间充质干细胞来源外泌体及衍生miRNA治疗病理性瘢痕的作用机制

miRNA derived from mesenchymal stem cells and its derivatives in treatment of pathological scar

背景:干细胞疗法已成为治疗病理性瘢痕的新兴方法。miRNA参与瘢痕疙瘩发病机制,且部分干细胞来源miRNA的靶向作用由外泌体介导。目的:综述间充质干细胞来源外泌体及衍生miRNA的生物学特性,通过抗炎、抑制过度组织重塑和抗氧化3个方面回顾了间充质干细胞来源外泌体衍生miRNA治疗瘢痕的作用机制。方法:第一作者于2023年9月使用计算机在PubMed、Web of Science、中国知网等数据库检索2000年1月至2023年9月发表的相关文献,以“stem cell,exosome,miRNA,keloid”为英文检索词,以“干细胞,外泌体,瘢痕”为中文检索词,最终纳入74篇文献进行分析。结果与结论:①间充质干细胞来源外泌体高表达的miRNAs通过促进巨噬细胞极化增加M2型巨噬细胞比例,靶向调节转化生长因子β、转化生长因子β受体或相关信号通路,抑制促炎因子的表达、促进抗炎因子的表达等机制抑制炎症反应进而抑制瘢痕病变;②间充质干细胞来源外泌体高表达的miRNAs可以通过减少基质金属蛋白酶分泌,调节基质金属蛋白酶抑制剂与基质金属蛋白酶的平衡,抑制成纤维细胞、肌成纤维细胞的增殖和迁移,直接减少胶原蛋白的产生等机制最终使得细胞外基质正常降解,从而抑制过度的组织重塑而抑制瘢痕病变;③间充质干细胞来源外泌体高表达的miRNAs可以通过调节活性氧和缺氧诱导因子等途径提高瘢痕成纤维细胞对氧化应激的抵抗力,进而调节瘢痕成纤维细胞的增殖凋亡从而抑制瘢痕病变;④间充质干细胞来源外泌体具有较好的瘢痕治疗前景,对该方面的研究可以从炎症、组织重塑、氧化应激3个方面发现对炎症细胞、炎症因子、信号通路、基质金属蛋白酶、成纤维细胞、活性氧、缺氧诱导因子等关键因素起调控作用的miRNA,而后通过诱导高表达以上miRNA的间充质干细胞,提取其外泌体,最后加以验证并进行临床试验。

BACKGROUND:Stem cell therapy has become an emerging method of treating pathological scars.miRNAs are involved in scarring mechanisms,and the targeted action of some stem cell sources of miRNA is mediated by exosomes.OBJECTIVE:To review the biological properties of miRNA derived from mesenchymal stem cells and its derivatives,the mechanism of treatment of scarring through anti-inflammation,suppression of excessive tissue reconstruction and antioxidation.METHODS:The first author used a computer in September 2023 to retrieve the relevant literature published from January 2000 to September 2023,searching for“stem cell,exosome,miRNA,keloid”in English,and“stem cells,exosome,keloid”in Chinese,eventually incorporating 74 papers for analysis.RESULTS AND CONCLUSION:(1)miRNAs with high expression of exosomes derived from mesenchymal stem cells increase the proportion of M2-type macrophages by promoting the polarization of macrophages,target the regulation of transforming growth factorβ,transforming growth factorβreceptors or related signaling pathways,inhibit the expression of pro-inflammatory factors,promote the expression of anti-inflammatory factors and other mechanisms to inhibit inflammation and thus suppress scar lesions.(2)miRNAs with high expression of exosomes derived from mesenchymal stem cells can reduce the secretion of matrix metalloproteinases,regulate the balance between matrix metalloproteinase inhibitors and matrix metalloproteinases,inhibit the proliferation and migration of fibroblasts and myofibroblasts,directly reduce the production of collagen and other mechanisms,and ultimately lead to the normal degradation of extracellular matrix,thereby inhibiting excessive tissue remodeling and cicatricial lesions.(3)miRNAs with high expression of exosomes from mesenchymal stem cells can improve the resistance of scar fibroblasts to oxidative stress by regulating reactive oxygen species and hypoxia-inducing factors,and then regulate the proliferation and apoptosis of scar fibroblasts to inhibit scar lesions.(4)Exosomes derived from mesenchymal stem cells have good prospects for scar treatment.Studies on this aspect can find mirnas that regulate inflammatory cells,inflammatory factors,signaling pathways,matrix metalloproteinases,fibroblasts,reactive oxygen species,hypoxia-inducing factors and other key factors from the three aspects of inflammation,tissue remodeling and oxidative stress.Then,by inducing mesenchymal stem cells with high expression of the above miRNA,exosomes were extracted,and finally verified and clinical trials were carried out.