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Hair follicle stem cell fate supports distinct clinical endotypes in Hidradenitis Suppurativa

ABSTRACT: Hidradenitis suppurativa (HS) is a severe skin disorder affecting 1% of the global population. Its pathogenesis is multifactorial and poorly understood, involving aberrant keratinization and autoinflammation. Whether autoinflammatory events precede or follow hyperkeratotic changes in hair follicle (HF) epithelia is unknown. Using single-cell RNA sequencing (scRNA-Seq), we defined the cellular composition of HF cells, the primary cells involved in HS, and confirmed these findings in the Fol-HYDRA cohort. We identified three main cell families: i) HF matrix lineage enriched for MSX2, ii) non-matrix lineage enriched for KRT14, and iii) immune cells enriched for PTPRC. Unsupervised clustering of HF cells from controls and HS patients revealed significant differences in non-matrix cells, segregating patients into two groups. Group one is enriched in cluster 1 (IBL), while group two is enriched in cluster 0 (mORS), each displaying distinct transcriptomic changes. Gene set enrichment analysis showed IBLs enriched for keratinization genes and mORS for interferon response genes. Trajectory analysis revealed HF stem cells differentiating into either IBL or mORS pathways. Confirmed in 49 HS patients, these pathways correspond to different clinical phenotypes. Our findings provide a novel perspective on HS pathology, identifying two key pathways: one in keratinization and the other in inflammation. These pathways define different endotypes for HS patients, suggesting potential markers for personalized medicine.

ORGANISM(S): Homo sapiens

PROVIDER: GSE273109 | GEO | 2025/06/02

REPOSITORIES: GEO

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Project description:Vascular dysfunction and chronic inflammation are characteristics of obesity-induced adipose tissue dysfunction. Proinflammatory cytokines can drive an endothelial-to-mesenchymal transition (EndoMT), where endothelial cells undergo a phenotypic switch to mesenchymal-like cells that are pro-inflammatory and pro-fibrotic. In this study, we sought to determine whether obesity can promote EndoMT in adipose tissue. Mice in which endothelial cells are lineage-traced with eYFP were fed a high-fat/high-sucrose (HF/HS) or Control diet for 13, 26, and 52 weeks, and EndoMT was assessed in adipose tissue depots as percentage of CD45-CD31-Acta2+ mesenchymal-like cells that were eYFP+. EndoMT was also assessed in human adipose endothelial cells through cell culture assays and by the analysis of single cell RNA sequencing datasets obtained from the visceral adipose tissues of obese individuals. Quantification by flow cytometry showed that mice fed a HF/HS diet display a time-dependent increase in EndoMT over Control diet in subcutaneous adipose tissue (+3.0%, +2.6-fold at 13 weeks; +10.6%, +3.2-fold at 26 weeks; +11.8%, +2.9-fold at 52 weeks) and visceral adipose tissue (+5.5%, +2.3-fold at 13 weeks; +20.7%, +4.3-fold at 26 weeks; +25.7%, +4.8-fold at 52 weeks). Transcriptomic analysis revealed that EndoMT cells in visceral adipose tissue have enriched expression of genes associated with inflammatory and TGFb signaling pathways. Human adipose-derived microvascular endothelial cells cultured with TGF-β1, IFN-γ, and TNF-⍺ exhibited a similar upregulation of EndoMT markers and induction of inflammatory response pathways. Analysis of single cell RNA sequencing datasets from visceral adipose tissue of obese patients revealed a nascent EndoMT sub-cluster of endothelial cells with reduced PECAM1 and increased ACTA2 expression, which was also enriched for inflammatory signaling genes and other genes associated with EndoMT. These experimental and clinical findings show that chronic obesity can accelerate EndoMT in adipose tissue. We speculate that EndoMT is a feature of adipose tissue dysfunction that contributes to local inflammation and the systemic metabolic effects of obesity.

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Hair follicle stem cell fate supports distinct clinical endotypes in Hidradenitis Suppurativa

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