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

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.