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Journal of Zhejiang University SCIENCE B
ISSN 1673-1581(Print), 1862-1783(Online), Monthly
2024 Vol.25 No.7 P.594-604
MiR-4465-modified mesenchymal stem cell-derived small extracellular vesicles inhibit liver fibrosis development via targeting LOXL2 expression
Abstract: 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-sEVmiR-4465) on LOXL2 expression and liver fibrosis development. The results showed that miR-4465 can bind specifically to the promoter of the LOXL2 gene in HSC. Moreover, MSC-sEVmiR-4465 inhibited HSC activation and collagen expression by downregulating LOXL2 expression in vitro. MSC-sEVmiR-4465 injection could reduce HSC activation and collagen deposition in the CCl4-induced mouse model. MSC-sEVmiR-4465 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.
Key words: Mesenchymal stem cell (MSC); Small extracellular vesicle (sEV); MicroRNA-4465 (miR-4465); Hepatic stellate cell (HSC); Liver fibrosis
Chinese Summary <35> MiR-4465修饰的间质干细胞来源的小细胞外囊泡通过靶向LOXL2表达抑制肝纤维化的进展
1江苏大学附属武进医院检验科， 中国常州市， 213017
2江苏大学医学院检验医学系， 中国镇江市， 212013
3常州市分子诊断与肿瘤精准医学重点实验室， 徐州医科大学武进临床学院， 中国常州市， 213017
摘要：肝纤维化是慢性肝病向肝硬化发展的关键病理过程，其特征是胶原蛋白的过量沉积。然而，目前对于肝纤维化仍缺乏有效的治疗方法。肝星状细胞（HSC）分泌的赖氨酰氧化酶样蛋白2（LOXL2）是胶原交联和HSC活化的关键分子，也是治疗肝纤维化的重要靶点。研究表明，间质干细胞来源的小细胞外囊泡（MSC-sEV）是治疗慢性肝病的有效方法。MSC-sEV可将miRNA递送到靶细胞或组织中。但目前尚不明确miR-4465是否能够靶向LOXL2抑制HSC活化，同时MSC-sEV是否可以作为基因治疗载体通过携带miR-4465从而抑制肝纤维化进展也不清楚。本研究探讨了miR-4465对于LOXL2的调控作用及miR-4465修饰的MSC-sEV（MSC-sEVmiR-4465）对LOXL2表达和肝纤维化进展的影响。结果表明，miR-4465可以靶向HSC中LOXL2基因的启动子。此外，MSC-sEVmiR-4465在体外通过下调LOXL2的表达来抑制HSC的活化和胶原的表达。而MSC-sEVmiR-4465注射可减少CCl4诱导的小鼠模型中HSC的活化和胶原沉积。MSC-sEVmiR-4465也能通过调控LOXL2抑制肝癌细胞HepG2的迁移和侵袭。总之，我们发现MSC-sEV可以通过递送miR-4465到HSC中靶向LOXL2延缓肝纤维化的进展，有望成为未来肝病治疗的一种新策略。
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DOI:
10.1631/jzus.B2300305
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On-line Access:
2024-08-27
Received:
2023-10-17
Revision Accepted:
2024-05-08
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2024-07-17
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