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On-line Access: 2024-07-17

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Citations:  Bibtex RefMan EndNote GB/T7714

 ORCID:

Yanjin WANG

0000-0003-1020-2178

Yifei CHEN

0009-0000-3382-5672

Yongmin YAN

0000-0002-1990-1170

Jianbo XI

0000-0002-5302-8977

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Journal of Zhejiang University SCIENCE B 2024 Vol.25 No.7 P.594-604

http://doi.org/10.1631/jzus.B2300305


MiR-4465-modified mesenchymal stem cell-derived small extracellular vesicles inhibit liver fibrosis development via targeting LOXL2 expression


Author(s):  Yanjin WANG, Yifei CHEN, Fuji YANG, Xiaolong YU, Ying CHU, Jing ZHOU, Yongmin YAN, Jianbo XI

Affiliation(s):  Department of Laboratory Medicine, Wujin Hospital Affiliated with Jiangsu University, Jiangsu University, Changzhou 213017, China; more

Corresponding email(s):   xjb@wjrmyy.cn, yym@wjrmyy.cn

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


Yanjin WANG, Yifei CHEN, Fuji YANG, Xiaolong YU, Ying CHU, Jing ZHOU, Yongmin YAN, Jianbo XI. 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, 2024, 25(7): 594-604.

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author="Yanjin WANG, Yifei CHEN, Fuji YANG, Xiaolong YU, Ying CHU, Jing ZHOU, Yongmin YAN, Jianbo XI",
journal="Journal of Zhejiang University Science B",
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number="7",
pages="594-604",
year="2024",
publisher="Zhejiang University Press & Springer",
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%T MiR-4465-modified mesenchymal stem cell-derived small extracellular vesicles inhibit liver fibrosis development via targeting LOXL2 expression
%A Yanjin WANG
%A Yifei CHEN
%A Fuji YANG
%A Xiaolong YU
%A Ying CHU
%A Jing ZHOU
%A Yongmin YAN
%A Jianbo XI
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A1 - Yanjin WANG
A1 - Yifei CHEN
A1 - Fuji YANG
A1 - Xiaolong YU
A1 - Ying CHU
A1 - Jing ZHOU
A1 - Yongmin YAN
A1 - Jianbo XI
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DOI - 10.1631/jzus.B2300305


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.

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1,2, 陈逸菲2, 杨馥吉1,2, 虞晓龙3, 楚鹰3, 周静3, 严永敏1,3, 奚剑波3
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。

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

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article

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