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Single-cell transcriptomic profiling of frontal fibrosing alopecia reveals preserved cellular architecture with stress-driven epithelial reprogramming and non-cytotoxic inflammation

ABSTRACT: Background: Frontal fibrosing alopecia (FFA) is a primary cicatricial alopecia characterised by progressive follicular fibrosis and irreversible hair loss. Despite increasing clinical recognition, the cellular mechanisms sustaining disease persistence remain incompletely defined. Objectives: To define cell-type–specific transcriptional states and inter-compartmental signalling networks in lesional scalp from patients with FFA using single-cell RNA sequencing. Methods: Single-cell RNA sequencing was performed on lesional scalp biopsies from patients with FFA (n = 4) and matched control samples (n = 4). Cells were annotated into major lineages and refined subpopulations, and functional programmes and ligand–receptor-mediated communication were analysed. Results: Analysis of 38,984 high-quality cells revealed preservation of overall cellular composition and lineage architecture in FFA compared with controls. Despite this stability, marked disease-associated transcriptional reprogramming was observed across epithelial, immune and stromal compartments. Keratinocytes retained compartment-specific identity but exhibited prominent activation of stress-response and inflammatory pathways, particularly within upper follicle and bulge/outer root sheath populations. Dermal fibroblasts aligned along a continuous inflammation–fibrosis axis, with relative expansion of inflammatory and ACTA2⁺ states and strengthened coupling between inflammatory and fibrotic programmes. Immune profiling demonstrated skewing of CD4⁺ T cells towards Th1-, Th2- and Th22-associated signatures, together with macrophage reprogramming towards pro-fibrotic, tissue-remodelling states. Ligand–receptor analysis identified TGFB-centred signalling as the dominant inter-compartmental communication axis linking epithelial stress to immune modulation and fibroblast activation. Conclusions: FFA exhibits preserved cellular architecture but extensive, compartment-specific transcriptional reprogramming. Chronic epithelial stress and TGFB-driven inter-compartmental signalling, rather than overt cytotoxic inflammation, emerge as central disease mechanisms.

ORGANISM(S): Homo sapiens

PROVIDER: GSE314972 | GEO | 2026/06/29

REPOSITORIES: GEO

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Project description:Background: Alopecia areata (AA) is an autoimmune hair loss disorder characterized by follicular destruction. While bulk transcriptomic studies have identified contributory inflammatory axes, specific cell pathways remain underexplored. Objective: To characterize the single-cell transcriptomic landscape underpinning AA scalp compared to healthy controls. Methods: We performed single-cell RNA-sequencing on lesional and nonlesional scalp biopsies from 13 patients with moderate-to-severe AA (5 with alopecia totalis/universalis [AT/AU]) and 11 healthy controls. Results: Overall, we profiled 41,067 high-quality cells. Lesional AA samples demonstrated robust Th1 activation and cytotoxicity, with upregulated IFNG, GZMH/K, and XCL1/2. Concurrently, Th2 skewing (IL13, IL13RA1, IL4R) and TNFRSF4/OX40 elevations in lesional CD4+ and regulatory T-cells were also observed. IL15, JAK2/3, and STAT1 levels were increased in distinct lesional dendritic cell subsets, with JAK/STAT genes also upregulated in fibroblasts and keratinocytes. Fibroblasts and smooth muscle cells exhibited enriched pro-inflammatory and pro-fibrotic markers (CXCL9, CCL26, POSTN, COL5A3, COL6A6). Lesional keratinocytes further demonstrated downregulated hair keratins and increased interferon signaling. AA endothelial cells showed increased angiogenic and interferon signatures. Compared to patchy AA and controls, AT/AU demonstrated higher expression of multiple cytotoxic, Th1, Th2, and JAK/STAT markers in immune cells, and proliferative and inflammatory signatures in non-immune cells. Conclusion: This comprehensive high-resolution single-cell map uncovers potential communication networks between immune and non-immune cell populations in AA scalp, possibly disrupting immune privilege at the hair follicle and driving disease progression and/or severity. Clinical Implications: These data provide single-cell-resolution insights into AA pathogenesis and potential molecular targets for precision therapies tailored to AA severity.

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Single-cell transcriptomic profiling of frontal fibrosing alopecia reveals preserved cellular architecture with stress-driven epithelial reprogramming and non-cytotoxic inflammation

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