Human Wharton's jelly mesenchymal stem cells derived-exosomes enriched by miR-124 promote an anti-fibrotic response in an experimental model of liver fibrosis.

Abstract

Liver fibrosis is a significant challenge to global health that results in organ failure through inflammation and the release of fibrotic biomarkers. Due to the lack of effective treatments for liver fibrosis, anti-fibrotic and anti-inflammatory therapies are being developed. Since there has been an association between aberrant expression of miR-124 and liver disease progression, we investigated whether delivery of miR-124 through human Wharton's jelly mesenchymal stem cells derived-exosomes (hWJMSC-Exo) can improve liver fibrosis. We established a 6-week carbon tetrachloride (CCl4)-induced mouse model of liver fibrosis, then we administered hWJMSC-Exo and miR-124-3p-enriched exosomes (ExomiR-124) for three weeks. The extent of fibrosis and inflammation was assessed by histology, biochemistry, Real-time PCR, immunohistochemistry, and Enzyme-linked immunoassays (ELISA). The inflammatory status of the spleen was also investigated using flow cytometry. Based on the gene and protein expression measurement of IL-6, IL-17, TGF-β, STAT3, α-SMA, and COL1, In vivo administration of Exo and ExomiR-124 effectively reduce collagen accumulation and inhibition of inflammation. Regarding histopathology findings, the therapeutic effect of ExomiR-124 against liver fibrosis was significantly greater than hWJMSC-Exo. In addition, we found that Exo and ExomiR-124 was capable of phenotype switching of splenic monocytes from inflammatory Ly6Chi to restorative Ly6Clo. MSC-derived exosomes demonstrated anti-inflammatory effect via different aspects. Aside from the therapeutic approach, enrichment of exosomes as a nanocarrier by miR-124 revealed the down-regulation of STAT3, which plays a crucial role in liver fibrosis. The anti-inflammatory and anti-fibrotic properties of ExomiR-124 could be a promising option in liver fibrosis combination therapies.