MiR-4465-modified mesenchymal stem cell-derived small extracellular vesicles inhibit liver fibrosis development via targeting LOXL2 expression
- Author:
WANG YANJIN
1
,
2
;
CHEN YIFEI
;
YANG FUJI
;
YU XIAOLONG
;
CHU YING
;
ZHOU JING
;
YAN YONGMIN
;
XI JIANBO
Author Information
- Keywords: Mesenchymal stem cell(MSC); Small extracellular vesicle(sEV); MicroRNA-4465(miR-4465); Hepatic stellate cell(HSC); Liver fibrosis
- From: Journal of Zhejiang University. Science. B 2024;25(7):594-604,中插17-中插21
- CountryChina
- Language:Chinese
- 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.
