Experimental fibrosis alters matrix-bound vesicles cargo that do not revert after histologic recovery

Background: Although hepatic fibrosis can resolve, potential therapies to enhance fibrosis resolution are lacking. Matrix-bound vesicles (MBV) are nanometer-sized vesicles bound within the ECM collagen network. Changes in MBV cargo may contribute to the phenotypic changes driven by fibrosis and recovery. Methods: Fibrosis was induced by injecting C57BI/6J mice with CCl4; animals were sacrificed later. Liver injury and fibrosis was monitored by clinical chemistry, histology and gene expression. MBV were extracted from the livers and the proteome cargo was analyzed. Hierarchical clustering of changed MBV proteins was performed. To investigate the effect of MBV on the recovery of liver fibrosis, normal MBV from porcine urinary bladder were injected for up to 2 weeks after cessation of CCl4.Results: Fibrosis rapidly resolved after cessation, reverting to almost normal histology and expression after 28d recovery. The amount of proteins associated with the MBV tended to decrease in fibrosis, which was not reversed even after fibrosis recovery. Hierarchical clustering analysis indicated that the proteins lost in fibrosis/recovery were predominantly RNA-binding protein. Injection normal MBV accelerated the fibrotic resolution.Conclusion: Liver MBV alter their protein cargo in response to fibrosis. Importantly, these changes do not revert to baseline levels even after almost complete histological recovery. These data suggest MBV may be a novel prospect for mechanistic insight into hepatic disease recovery.