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Background <p>Mesenchymal stem cells (MSCs) secretome have shown promise in the treatment of alopecia areata (AA). However, the key therapeutic genes remain unclear. This study aimed to identify potential critical therapeutic molecules using multi-omics approaches.</p> Methods <p>MSCs extracellular vesicles related genes was retrieved from ExoCarta database, and which integrated with transcriptomic and proteomic sequencing data from AA for cross-analysis to identify AA-related therapeutic genes. Mfuzz clustering, PPI networks, and machine learning algorithms were employed to potential key therapeutic factors. Functional mechanisms were explored through gene expression analysis, immune infiltration, single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics. AA mice were used for experimental validation. </p> Results <p>We identified 146 MSCs-derived genes with potential therapeutic relevance for AA. Enrichment analysis suggests that they are involved in skin development and differentiation. Through Mfuzz clustering, 13 machine learning algorithms, and combined with SHAP interpretability analysis, the KRT6A was we further identified as the most critical candidate gene. Validation analyses demonstrated that KRT6A serves as a robust diagnostic marker for AA (AUC = 0.989), a predictor of disease severity (AUC = 0.769), and a protective factor (HR = 0.52, 95%CI: 0.34–0.79). Immune infiltration analysis revealed severe immune dysregulation in AA, and KRT6A was significantly negative correlated with dysregulated immune cells. By exploring the expression source of KRT6A, we found that it was mainly enriched in skin hair follicle tissues, and single-cell subset analysis and spatial transcriptomics further mapped KRT6A to hair follicle stem-like cells from the cellular level, yet KRT6A was significantly downregulated in AA models. Primary human hair follicle mesenchymal stem cells (HFMSCs) further confirmed KRT6A localization. Furthermore, KRT6A-overexpressing HFMSCs exhibited enhanced migration, whereas KRT6A knockdown reduced migration and suppressed WNT pathway activation. Conditioned medium from KRT6A-overexpressing HFMSCs effectively alleviated alopecia and reduced apoptosis in AA mice, whereas KRT6A knockdown reversed these effects.</p> Conclusion <p>MSCs-derived KRT6A may serve as a potentia biomarker and therapeutic target for AA, which provide novel insights into AA pathogenesis and may help the development of targeted therapeutic strategies.</p>

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KRT6A derived from mesenchymal stem cells as a potential biomarker and therapeutic target for alopecia areata: insights from multi-omics analysis and experimental evidence

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月29日

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  • Shixiong Peng,
  • Jia Deng,
  • Xiuming Meng,
  • Shuangjie Deng,
  • Wenjie Yan,
  • Xi Huang

摘要

Background

Mesenchymal stem cells (MSCs) secretome have shown promise in the treatment of alopecia areata (AA). However, the key therapeutic genes remain unclear. This study aimed to identify potential critical therapeutic molecules using multi-omics approaches.

Methods

MSCs extracellular vesicles related genes was retrieved from ExoCarta database, and which integrated with transcriptomic and proteomic sequencing data from AA for cross-analysis to identify AA-related therapeutic genes. Mfuzz clustering, PPI networks, and machine learning algorithms were employed to potential key therapeutic factors. Functional mechanisms were explored through gene expression analysis, immune infiltration, single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics. AA mice were used for experimental validation.

Results

We identified 146 MSCs-derived genes with potential therapeutic relevance for AA. Enrichment analysis suggests that they are involved in skin development and differentiation. Through Mfuzz clustering, 13 machine learning algorithms, and combined with SHAP interpretability analysis, the KRT6A was we further identified as the most critical candidate gene. Validation analyses demonstrated that KRT6A serves as a robust diagnostic marker for AA (AUC = 0.989), a predictor of disease severity (AUC = 0.769), and a protective factor (HR = 0.52, 95%CI: 0.34–0.79). Immune infiltration analysis revealed severe immune dysregulation in AA, and KRT6A was significantly negative correlated with dysregulated immune cells. By exploring the expression source of KRT6A, we found that it was mainly enriched in skin hair follicle tissues, and single-cell subset analysis and spatial transcriptomics further mapped KRT6A to hair follicle stem-like cells from the cellular level, yet KRT6A was significantly downregulated in AA models. Primary human hair follicle mesenchymal stem cells (HFMSCs) further confirmed KRT6A localization. Furthermore, KRT6A-overexpressing HFMSCs exhibited enhanced migration, whereas KRT6A knockdown reduced migration and suppressed WNT pathway activation. Conditioned medium from KRT6A-overexpressing HFMSCs effectively alleviated alopecia and reduced apoptosis in AA mice, whereas KRT6A knockdown reversed these effects.

Conclusion

MSCs-derived KRT6A may serve as a potentia biomarker and therapeutic target for AA, which provide novel insights into AA pathogenesis and may help the development of targeted therapeutic strategies.