Abstract
The discovery that the cells communicate through emission of vesicles has opened new opportunities for better understanding of physiological and pathological mechanisms. This discovery also provides a novel source for non-invasive disease biomarker research. Our group has previously reported that hepatocytes release extracellular vesicles with protein content reflecting the cell-type of origin. Here, we show that the extracellular vesicles released by hepatocytes also carry RNA. We report the messenger RNA composition of extracellular vesicles released in two non-tumoral hepatic models: primary culture of rat hepatocytes and a progenitor cell line obtained from a mouse foetal liver. We describe different subpopulations of extracellular vesicles with different densities and protein and RNA content. We also show that the RNA cargo of extracellular vesicles released by primary hepatocytes can be transferred to rat liver stellate-like cells and promote their activation. Finally, we provide in vitro and in vivo evidence that liver-damaging drugs galactosamine, acetaminophen, and diclofenac modify the RNA content of these vesicles. To summarize, we show that the extracellular vesicles secreted by hepatocytes contain various RNAs. These vesicles, likely to be involved in the activation of stellate cells, might become a new source for non-invasive identification of the liver toxicity markers.
Highlights
In recent years, intercellular transference of active macromolecules mediated by cell-released extracellular vesicles (EVs) has become a recognized key regulatory mechanism in a growing number of biological processes including development, cancer, immunity and inflammation [1,2,3]
In EVs released by endothelial progenitor cells, at least 298 different transcripts were identified, and a role in the activation of angiogenic program in quiescent endothelial cells has been proposed for these vesicles [48]
De Jong and co-workers have reported the presence of at least 1992 different transcripts in EVs released by microvascular endothelial cells; they demonstrated that the RNA cargo of these vesicles changed under hypoxia or endothelial activating conditions [34]
Summary
Intercellular transference of active macromolecules mediated by cell-released extracellular vesicles (EVs) has become a recognized key regulatory mechanism in a growing number of biological processes including development, cancer, immunity and inflammation [1,2,3]. Exosomes are released to extracellular media by the fusion of multivesicular bodies to the plasma membrane [4]. Of their biogenesis, EVs carry lipids, proteins, and nucleic acids: both coding and non-coding RNAs [6,7]. A wide range of cells, of either tumoral or non-tumoral origin, can release EVs to the culture media [8]. EVs have been detected in biological fluids such as blood, urine, and ascitic fluid [14] They have the potential to release their cargo in both paracrine and long distance manner; this feature is being widely exploited in non-invasive disease biomarker discovery
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