Fig. 1

EVs in the onset of liver fibrosis. EVs of different origin promote fibrogenesis in the liver. Damaged hepatocytes release EVs containing CytP450s, which induces hepatocyte apoptosis, EVs containing TGF-β1 mRNA, which induces HSC activation and EVs that increase IL-17A expression in T cells, via TLR3. In turn, IL-17-producing T cells induce the expression of TGF-β1 in Kupffer cells, which prompt ECM deposition by HSCs. Coagulation cascade is activated by granulocyte and platelet-derived EVs which expose procoagulant proteins on their surface, such as tissue factor and phosphatidylserine. Angiogenesis is induced by hepatocyte-derived EVs that shuttle vanin-1 and EVs released by cholangiocytes and HSCs that contain Hh ligands, which increase the iNOS expression in endothelial cells. In turn, sinusoidal endothelial cells release EVs containing SK1 that prompt HSC migration. Activated HSCs release EVs containing CCN2 mRNA and protein that are taken up into quiescent HSCs, upregulating α-SMA expression. Abbreviations: CCN2, connective tissue growth factor; CytP450s, cytochrome P450 family; ECM, extracellular matrix; Hh ligand, Hedgehog ligand; HSC, hepatic stellate cell; iNOS, inducible nitric oxide synthase; SK1, sphingosine kinase 1; TGF-β1, transforming growth factor β1; TLR3, toll-like receptor 3.