Extracellular vesicles: Novel mediator for cell to cell communications in liver pathogenesis

Abstract

Extracellular vesicles (EVs) are membrane derived nanometer-sized vesicles. EVs are released by normal, diseased, and transformed cells in vitro and in vivo, and carry lipids, proteins, mRNAs, non-coding RNAs, and even DNA out of cells. Transferring biological information via EVs to neighboring cells and inter-cellular communication not only maintain physiological functions, but also involve in the pathogenesis of several diseases, including cancer. The aim of this review is to discuss the emerging role of EVs in viral hepatitis, non-alcoholic or alcoholic liver disease and liver cancers. We summarize what is known about exosome biogenesis, and role in liver disease progression, and discuss the potential clinical applications of EVs as predictive biomarkers and therapeutic modalities.

Keywords: Exosomes; Extracellular vesicles; HCC; Liver; NAFLD; NASH.

Conflict of interest statement

Conflicts of Interest

The authors declare no conflict of interest.

Copyright © 2017 Elsevier Ltd. All rights reserved.

Figures

Figure 1. Classification of extracellular vesicles according to the mechanism of generation

Exosomes are generated intracellularly from multivesicular bodies. Microvesicles are produced by budding from the extracellular membrane. Apoptotic vesicles are released upon cell fragmentation during apoptotic cell death. Representative sizes are shown at the bottom.

Figure 2. Schematic representation of exosome biogenesis by eukaryotic cells

Exosomes are formed as ILVs by budding into early endosomes and MVBs. Several molecules are involved in the biogenesis of ILVs, such as the ESCRT machinery, lipids (such as ceramide) and the tetraspanins. The fate of MVBs can be either fusion with lysosomes or fusion with the PM, which allows the release of their content to the extracellular milieu. Several RAB proteins (RAB11, RAB27 and RAB35) have been shown to be involved in the transport of MVBs to the PM and in exosome secretion. Other types of secreted vesicles bud directly from the plasma membrane, and are often called microvesicles.

Figure 3. Schematic representation showing role of exosomes in HCV mediated liver disease

Exosomes released from HCV infected hepatocytes carry microRNA including miR-19a (Exo-miR-19a). Exo-miR-19a enters in quiescent hepatic stellate cells for fibrogenic activation. Circulatory miR-19a, miR-20a and miR-92a were upregulated in HCV-infected fibrosis patients’ sera.