Geriatric Department, 117947Jining No. 1 People's Hospital, Jining, Shandong, China.
Hum Exp Toxicol. 2020 Dec;39(12):1619-1627. doi: 10.1177/0960327120931152. Epub 2020 Jul 7.
Prolonged parenchymal cell death leads to activation of fibrogenic cells, extracellular matrix accumulation, and eventually liver fibrosis. Increasing evidence shows that exosomes (Exos) secreted by adipose-derived mesenchymal stem cells (ADSCs) can be used to deliver circular RNAs (circRNAs) to treat liver fibrosis. To explore the uses of circRNA, circRNA expression profiles of hepatic tissue from normal and CCl-induced mice were analyzed using high-throughput circRNA microarrays. The result showed that mmu_circ_0000623 expression was downregulated in CCl-induced mice. Bioinformatics analysis and luciferin reporter experiments showed that mmu_circ_0000623 interacted with and regulated miR-125/ATG4D. In vitro and in vivo experiments showed that Exos from ADSCs, especially from mmu_circ_0000623-modified ADSCs, significantly suppressed CCl-induced liver fibrosis by promoting autophagy activation. Autophagy inhibitor treatment significantly reversed the treatment effects of Exos. Proteins involved in autophagy and autophagy plaques positive for ATG4D expression were regulated by mmu_circ_0000623/miR-125. Our study found that Exos derived from mmu_circ_0000623-modified ADSCs prevented liver fibrosis via activating autophagy.
实质细胞的长期死亡会导致成纤维细胞的激活、细胞外基质的积累，并最终导致肝纤维化。越来越多的证据表明，脂肪间充质干细胞（ADSCs）分泌的外泌体（Exos）可用于递送环状 RNA（circRNA）来治疗肝纤维化。为了探索 circRNA 的用途，使用高通量 circRNA 微阵列分析了正常和 CCl 诱导的小鼠肝组织中的 circRNA 表达谱。结果表明，mmu_circ_0000623 在 CCl 诱导的小鼠中表达下调。生物信息学分析和荧光素酶报告实验表明，mmu_circ_0000623 与 miR-125/ATG4D 相互作用并调节其表达。体外和体内实验表明，ADSCs 来源的外泌体，特别是 mmu_circ_0000623 修饰的 ADSCs 来源的外泌体，通过促进自噬激活显著抑制 CCl 诱导的肝纤维化。自噬抑制剂处理显著逆转了外泌体的治疗效果。自噬和自噬斑中与 ATG4D 表达相关的蛋白受到 mmu_circ_0000623/miR-125 的调节。我们的研究发现，mmu_circ_0000623 修饰的 ADSCs 来源的外泌体通过激活自噬来预防肝纤维化。
