Integrins and heparan sulfate proteoglycans on hepatic stellate cells (HSC) are novel receptors for HSC-derived exosomes

Exosomes mediate intercellular microRNA delivery between hepatic stellate cells (HSC), the principal fibrosis-producing cells in the liver. The purpose of this study was to identify receptors on HSC for HSC-derived exosomes, which bind to HSC rather than to hepatocytes. Our findings indicate that exosome binding to HSC is blocked by treating HSC with RGD, EDTA, integrin v or 1 siRNAs, integrin v3 or 51 neutralizing antibodies, heparin, or sodium chlorate. Furthermore, exosome cargo delivery and exosome-regulated functions in HSC, including expression of fibrosis- or activation-associated genes and/or miR-214 target gene regulation, are dependent on cellular integrin v3, integrin 51, or heparan sulfate proteolgycans (HSPG). Thus, integrins and HSPG mediate the binding of HSC-derived exosomes to HSC as well as the delivery and intracellular action of the exosomal payload.