Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Int Immunopharmacol. 2023 Jun;119:110294. doi: 10.1016/j.intimp.2023.110294. Epub 2023 May 10.
Liver fibrosis is a significant challenge to global health that results in organ failure through inflammation and the release of fibrotic biomarkers. Due to the lack of effective treatments for liver fibrosis, anti-fibrotic and anti-inflammatory therapies are being developed. Since there has been an association between aberrant expression of miR-124 and liver disease progression, we investigated whether delivery of miR-124 through human Wharton's jelly mesenchymal stem cells derived-exosomes (hWJMSC-Exo) can improve liver fibrosis.
We established a 6-week carbon tetrachloride (CCl4)-induced mouse model of liver fibrosis, then we administered hWJMSC-Exo and miR-124-3p-enriched exosomes (ExomiR-124) for three weeks. The extent of fibrosis and inflammation was assessed by histology, biochemistry, Real-time PCR, immunohistochemistry, and Enzyme-linked immunoassays (ELISA). The inflammatory status of the spleen was also investigated using flow cytometry.
Based on the gene and protein expression measurement of IL-6, IL-17, TGF-β, STAT3, α-SMA, and COL1, In vivo administration of Exo and ExomiR-124 effectively reduce collagen accumulation and inhibition of inflammation. Regarding histopathology findings, the therapeutic effect of ExomiR-124 against liver fibrosis was significantly greater than hWJMSC-Exo. In addition, we found that Exo and ExomiR-124 was capable of phenotype switching of splenic monocytes from inflammatory Ly6C to restorative Ly6C.
MSC-derived exosomes demonstrated anti-inflammatory effect via different aspects. Aside from the therapeutic approach, enrichment of exosomes as a nanocarrier by miR-124 revealed the down-regulation of STAT3, which plays a crucial role in liver fibrosis. The anti-inflammatory and anti-fibrotic properties of ExomiR-124 could be a promising option in liver fibrosis combination therapies.
肝纤维化是全球健康的一个重大挑战，它通过炎症和释放纤维化生物标志物导致器官衰竭。由于缺乏有效的肝纤维化治疗方法，正在开发抗纤维化和抗炎治疗方法。由于 miR-124 的异常表达与肝病进展有关，我们研究了通过人 Wharton 胶间充质干细胞衍生的外泌体（hWJMSC-Exo）递送 miR-124 是否可以改善肝纤维化。
我们建立了一个 6 周的四氯化碳（CCl4）诱导的小鼠肝纤维化模型，然后用 hWJMSC-Exo 和富含 miR-124-3p 的外泌体（ExomiR-124）治疗 3 周。通过组织学、生物化学、实时 PCR、免疫组织化学和酶联免疫吸附试验（ELISA）评估纤维化和炎症的程度。还使用流式细胞术研究了脾脏的炎症状态。
基于 IL-6、IL-17、TGF-β、STAT3、α-SMA 和 COL1 的基因和蛋白表达测量，外泌体和 ExomiR-124 的体内给药可有效减少胶原蛋白的积累并抑制炎症。关于组织病理学发现，ExomiR-124 对肝纤维化的治疗效果明显优于 hWJMSC-Exo。此外，我们发现外泌体和 ExomiR-124 能够使脾脏单核细胞从炎症性 Ly6C 表型向修复性 Ly6C 表型转化。
MSC 衍生的外泌体通过不同方面表现出抗炎作用。除了治疗方法外，miR-124 对外泌体作为纳米载体的富集揭示了 STAT3 的下调，STAT3 在肝纤维化中起着至关重要的作用。ExomiR-124 的抗炎和抗纤维化特性可能是肝纤维化联合治疗的一个有前途的选择。
