Abstract：
End-stage of liver fibrosis as a precancerous state could lead to cirrhosis and hepatocellular carcinoma which liver transplantation is the only effective treatment. Previous studies have indicated that farnesoid X receptor (FXR) agonists, such as obeticholic acid (OCA) protect against hepatic injuries. However, free OCA administration results in side effects in clinical trials that could be alleviated by applying bio carriers such as MSC-derived exosomes (Exo) with the potential to mimic the biological regenerative effect of their parent cells, as proposed in this study. Loading OCA into the Exo was conducted via water bath sonication. Ex vivo bio distribution studies validated the Exo-loaded OCA more permanently accumulated in the liver. Using CCL4-induced liver fibrosis, we proposed whether Exo isolated from human Warton\'s Jelly mesenchymal stem cells loaded with a minimal dosage of OCA can facilitate liver recovery. Notably, Exo-loaded OCA exerted additive anti-fibrotic efficacy on histopathological features in CCL4-induced fibrotic mice. Compared to baseline, Exo-mediated delivery OCA results in marked improvements in the fibrotic-related indicators as well as serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) concentrations. Accordingly, the synergistic impact of Exo-loaded OCA as a promising approach is associated with the inactivation of hepatic stellate cells (HSCs), extracellular matrix (ECM) remodeling, and Fxr-Cyp7a1 cascade on CCL4-induced liver fibrosis mice. In conclusion, our data confirmed the additive protective effects of Exo-loaded OCA in fibrotic mice, which suggests a valuable therapeutic strategy to combat liver fibrosis. Furthermore, the use of Exo for accurate drug delivery to the liver tissue can be inspiring.
摘要：
肝纤维化终末期作为癌前状态可导致肝硬化和肝细胞癌，肝移植是唯一有效的治疗方法。先前的研究表明，法尼醇X受体（FXR）激动剂，如奥贝胆酸（OCA）保护免受肝损伤。然而,在临床试验中，游离的OCA给药导致副作用，可以通过应用生物载体如MSC衍生的外泌体（Exo）来缓解，具有模拟其亲本细胞的生物再生效应的潜力，正如本研究中提出的那样。通过水浴超声处理将OCA加载到Exo中。离体生物分布研究验证了外载OCA在肝脏中更永久地积累。使用CCL4诱导的肝纤维化，我们提出了从人类Warton'sJelly间充质干细胞中分离的Exo是否负载了最小剂量的OCA可以促进肝脏恢复。值得注意的是,外载OCA对CCL4诱导的纤维化小鼠的组织病理学特征发挥附加的抗纤维化功效。与基线相比，外介导的递送OCA导致纤维化相关指标以及血清天冬氨酸氨基转移酶(AST)和丙氨酸氨基转移酶(ALT)浓度的显著改善。因此，外载OCA作为一种有前途的方法的协同作用与肝星状细胞（HSC）的失活有关，细胞外基质（ECM）重塑，和Fxr-Cyp7a1级联对CCL4诱导的肝纤维化小鼠的影响。总之,我们的数据证实了外载OCA在纤维化小鼠中的附加保护作用，这表明有价值的治疗策略，以对抗肝纤维化。此外，使用Exo将药物准确输送到肝脏组织可能是鼓舞人心的。
