Exosomes Derived from Epidermal Stem Cells Improve Diabetic Wound Healing
Exosomes Derived from Epidermal Stem Cells Improve Diabetic Wound Healing
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表皮干细胞衍生的外泌体可改善糖尿病伤口愈合
DOI：
10.1016/j.jid.2022.01.030
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发表时间：
2022
影响因子：
6.5
通讯作者：
Aristidis Veves
中科院分区：
文献类型：
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作者：
Peng Wang;Georgios Theocharidis;Ioannis S. Vlachos;Konstantinos Kounas;Antonio Lobao;Bin Shu;Biaoliang Wu;Julin Xie;Zhicheng Hu;Shaohai Qi;Bing Tang;Jiayuan Zhu;Aristidis Veves
糖尿病足溃疡是糖尿病的一种主要并发症，其需求尚未得到满足。我们研究了表皮干细胞和表皮干细胞来源的外切体(ESCS-Exo)在改善受损的糖尿病创面愈合方面的效果及其作用机制。体外实验表明，ESCS-Exo可促进糖尿病成纤维细胞和巨噬细胞的增殖和迁移，并促进M2巨噬细胞的交替极化。在db/db小鼠的创面中，与成纤维细胞外切体和PBS对照相比，表皮干细胞和ESCS-Exo联合治疗可以通过减少炎症、促进伤口细胞增殖、刺激血管生成和诱导M2巨噬细胞极化来促进伤口愈合。创伤裂解产物的复合蛋白定量显示转化生长因子β信号受ESCs-Exo的影响。对ESCs-Exo中包含的小RNA进行高通量测序显示，与成纤维细胞外体中包含的相比，microRNAs所占比例更高。电子功能分析表明，ESC-Exo microRNAs靶基因主要参与内环境平衡过程和细胞分化，并强调了对磷脂酰肌醇-3激酶/蛋白激酶B和转化生长因子β信号通路的调控。这也在体外得到了验证。总而言之，我们的结果表明，表皮干细胞和ESCs-Exo在促进受损的糖尿病伤口愈合方面同样有效，ESCs-Exo治疗可能是一种有前途的、技术上具有优势的干细胞治疗替代方案。
Diabetic foot ulceration is a major diabetic complication with unmet needs. We investigated the efficacy of epidermal stem cells and epidermal stem cells–derived exosomes (ESCs-Exo) in improving impaired diabetic wound healing and their mechanisms of action. In vitro experiments showed that ESCs-Exo enhanced the proliferation and migration of diabetic fibroblasts and macrophages and promoted alternative or M2 macrophage polarization. In wounds of db/db mice, treatment with both epidermal stem cells and ESCs-Exo, when compared with fibroblast exosomes and PBS control, accelerated wound healing by decreasing inflammation, augmenting wound cell proliferation, stimulating angiogenesis, and inducing M2 macrophage polarization. Multiplex protein quantification of wound lysates revealed TGFβ signaling influenced by ESCs-Exo. High-throughput sequencing of small RNAs contained in the ESCs-Exo showed higher proportions of microRNAs than those contained in fibroblast exosomes. In silico functional analysis showed that the ESCs-Exo microRNAs‒target genes were primarily involved in homeostatic processes and cell differentiation and highlighted regulatory control of phosphatidylinositol-3 kinase/protein kinase B and TGFβ signaling pathways. This was also validated in vitro. Collectively, our results indicate that epidermal stem cells and ESCs-Exo are equally effective in promoting impaired diabetic wound healing and that ESCs-Exo treatment may be a promising and technically advantageous alternative to stem cell therapies.