FGF21 promotes migration and differentiation of epidermal cells during wound healing via SIRT1-dependent autophagy
FGF21 promotes migration and differentiation of epidermal cells during wound healing via SIRT1-dependent autophagy
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FGF21 通过 SIRT1 依赖性自噬促进伤口愈合过程中表皮细胞的迁移和分化
DOI：
10.1111/bph.15701
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发表时间：
2021-11-16
影响因子：
7.3
通讯作者：
Zhu, Zhongxin
中科院分区：
文献类型：
--
作者：
Chen, Xixi;Tong, Gaozan;Zhu, Zhongxin
背景和目的表皮细胞的迁移和分化是创伤愈合过程中表皮再生的关键。成纤维细胞生长因子21（FGF 21）在介导多种生物学活性中起关键作用。然而，其在皮肤伤口愈合中的作用仍然未知。使用Fgf 21敲除（Fgf 21 KO）小鼠来确定FGF 21对伤口愈合的影响。通过免疫组化、免疫印迹和ELISA测定确定FGF 21的来源及其靶细胞。此外，Sirt 1（flox/flox）和Atg 7（flox/flox）小鼠的构建和注射表皮特异性Cre病毒，以阐明潜在的机制。通过细胞划痕试验、免疫荧光和qRT-RCR在体外评价角质形成细胞的迁移和分化。当SIRT 1、ATG 7、ATG 5、BECN 1和P53被沉默时，进一步评估效果。SIRT 1和自噬相关基因之间的相互作用使用免疫沉淀分析进行了评估。FGF 21在成纤维细胞中具有活性，并促进损伤后角质形成细胞的迁移和分化。创伤后，SIRT 1表达和自噬体合成在Fgf 21 KO小鼠中较低。角质形成细胞中ATG 7的消耗抵消了FGF 21诱导的迁移和分化的增加，表明自噬是FGF 21介导的促愈合作用所需的。此外，上皮特异性Sirt 1敲除消除了FGF 21介导的自噬和伤口愈合的改善。SIRT 1在角质形成细胞中的沉默，减少了p53和自噬相关蛋白的脱乙酰化，揭示了在伤口愈合过程中FGF 21诱导的自噬是SIRT 1依赖的。结论和意义FGF 21是伤口愈合过程中角质形成细胞迁移和分化的关键调节因子。FGF 21可能成为促进伤口愈合的新的治疗靶点。
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 Fgf21 knockout (Fgf21 KO) mice were used to determine the effect of FGF21 on wound healing. The source of FGF21 and its target cells were determined by immunohistochemistry, immunoblotting, and ELISA assay. Moreover, Sirt1(flox/flox) and Atg7(flox/flox) 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.