TWEAK regulates the functions of hair follicle stem cells via the Fn14-Wnt/β-catenin-CXCR4 signalling axis.

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Hair follicle stem cells (HFSCs) are crucial for maintaining cutaneous functions under various pathological conditions, including wounds. Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) interacts with its receptor, fibroblast growth factor-inducible 14 (Fn14), and plays a role in the development and tissue repair of skin diseases. This study aims to elucidate the effects of TWEAK/Fn14 signalling on HFSCs and the associated mechanisms. The expressions of HFSC markers, including K19, integrin β1 and K15, were analysed via immunohistochemistry in normal and Fn14-deficient mouse skin. Primary HFSCs were cultured in vitro and then treated with TWEAK or a chemokine (CXC motif) (CXCR) 4 inhibitor. The phenotype markers and secreted cytokines of HFSCs were assessed via immunofluorescence analysis, Western blotting and real-time polymerase chain reaction. Our results showed that both Fn14 and CXCR4 were highly expressed in hair follicles. Fn14 deficiency led to a decrease in the expression levels of K19 and CD34. Exogenous TWEAK enhanced the expression of K15, K19, integrin β1, tumour necrosis factor receptor type 2 and CXCR4 in cultured HFSCs. Additionally, TWEAK induced the proliferation, migration and cytokine production in HFSCs. Furthermore, the Wnt/β-catenin signalling pathway was upregulated in HFSCs upon TWEAK stimulation, and inhibitors of β-catenin or CXCR4 suppressed the effects of TWEAK on the differentiation and secretory functions of HFSCs. In conclusion, TWEAK/Fn14 interaction regulates the expression of differentiation markers and secretory functions of HFSCs in vitro. Wnt/β-catenin signalling or CXCR4 activation mediates the effects of TWEAK on HFSCs. Targeting the Fn14-Wnt/β-catenin-CXCR4 signalling axis may offer a potential approach for managing HFSC-related skin diseases, such as wounds.