Bone marrow mesenchymal stem cell-derived exosomes attenuate hepatic stellate cell activation through miR-223-3p-mediated mitophagy.

Abstract

Background: Liver fibrosis is a common pathological process in chronic liver diseases and effective treatments are lacking. The activation of hepatic stellate cells (HSCs) is a critical step in the development of liver fibrosis. Our previous research confirmed that bone marrow mesenchymal stem cell-derived exosomes (BMSC-exosomes) could regulate the level of miR-223-3p to alleviate intrahepatic inflammation, but whether they contribute to the protection of the liver against fibrosis remains unknown.

Methods: In this study, the antifibrotic function of BMSC-exosomes was validated through cell experiments. JS-1 cells (murine HSC line) were used as activated cells to simulate liver fibrosis. TGF-β is a stimulating factor for JS-1 cell activation. BMSC-exosomes were isolated via ultracentrifugation.

Results: Our results demonstrated that BMSC-exosomes internalized by JS-1 cells attenuated TGF-β-induced HSC activation and promoted HSC apoptosis. Moreover, BMSC-exosomes significantly reversed the upregulation of miR-223-3p levels and mitophagy induced by TGF-β. Luciferase activity reporter analysis further verified that hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) was a downstream target of miR-223-3p. By transfecting a miR-223-3p inhibitor, we found that downregulating miR-223-3p could increase the expression level of HMGCS1 and alleviate mitophagy, thereby reducing TGF-β-induced HSC activation and promoting HSC apoptosis.

Conclusions: These results suggest that BMSC-exosomes may have antifibrotic effects. The mechanism may be related to regulating miR-223-3p in HSCs to target HMGCS1 and mitophagy.