FGF21 promotes migration and differentiation of epidermal cells during wound healing via SIRT1‐dependent autophagy
Xixi Chen, Gaozan Tong, Junfu Fan, Yingjie Shen, Nan Wang, Wenjie Gong, Zijing Hu, Kunxuan Zhu, Xiaokun Li, Litai Jin, Weitao Cong, Jian Xiao, Zhongxin Zhu
Abstract
BACKGROUND AND PURPOSE: Migration and differentiation of epidermal cells are essential for epidermal regeneration during wound healing. Fibroblast growth factor 21 (FGF21) plays key roles in mediating a variety of biological activities. However, its role in skin wound healing remains unknown. EXPERIMENTAL APPROACH: mice were constructed and injected with the epidermal-specific Cre virus to elucidate the underlying mechanisms. Migration and differentiation of keratinocytes were evaluated in vitro by cell scratch assays, immunofluorescence, and qRT-RCR. The effects were further assessed when SIRT1, ATG7, ATG5, BECN1, and P53 were silenced. Interactions between SIRT1 and autophagy-related genes were assessed using immunoprecipitation assays. KEY RESULTS: FGF21 was active in fibroblasts and promoted migration and differentiation of keratinocytes following injury. After wounding, SIRT1 expression and autophagosome synthesis were lower in Fgf21 KO mice. Depletion of ATG7 in keratinocytes counteracted the FGF21-induced increases in migration and differentiation, suggesting that autophagy is required for the FGF21-mediated pro-healing effects. Furthermore, epithelial-specific Sirt1 knockout abolished the FGF21-mediated improvements of autophagy and wound healing. Silencing of SIRT1 in keratinocytes, which decreased deacetylation of p53 and autophagy-related proteins, revealed that FGF21-induced autophagy during wound healing was SIRT1-dependent. CONCLUSIONS AND IMPLICATIONS: FGF21 is a key regulator of keratinocyte migration and differentiation during wound healing. FGF21 may be a novel therapeutic target to accelerate would healing.