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 αv or β1 siRNAs, Integrin αvβ3 or α5β1 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 αvβ3, Integrin α5β1, 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.