Abstract
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.
Highlights
Previous reports have identified that human bone marrow mesenchymal stem cell-derived extracellular vesicles (BMSC-EVs) with their cargo microRNAs are a promising therapeutic approach for the treatment of idiopathic pulmonary fibrosis (IPF)
EVs derived from bone mesenchymal stem cell (BMSCs) contain diverse cargoes of proteins, mRNAs, and microRNAs that impact a range of biological activities in tissue repair [8]
The key finding was the demonstration of a mitigatory role of miR-186 in BMSC-EVs via interaction with SRY-related HMG box transcription factor 4 (SOX4) and DKK1 in PF
Summary
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). We explored whether delivery of microRNA-186 (miR186), a downregulated miRNA in IPF, by BMSC EVs could interfere with the progression of IPF in a murine model. Mesenchymal stem cells (MSCs) have shown promising therapeutic effects on IPF [6]. EVs derived from bone mesenchymal stem cell (BMSCs) contain diverse cargoes of proteins, mRNAs, and microRNAs (miRNAs) that impact a range of biological activities in tissue repair [8]. Among the miRNAs, miR-186 is poorly expressed in lung tissues of patients with IPF [13]. We speculated that BMSC-EVs could deliver miR-186 with beneficial effects on fibroblast activation during IPF
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