower rings, blue) and that cite this one (upper rings, green). Dot size scales with the paper's in-corpus citation count — bigger dot = more influential within the endo/adeno field. Click a dot to open that paper. [ expand to 2 hops ] — adds papers reached through this work's immediate citers/citees. Heavier; up to 60 extra dots.

References (59)

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