miRNA-221-3p in Endothelial Progenitor Cell-Derived Exosomes Accelerates Skin Wound Healing in Diabetic Mice
miRNA-221-3p in Endothelial Progenitor Cell-Derived Exosomes Accelerates Skin Wound Healing in Diabetic Mice
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DOI：
10.2147/dmso.s243549
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发表时间：
2020-04
期刊：
影响因子：
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通讯作者：
Juan Xu;Suwen Bai;Yadi Cao;Lei Liu;Yang Fang;Juan Du;Li Luo;Mingwei Chen;Bing Shen
中科院分区：
文献类型：
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作者：
Juan Xu;Suwen Bai;Yadi Cao;Lei Liu;Yang Fang;Juan Du;Li Luo;Mingwei Chen;Bing Shen
背景糖尿病皮肤溃疡患者经历经济负担和较低的生活质量和预期寿命。内皮祖细胞（EPC）衍生的外泌体通过积极调节血管内皮细胞功能促进皮肤伤口愈合。外泌体通过microRNA（miRNA）发挥重要的调控作用。我们探讨了miRNA在EPC来源的外泌体愈合糖尿病皮肤伤口中的潜在作用和分子机制。方法从小鼠骨髓来源的EPCs培养液中分离外泌体。采用高通量测序技术检测外泌体miRNA的表达，并利用在线数据库预测miRNA靶基因。建立糖尿病小鼠皮肤伤口模型，并用外泌体、miRNA-221- 3 p或磷酸盐缓冲盐水处理伤口。结果EPCs分泌的外泌体促进糖尿病小鼠和对照小鼠皮肤创面愈合。高通量测序结果显示miRNA-221- 3 p在EPC来源的外泌体中高度表达。对照和糖尿病小鼠的皮肤伤口愈合通过EPC衍生的外泌体和miRNA-221- 3 p施用显著增强。免疫组织化学分析显示，EPC衍生的外泌体和miRNA-221- 3 p增加了血管生成相关因子VEGF、CD 31和细胞增殖标志物Ki 67的蛋白表达水平。生物信息学分析表明，miRNA-221- 3 p可能参与了糖尿病并发症的AGE-beta信号通路、细胞周期和p53信号通路。结论miRNA-221- 3 p是EPC来源exosomes中高表达的miRNA之一，可促进糖尿病小鼠皮肤创面愈合。这一发现揭示了EPC来源的外泌体的分子机制，并为糖尿病皮肤伤口的临床治疗提供了一种潜在的新方法。
Background Patients with diabetic cutaneous ulcers experience financial burden and a lower quality of life and life expectancy. Endothelial progenitor cell (EPC)-derived exosomes facilitate skin wound healing by positively modulating vascular endothelial cell function. Exosomes play their important regulatory role through microRNA (miRNA). We explored the potential role and molecular mechanisms of miRNA in EPC-derived exosome healing of diabetic skin wounds. Methods Exosomes were isolated from the media of EPCs derived from mice bone marrow. High-throughput sequencing was used to detect the expression of exosome miRNA, and miRNA target genes were predicted using online databases. A diabetic mouse skin wound model was established, and wounds were treated with exosomes, miRNA-221-3p, or phosphate-buffered saline. Results Exosomes from EPCs accelerated skin wound healing in both control and diabetic mice. High-throughput sequencing showed that miRNA-221-3p was highly expressed in EPC-derived exosomes. Skin wound healing in control and diabetic mice was significantly enhanced by EPC-derived exosomes and miRNA-221-3p administration. Immunohistochemical analyses showed that EPC-derived exosomes and miRNA-221-3p increased protein expression levels of the angiogenesis-related factors VEGF, CD31 and cell proliferation marker Ki67. Bioinformatics analyses indicated that miRNA-221-3p may be involved in the AGE-RAGE signaling pathway in diabetic complications, cell cycle, and the p53 signaling pathway. Conclusion We concluded that miRNA-221-3p is one of the high-expressed miRNAs in EPC-derived exosomes and promoted skin wound healing in diabetic mice. The finding uncovers the molecular mechanism of EPC-derived exosomes and provides a potential novel approach to the clinical treatment of diabetic skin wounds.