Department of Laboratory Medicine, Wujin Hospital Affiliated with Jiangsu University, Jiangsu University, Changzhou 213017, China.
Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang 212013, China.
J Zhejiang Univ Sci B. 2024 May 17;25(7):594-604. doi: 10.1631/jzus.B2300305.
Liver fibrosis is a significant health burden, marked by the consistent deposition of collagen. Unfortunately, the currently available treatment approaches for this condition are far from optimal. Lysyl oxidase-like protein 2 (LOXL2) secreted by hepatic stellate cells (HSCs) is a crucial player in the cross-linking of matrix collagen and is a significant target for treating liver fibrosis. Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEVs) have been proposed as a potential treatment option for chronic liver disorders. Previous studies have found that MSC-sEV can be used for microRNA delivery into target cells or tissues. It is currently unclear whether microRNA-4465 (miR-4465) can target LOXL2 and inhibit HSC activation. Additionally, it is uncertain whether MSC-sEV can be utilized as a gene therapy vector to carry miR-4465 and effectively inhibit the progression of liver fibrosis. This study explored the effect of miR-4465-modified MSC-sEV (MSC-sEV) on LOXL2 expression and liver fibrosis development. The results showed that miR-4465 can bind specifically to the promoter of the gene in HSC. Moreover, MSC-sEV inhibited HSC activation and collagen expression by downregulating LOXL2 expression in vitro. MSC-sEV injection could reduce HSC activation and collagen deposition in the CCl-induced mouse model. MSC-sEV mediating via LOXL2 also hindered the migration and invasion of HepG2 cells. In conclusion, we found that MSC-sEV can deliver miR-4465 into HSC to alleviate liver fibrosis via altering LOXL2, which might provide a promising therapeutic strategy for liver diseases.
肝纤维化是一种严重的健康负担，其特征是胶原蛋白的持续沉积。不幸的是，目前针对这种疾病的治疗方法远非理想。肝星状细胞（HSCs）分泌的赖氨酰氧化酶样蛋白 2（LOXL2）是基质胶原交联的关键因子，也是治疗肝纤维化的重要靶点。间充质干细胞衍生的小细胞外囊泡（MSC-sEV）已被提议作为治疗慢性肝脏疾病的潜在治疗选择。先前的研究发现，MSC-sEV 可用于将 microRNA 递送至靶细胞或组织。目前尚不清楚 microRNA-4465（miR-4465）是否可以靶向 LOXL2 并抑制 HSC 活化。此外，尚不清楚 MSC-sEV 是否可作为基因治疗载体携带 miR-4465 并有效抑制肝纤维化的进展。本研究探讨了 miR-4465 修饰的 MSC-sEV（MSC-sEV）对 LOXL2 表达和肝纤维化发展的影响。结果表明，miR-4465 可以特异性结合 HSC 基因的启动子。此外，MSC-sEV 通过下调 LOXL2 的表达在体外抑制 HSC 活化和胶原表达。MSC-sEV 注射可减少 CCl 诱导的小鼠模型中 HSC 的活化和胶原沉积。MSC-sEV 通过 LOXL2 介导也阻碍了 HepG2 细胞的迁移和侵袭。总之，我们发现 MSC-sEV 可以通过改变 LOXL2 将 miR-4465 递送至 HSC 以减轻肝纤维化，这可能为肝脏疾病提供一种有前途的治疗策略。
