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

Abstract

Background Previous 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. Methods In 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). Results BMSC-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. Conclusion In 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.

Every road leads to Rome: therapeutic effect and mechanism of the extracellular vesicles of human embryonic stem cell-derived immune and matrix regulatory cells administered to mouse models of pulmonary fibrosis through different routes

“…Numerous countries around the world have carried out phase I clinical trials on MSCs for the treatment of IPF to evaluate the safety of stem cell therapy [ 26 , 27 ]. EVs derived from MSCs are considered as a potential method for the treatment of fibrotic diseases[ 15 , 28 ]. Therefore, we extracted EVs from IMRCs to further evaluate their tissue repair and anti-inflammatory, anti-fibrosis and immune regulation effects.…”

Mesenchymal Stem Cell-Derived Extracellular Vesicles in Liver Immunity and Therapy

“…Recently, numerous preclinical studies have demonstrated the antifibrotic effect of MSC-EVs in the lung (139), liver (140), kidney (141), and heart (142). Focusing on liver fibrosis, MSC-EVs promote liver tissue repair by reducing inflammation, therefore alleviating fibrosis.…”

Emerging Therapeutic Potential of Mesenchymal Stem Cell-Derived Extracellular Vesicles in Chronic Respiratory Diseases: An Overview of Recent Progress

“…Three studies indicated MSC-EVs inhibited pulmonary fibrosis by transferring microRNAs. Zhou et al (Zhou et al, 2021) found that EVs from human BM-MSCs blocked fibroblast activation and suppressed SOX4, DKK1 expression by transferring miR-186. Human BM-MSCs derived EVs could also suppress the fibroblast proliferation by downregulating FZD6 expression via carrying miR-29b-3p (Wan et al, 2020).…”