Therapeutic effect of exosomes derived from hepatocyte-growth-factor-overexpressing adipose mesenchymal stem cells on liver injury.

IF 16.4 1区化学 Q1 CHEMISTRY, MULTIDISCIPLINARY Accounts of Chemical Research Pub Date : 2023-01-01 Epub Date: 2023-10-03 DOI:10.5603/fhc.95291

Liushenyan Yu, Junchao Xue, Yanyan Wu, Hanyu Zhou

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Abstract

Adipose mesenchymal stem cell-derived exosomes (ADMSC-Exo) are a new strategy for the treatment of liver injury. However, mesenchymal stem cells (MSCs) exert therapeutic effects mainly by secreting hepatocyte growth factor (HGF). Therefore, we investigated the role of exosomes derived from ADMSC that overexpress HGF (ADMSCHGF-Exo) on liver injury.

Material and methods: ADMSCs were isolated from young BALB/c female mice. Then exosomes derived from ADMSC transfecting negative control (ADMSCNC-Exo) and HGF overexpression (ADMSCHGF-Exo) were isolated and identified by quantitative polymerase chain reaction (qPCR), flow cytometry, western blot, transmission electron microscope and Nanosight particle tracking analysis. These exosomes were injected into male mice via tail vein after inducing liver injury by administering 40% carbon tetrachloride (CCl₄)-olive oil twice a week (3 mL/kg, subcutaneously) for 6 weeks. Liver injury and liver collagen fiber accumulation were determined by histopathological analysis. Then, the levels of serum liver function indexes (alanine aminotransferase, aspartate aminotransferase, albumin, total bilirubin), hepatocyte-specific markers (albumin, cytokeratin-18 and hepatocyte nuclear factor 4α), hepatic fibrosis-related proteins (α-smooth muscle actin and collagen I) and Rho GTPase (cell division cycle 42 and ras-related C3 botulinum toxin substrate 1) were determined by Enzyme-linked immunosorbent assay (ELISA), immunohistochemistry, Western blot and qPCR.

Results: ADMSCs were identified by high expression of CD105 and CD44 molecules and low expression of CD45 and CD34. ADMSCs-Exo, ADMSCNC-Exo and ADMSCHGF-Exo transfected cells had similar expression of exosome-specific membrane proteins (CD63, CD81 and CD9). Mice with CCl₄-induced liver injury exhibited abnormal serum liver function indexes, altered expression of hepatocyte-specific markers, hepatic fibrosis-related proteins and Rho GTPase protein as well as histopathological changes and collagen fiber accumulation in the liver. These changes were reversed by ADMSC-Exo, ADMSCNC-Exo and ADMSCHGF-Exo administration with ADMSCHGF-Exo displaying the most significant impact.

Conclusions: ADMSCHGF-Exo exerted a hepatoprotective effect in mice with experimental liver injury by alleviating hepatic fibrosis and restoring liver function.

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来源于肝细胞生长因子的外泌体过表达脂肪间充质干细胞对肝损伤的治疗作用。

脂肪间充质干细胞来源的外泌体（ADMSC-Exo）是治疗肝损伤的一种新策略。然而，间充质干细胞主要通过分泌肝细胞生长因子发挥治疗作用。因此，我们研究了来源于过表达HGF的ADMSC的外泌体（ADMSCHGF-Exo）在肝损伤中的作用。材料和方法：从年轻的BALB/c雌性小鼠中分离ADMSC。然后通过定量聚合酶链式反应（qPCR）、流式细胞术、蛋白质印迹、透射电子显微镜和Nanosight粒子追踪分析分离和鉴定来自ADMSC转染阴性对照（ADMSCNC-Exo）和HGF过表达（ADMSCHGF-Exo。在通过施用40%四氯化碳（CCl）诱导肝损伤后，通过尾静脉将这些外泌体注射到雄性小鼠中₄)-橄榄油，每周两次（3mL/kg，皮下），持续6周。通过组织病理学分析确定肝损伤和肝胶原纤维积聚。然后，测定血清肝功能指标（丙氨酸氨基转移酶、天冬氨酸氨基转移酶和白蛋白、总胆红素）、肝细胞特异性标志物（白蛋白、细胞角蛋白-18和肝细胞核因子4α）的水平，采用酶联免疫吸附试验（ELISA）、免疫组织化学、Western blot和qPCR检测肝纤维化相关蛋白（α-平滑肌肌动蛋白和I型胶原）和Rho GTPase（细胞分裂周期42和ras相关C3肉毒杆菌毒素底物1）。ADMSCs-Exo、ADMSCNC-Exo和ADMSCHGF-Exo转染的细胞具有相似的外泌体特异性膜蛋白（CD63、CD81和CD9）表达。CCl小鼠₄-诱导性肝损伤表现为血清肝功能指标异常、肝细胞特异性标志物、肝纤维化相关蛋白和Rho-GTPase蛋白表达改变、组织病理学变化和肝内胶原纤维积聚。ADMSC-Exo、ADMSCNC-Exo和ADMSCHGF-Exo给药逆转了这些变化，其中ADMSCHGF-Exo表现出最显著的影响。结论：ADMSCHGF-Exo通过减轻肝纤维化和恢复肝功能，对实验性肝损伤小鼠具有保肝作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Accounts of Chemical Research 化学-化学综合

CiteScore

31.40

自引率

1.10%

发文量

312

审稿时长

2 months

期刊介绍： Accounts of Chemical Research presents short, concise and critical articles offering easy-to-read overviews of basic research and applications in all areas of chemistry and biochemistry. These short reviews focus on research from the author’s own laboratory and are designed to teach the reader about a research project. In addition, Accounts of Chemical Research publishes commentaries that give an informed opinion on a current research problem. Special Issues online are devoted to a single topic of unusual activity and significance. Accounts of Chemical Research replaces the traditional article abstract with an article "Conspectus." These entries synopsize the research affording the reader a closer look at the content and significance of an article. Through this provision of a more detailed description of the article contents, the Conspectus enhances the article's discoverability by search engines and the exposure for the research.

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