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干细胞衍生的外泌体在肝脏疾病治疗中的作用
DOI: 10.3969/j.issn.1001-5256.2023.03.034
利益冲突声明：所有作者均声明不存在利益冲突。
作者贡献声明：游绍莉、王卓然负责论文起草与撰写；游绍莉、朱冰负责拟定写作思路，指导撰写文章并最后定稿。
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摘要: 肝脏容易受多种病因影响发生肝损伤，严重情况下可引起其合成、解毒、代谢和生物转化等功能发生障碍，当前针对肝衰竭、失代偿性肝硬化等终末期肝病仍缺乏高效的临床治疗手段。近年来间充质干细胞的临床疗效已被证实，基于干细胞外泌体的相关治疗成为研究热点。本文介绍了干细胞外泌体治疗的优势、机制研究进展、临床前研究现状等。从目前研究结果来看，干细胞衍生的外泌体治疗肝脏疾病具有良好应用前景，但临床前研究仍需进一步深入，临床研究有待开展。Abstract: The liver is easily affected by a variety of factors to induce liver damage, which can cause disorders in the synthesis, detoxification, metabolism, and biotransformation functions of the liver in severe cases, and at present, there is still a lack of efficient clinical treatment methods for end-stage liver diseases such as liver failure and decompensated liver cirrhosis. Recent studies have confirmed the clinical efficacy of stem cells, and treatment methods based on stem cell-derived exosomes have become a research hotspot. This article introduces the advantages of treatment based on stem cell-derived exosomes, the research advances in related mechanisms, and the current status of preclinical research. Current research findings suggest that treatment based on stem cell-derived exosomes has a good application prospect in the treatment of liver diseases, but it is still needed to conduct in-depth preclinical and clinical studies.
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Key words:
- Liver Diseases /
- Stem Cells /
- Mesenchymal Stem Cells /
- Exosomes
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图 1 干细胞外泌体治疗肝脏疾病相关机制示意图
Figure 1. The function of stem cells-derived exosomes in the treatment of liver diseases
图 2 干细胞外泌体相关临床治疗性研究(
https://clinicaltrials.gov/ )Figure 2. Clinical therapeutic studies of stem cells-derived exosomes(
https://clinicaltrials.gov/ )表 1 干细胞外泌体治疗肝脏疾病的实验研究
Table 1. Experimental studies of stem cells-derived exosomes in the treatment of liver diseases
外泌体来源 重要活性因子 疾病模型 动物/细胞 结果 BMSC-Exo - LO2细胞损伤 LO2细胞 促进自噬，减少肝细胞凋亡[32] BMSC-Exo MIP2、IL-6、Y-RNA-1 暴发性肝衰竭 C57BL/6小鼠 减轻炎症反应，提高存活率[33] BMSC-Exo PPARγ、β-catenin等 肝纤维化 Sprague-Dawley大鼠 抑制Wnt/β-catenin信号通路，减轻纤维化程度，抑制炎症，促进肝细胞再生[34] BMSC-Exo miR223-3p 自身免疫性肝炎 C57BL/6小鼠 调节STAT3相关信号通路，抑制炎性细胞因子释放，减轻炎症反应[35] AMSC-Exo miR-17 ALF C57BL/6小鼠 靶向TXNIP，抑制炎症反应，改善肝损伤[36] AMSC-EV - NASH Mc4r-KO小鼠 减轻炎症反应并抑制纤维化[15] AMSC-EV lncRNA H19 ALF Sprague-Dawley大鼠 减轻炎症反应，促进肝细胞的增殖、抑制凋亡[37] ucMSC-Exo - ALF C57BL/6小鼠、LO2细胞 激活IGF-1R/PI3K/AKT和ERK1/2信号通路，减少氧化应激、抑制细胞凋亡[38] ucMSC-Exo GPX1 急性肝损伤 BALB/c-nu/nu小鼠 抑制IKKB/NF-κB/caspase3/9通路，减少氧化应激、抑制细胞凋亡[24] MenSC-Exo ICAM-1、血管生成素-2、Axl 爆发性肝衰竭 C57BL/6小鼠 抑制caspase-3的表达，减少细胞凋亡，降低病死率[39] 注：MIP2，巨噬细胞炎性蛋白2；PPARγ，过氧化物酶体增殖物激活受体γ；ALF，急性肝衰竭；GPX1，谷胱甘肽过氧化物酶1；ICAM，细胞间黏附分子；MenSC-Exo，经血来源间充质干细胞外泌体。 
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表 2 培养环境变化对干细胞外泌体治疗肝脏疾病影响的实验研究
Table 2. Studies on the influence of different culture environments on stem cell-derived exosomes for liver diseases
外泌体来源 预处理方式 模型 动物/细胞 结果 ucMSC-Exo TNFα ALF C57BL/6小鼠 抑制NLRP3信号通路，抑制炎症反应[40] ucMSC-Exo IL-6 急性肝损伤 C57BL/6小鼠 减轻巨噬细胞浸润和局部肝损伤，改善肝脏组织形态和全身疾病[19] AMCS-EV IFNγ 肝硬化 C57BL/6小鼠 减轻炎症反应，抑制肝纤维化[16] AMSC-CM 低氧 部分肝切除 BALB/c小鼠 促进肝再生、抑制促炎细胞因子和降低异常升高的肝酶[22] AMSC-CM IFNγ 缺血再灌注 M1型巨噬细胞和THLE-2细胞 阻断caspase3/7的激活，抑制炎症反应和细胞凋亡[17] BMSC-CM 低氧 ALF BaLb小鼠 减轻ALF的损伤程度，抗炎、抗氧化[25] BMSC-CM 肝细胞共培养 ALF Sprague-Dawley大鼠、L02细胞 增强细胞活力，促进肝脏结构恢复[41] 注：NLRP3，NOD样受体热蛋白结构域相关蛋白3。
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