Extracellular vesicles in liver disease and beyond

Abstract

Extracellular vesicles (EVs) are membrane-derived vesicles which can be released by different cell types, including hepatocytes, hepatic stellate cells and immune cells in normal and pathological conditions. EVs carry lipids, proteins, coding and non-coding RNAs and mitochondrial DNA causing modifications on the recipient cells. These vesicles are considered potential biomarkers and therapeutic agents for human diagnostic and prognostic due to their function as intercellular mediators of cell-cell communication within the liver and between other organs. However, the development and optimization of methods for EVs isolation is required to characterize their biological functions as well as their potential as a treatment option in the clinic. Nevertheless, many questions remain unanswered related to the function of EVs under physiological and pathological conditions. In the current editorial, the results obtained in different studies that investigated the role of intrahepatic EVs during liver diseases, including drug-induced liver injury, non-alcoholic fatty liver, non-alcoholic steatohepatitis, alcoholic liver disease and hepatocellular carcinoma and extrahepatic EVs in remote organs during pathological events such as pulmonary disease, cardiovascular diseases, neurodegenerative disorders e.g., Alzheimer’s disease, Parkinson’s disease and multiple sclerosis as well as in immunopathological processes, are discussed. Although much light needs to be shed on the mechanisms of EVs, these membrane-derived vesicles represent both a novel promising diagnostic, and a therapeutic tool for clinical use that we emphasize in the current editorial.

Extracellular Vesicles in NAFLD/ALD: From Pathobiology to Therapy

“…In general, EVs are classified according to size and biogenetic pathway, such as exosomes, microvesicles, and apoptotic bodies [23]. Exosomes are bilayer lipid vesicles with a diameter of 30-150 nm that are derived from endosomal multivesicular bodies (MVBs) [15,23].…”

“…In general, EVs are classified according to size and biogenetic pathway, such as exosomes, microvesicles, and apoptotic bodies [23]. Exosomes are bilayer lipid vesicles with a diameter of 30-150 nm that are derived from endosomal multivesicular bodies (MVBs) [15,23]. Their formation results from the invagination of the plasma membrane (early endosome) and the subsequent fusion of endocytic vesicles mediated by the endosomal sorting complex responsible for transport (ESCRTs) and other components (such as ceramides and tetraspanins) [24].…”

“…MVBs can release the intraluminal vesicles known as exosomes by the fusion of MVBs to the plasma membrane, a process mediated in part by Rab GTPases [25]. Microvesicles (MVs) have a diameter of 50-1000 nm and originate from the plasma membrane by budding and fission, followed by release into the extracellular space [15,23]. MVs contain a subset of cell surface proteins depending on the composition of the parental plasma membrane [26,27].…”

“…All EVs transport a variety of bioactive molecules including cytoplasmic proteins, lipids, specific lipid-raft-interacting proteins, messenger RNA (mRNA), microRNA (miRNA), ribosomal RNA (rRNA), transfer RNA (tRNA), noncoding RNAs (ncRNAs), DNA, mitochondrial DNA (mtDNA), and metabolites [24,30]. Lipidomic analysis has shown that EVs, independently of their biogenesis, contain a multitude of lipids such as cholesterol, sphingomyelin, ceramide, saturated fatty acids, phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine [4,23,29,30]. In addition, proteomic analysis has shown that EVs contain different types of proteins, such as heat shock proteins (Hsp70 and Hsp90), tetraspanins (CD9, CD63, CD81, CD82), endosomal sorting complex proteins required for transport (Alix and Tsg101), receptors including epidermal growth factor receptor (EGFR), membrane trafficking proteins (GTPases, Flotillin and Annexins), cytoskeletal proteins (tubulin and actin), and cytosolic proteins [5,26].…”

Extracellular Vesicles, A Possible Theranostic Platform Strategy for Hepatocellular Carcinoma—An Overview

“…The liver is composed of several different cell types, including cancer-associated fibroblasts (CAFs), Kupffer cells, hepatic stellate cells (HSCs), endothelial cells, infiltrating immune cells, recruited mesenchymal stem cells (MSCs), and cancer cells, each capable of producing different types of EVs, contributing to interactions between them. Since different stages of liver disease are associated with different EV cargoes, EV profiling has potential diagnostic and prognostic value in HCC [11,34]. Increasing number of reports indicate that EVs also have an important role in liver metastasis from other tumor types, preparing the premetastatic niche to receive metastatic tumor cells, creating a favorable environment for the propagation of metastatic tumor cells [35][36][37].…”