microRNA-186 in extracellular vesicles from bone marrow mesenchymal stem cells alleviates idiopathic pulmonary fibrosis via interaction with SOX4 and DKK1

Stem Cell Research & Therapy

Jing Zhou¹  Xiuhua Kang¹  Wei Zhang¹  Yang Lin¹  Fei Xu¹  Zhicheng Liu¹ 

[1] Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanchang University, No. 17, Yongwaizheng Street, 330006, Nanchang, Jiangxi Province, China;

关键词: Idiopathic pulmonary fibrosis;    Fibroblasts;    Human bone marrow mesenchymal stem cells;    Extracellular vesicles;    microRNA-186;    SRY-related HMG box transcription factor 4;   

DOI  :  10.1186/s13287-020-02083-x

来源: Springer

【 摘 要 】

BackgroundPrevious reports have identified that human bone marrow mesenchymal stem cell-derived extracellular vesicles (BMSC-EVs) with their cargo microRNAs (miRNAs) are a promising therapeutic approach for the treatment of idiopathic pulmonary fibrosis (IPF). Therefore, we explored whether delivery of microRNA-186 (miR-186), a downregulated miRNA in IPF, by BMSC EVs could interfere with the progression of IPF in a murine model.MethodsIn a co-culture system, we assessed whether BMSC-EVs modulated the activation of fibroblasts. We established a mouse model of PF to evaluate the in vivo therapeutic effects of BMSC-EVs and determined miR-186 expression in BMSC-EVs by polymerase chain reaction. Using a loss-of-function approach, we examined how miR-186 delivered by BMSC-EVs affected fibroblasts. The putative relationship between miR-186 and SRY-related HMG box transcription factor 4 (SOX4) was tested using luciferase assay. Next, we investigated whether EV-miR-186 affected fibroblast activation and PF by targeting SOX4 and its downstream gene, Dickkopf-1 (DKK1).ResultsBMSC-EVs suppressed lung fibroblast activation and delayed IPF progression in mice. miR-186 was downregulated in IPF but enriched in the BMSC-EVs. miR-186 delivered by BMSC-EVs could suppress fibroblast activation. Furthermore, miR-186 reduced the expression of SOX4, a target gene of miR-186, and hence suppressed the expression of DKK1. Finally, EV-delivered miR-186 impaired fibroblast activation and alleviated PF via downregulation of SOX4 and DKK1.ConclusionIn conclusion, miR-186 delivered by BMSC-EVs suppressed SOX4 and DKK1 expression, thereby blocking fibroblast activation and ameliorating IPF, thus presenting a novel therapeutic target for IPF.

【 授权许可】

CC BY