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

王岩金; 陈逸菲; 杨馥吉; 虞晓龙; 楚鹰; 周静; 严永敏; 奚剑波

doi:10.1631/jzus.B2300305

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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

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Research Article | Updated：2024-07-17

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
MiR-4465-modified mesenchymal stem cell-derived small extracellular vesicles inhibit liver fibrosis development via targeting LOXL2 expression
浙江大学学报（英文版）（B辑：生物医学和生物技术） 2024年25卷第7期页码：594-604
Affiliations：

1.Department of Laboratory Medicine, Wujin Hospital Affiliated with Jiangsu University, Jiangsu University, Changzhou 213017, China
2.Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang 212013, China
3.Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Wujin Clinical College of Xuzhou Medical University, Changzhou 213017, China
Funds：

the National Natural Science Foundation of China(82272421);the Jiangsu Provincial Key Research and Development Program(BE2021690);the Changzhou’s 14th Five-year Plan Project to Train High-level Health Professionals(2022CZLJ027);the Scientific Project of Jiangsu Health Commission(Z2020038);the Changzhou Sci & Tech Program(CJ20220164)
DOI：10.1631/jzus.B2300305
中图分类号：
CSTR：
纸质出版日期： 2024-07-15 ，

网络出版日期： 2024-05-17 ，

收稿日期： 2023-05-09 ，

修回日期： 2023-07-29 ，
Accepted：

王岩金,陈逸菲,杨馥吉等.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[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2024,25(07):594-604.

Yanjin WANG, Yifei CHEN, Fuji YANG, et al. MiR-4465-modified mesenchymal stem cell-derived small extracellular vesicles inhibit liver fibrosis development via targeting LOXL2 expression[J]. Journal of Zhejiang University-SCIENCE B (Biomedicine & Biotechnology), 2024,25(7):594-604.
王岩金,陈逸菲,杨馥吉等.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[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2024,25(07):594-604. DOI： 10.1631/jzus.B2300305.

Yanjin WANG, Yifei CHEN, Fuji YANG, et al. MiR-4465-modified mesenchymal stem cell-derived small extracellular vesicles inhibit liver fibrosis development via targeting LOXL2 expression[J]. Journal of Zhejiang University-SCIENCE B (Biomedicine & Biotechnology), 2024,25(7):594-604. DOI： 10.1631/jzus.B2300305.

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-sEV

miR-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-sEV

miR-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-sEV

miR-4465

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

miR-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。

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 liv

er fibrosis. This study explored the effect of miR-4465-modified MSC-sEV (MSC-sEV

miR-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-sEV

miR-4465

inhibited HSC activation and collagen expression by downregulating LOXL2 expression in vitro. MSC-sEV

miR-4465

injection could reduce HSC activation and collagen deposition in the CCl

-induced mouse model. MSC-sEV

miR-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.

关键词

间质干细胞（MSC）小细胞外囊泡MiR-4465肝星状细胞（HSC）肝纤维化

Keywords

Mesenchymal stem cell (MSC)Small extracellular vesicle (sEV)MicroRNA-4465 (miR-4465)Hepatic stellate cell (HSC)Liver fibrosis

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