Abstract

Skin epidermal stem cells (EpSCs) play an important role in wound healing. Quercetin is a phytoestrogen reported to accelerate skin wound healing, but its effect on EpSCs is unknown. In this study, we investigated the effect of quercetin on human EpSC proliferation and explored the underlying mechanisms. We found that quercetin at 0.1~1 μM significantly promoted EpSC proliferation and increased the number of cells in S phase. The pro-proliferative effect of quercetin on EpSCs was confirmed in cultured human skin tissue. Mechanistic studies showed that quercetin significantly upregulated the expressions of β-catenin, c-Myc, and cyclins A2 and E1. Inhibitor for β-catenin or c-Myc significantly inhibited quercetin-induced EpSC proliferation. The β-catenin inhibitor XAV-939 suppressed quercetin-induced expressions of β-catenin, c-Myc, and cyclins A2 and E1. The c-Myc inhibitor 10058-F4 inhibited the upregulation of c-Myc and cyclin A2 by quercetin. Pretreatment of EpSCs with estrogen receptor (ER) antagonist ICI182780, but not the G protein-coupled ER1 antagonist G15, reversed quercetin-induced cell proliferation and upregulation of β-catenin, c-Myc, and cyclin A2. Collectively, these results indicate that quercetin promotes EpSC proliferation through ER-mediated activation of β-catenin/c-Myc/cyclinA2 signaling pathway and ER-independent upregulation of cyclin E1 and that quercetin may accelerate skin wound healing through promoting EpSC proliferation. As EpSCs are used not only in clinic to treat skin wounds but also as seed cells in skin tissue engineering, quercetin is a useful reagent to expand EpSCs for basic research, skin wound treatment, and skin tissue engineering.

中文翻译：

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槲皮素通过雌激素受体/β-catenin/ c-Myc / cyclin A2信号通路促进人表皮干细胞增殖。

摘要

皮肤表皮干细胞（EpSCs）在伤口愈合中起重要作用。槲皮素是一种植物雌激素，据报道可促进皮肤伤口愈合，但其对EpSC的作用尚不清楚。在这项研究中，我们调查了槲皮素对人类EpSC增殖的影响，并探讨了其潜在机制。我们发现，槲皮素在0.1〜1μM时可显着促进EpSC的增殖并增加S期细胞的数量。在培养的人皮肤组织中证实了槲皮素对EpSCs的增殖作用。机理研究表明，槲皮素显着上调了β-catenin，c-Myc和cyclins A2和E1的表达。β-catenin或c-Myc抑制剂可显着抑制槲皮素诱导的EpSC增殖。β-catenin抑制剂XAV-939抑制槲皮素诱导的β-catenin，c-Myc，以及细胞周期蛋白A2和E1。c-Myc抑制剂10058-F4抑制槲皮素上调c-Myc和细胞周期蛋白A2。用雌激素受体（ER）拮抗剂ICI182780而不是G蛋白偶联的ER1拮抗剂G15预处理EpSC，可以逆转槲皮素诱导的细胞增殖和β-catenin，c-Myc和cyclin A2的上调。总体而言，这些结果表明槲皮素通过ER介导的β-catenin/ c-Myc / cyclinA2信号通路的激活和ER依赖性细胞周期蛋白E1的上调来促进EpSC增殖，并且槲皮素可以通过促进EpSC增殖来加速皮肤伤口愈合。由于EpSC不仅在临床上用于治疗皮肤伤口，而且在皮肤组织工程中用作种子细胞，所以槲皮素是扩展EpSC在基础研究，皮肤伤口治疗和皮肤组织工程中的有用试剂。