# Hair follicle stem cell fate supports distinct clinical endotypes in hidradenitis suppurativa

## TL;DR

This study identifies distinct hair follicle stem cell differentiation patterns in hidradenitis suppurativa, linking them to three clinical subtypes that could guide personalized treatment.

## Contribution

The study reveals two hair follicle stem cell differentiation trajectories and defines three HS endotypes based on epithelial-immune interactions.

## Key findings

- HF stem cells differentiate into inflammatory IFE basal cells or keratinizing ORS cells in HS.
- Three HS endotypes were identified: inflammatory, keratinizing, and mixed, each with distinct HF cell profiles.
- Altered HF cell populations correlate with immune infiltration and clinical features like fistulas and inflammation.

## Abstract

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease affecting approximately 1% of the global population. Its pathogenesis involves both aberrant keratinization and autoinflammation, but the temporal relationship between these processes remains unclear.

To investigate the role of HF stem cell (HF‐SC) fate in the early pathogenesis of HS.

We performed single‐cell RNA sequencing of HF cell populations from HS patients and healthy donors. We then analysed HF cell composition isolated from perilesional skin of 49 HS patients and integrated these data with clinical phenotypes to define disease endotypes.

Our data revealed two distinct differentiation trajectories of HF stem cells (HF‐SCs): one leading to interfollicular epidermis (IFE) basal cells enriched in inflammatory pathways, and another giving rise to outer root sheath (ORS) cells associated with keratinization. In HS lesions, both populations displayed altered inflammatory phenotypes and were closely linked to immune cell infiltration, pointing to a role in disease heterogeneity. By integrating clinical features with HF cell composition from 49 HS patients, we identified three major endotypes: (i) an inflammatory subtype, marked by T cell infiltration and an expansion of IFE basal cells; (ii) a keratinizing subtype, characterized by ORS enrichment and minimal inflammation; and (iii) a mixed subtype, exhibiting features of follicular remodelling, fistula formation and variable immune involvement.

These findings provide novel insights into the epithelial‐immune interactions that drive HS and support a stratified therapeutic approach tailored to distinct epithelial dysfunctions.

Hidradenitis suppurativa (HS) is a chronic and painful inflammatory skin disease that affects about 1% of the population worldwide. Its causes are not fully understood, and this lack of knowledge limits the development of effective treatments.

In this study, conducted in France, we investigated the role of hair follicle stem cells (HF‐SCs) in HS. Firstly, using single‐cell transcriptomics data, we compared hair follicle (HF) cell populations between HS patients and healthy donors. Secondly, we analysed the composition of HFs in skin biopsies from 49 patients and linked these data with their clinical features.

We found that HF‐SCs can differentiate into two HF populations: (i) the basal interfollicular epidermis, associated with inflammation and, (ii) the outer root sheath, associated with keratinization. In the context of HS, these populations further displayed an altered inflammatory phenotype and were associated with the infiltration of immune cells. Finally, the integrated analysis of clinical features and HF cell composition identified three main endotypes. Each endotype displays a specific enrichment in HF cells and is related to keratinization, inflammation or both.

These findings suggest that the identified HF cell populations and their markers could serve as novel diagnostic biomarkers and therapeutic targets for HS.

Hair follicles (HFs) were extracted from skin biopsies. From these, original sequencing data were obtained and integrated with two independent studies to build a HF single‐cell transcriptomic atlas. It enabled delineating the fate of HF stem cells. Clustering analysis of a patient cohort identified three endotypes, advancing personalized medicine development.