Heparan sulfate proteoglycan-mediated internalization of extracellular vesicles ameliorates liver fibrosis by targeting hepatic stellate cells

Accumulating evidence shows that stem cell-derived extracellular vesicles (EVs) have shown great promise for tissue regeneration and are considered an alternative to cell-based therapy. However, the mechanisms by which EVs induce tissue repair have not been well demonstrated. Previous work indicates that activation of hepatic stellate cells (HSCs) may contribute to the progression of liver fibrosis. Here, we investigate the therapeutic potential of EVs derived from human placental mesenchymal stem cells (hP-MSCs) for the treatment of carbon tetrachloride (CCl4)-induced liver injury. Our data revealed that EVs derived from hP-MSCs effectively ameliorate liver injury by attenuating inflammation and fibrosis. Further data revealed that heparan sulfate proteoglycans (HSPGs) on the surface of HSCs mediate the internalization of EVs. Furthermore, EVs could inhibit the epithelial–mesenchymal transition (EMT) process in HSCs through the downregulated TGF-$\beta$/Smad pathway, which was mediated by miR-744-5p in EVs. Meanwhile, glycosaminoglycans on the surface of EVs play a crucial anti-inflammatory role. In conclusion, our results provide evidence that hP-MSC-derived EVs promote the recovery of liver injury by targeting HSPGs on HSCs and inhibiting liver inflammation through glycosaminoglycans from EVs. These findings may provide a novel theoretical basis for the treatment of liver fibrosis based on EVs.