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      Autophagy and Exosomes: Cross-Regulated Pathways Playing Major Roles in Hepatic Stellate Cells Activation and Liver Fibrosis

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          Abstract

          Chronic liver injury, regardless of the underlying disease, results in gradual alteration of the physiological hepatic architecture and in excessive production of extracellular matrix, eventually leading to cirrhosis Liver cellular architecture consists of different cell populations, among which hepatic stellate cells (HSCs) have been found to play a major role in the fibrotic process. Under normal conditions, HSCs serve as the main storage site for vitamin A, however, pathological stimuli lead to their transdifferentiation into myofibroblast cells, with autophagy being the key regulator of their activation, through lipophagy of their lipid droplets. Nevertheless, the role of autophagy in liver fibrosis is multifaceted, as increased autophagic levels have been associated with alleviation of the fibrotic process. In addition, it has been found that HSCs receive paracrine stimuli from neighboring cells, such as injured hepatocytes, Kupffer cells, sinusoidal endothelial cells, which promote liver fibrosis. These stimuli have been found to be transmitted via exosomes, which are incorporated by HSCs and can either be degraded through lysosomes or be secreted back into the extracellular space via fusion with the plasma membrane. Furthermore, it has been demonstrated that autophagy and exosomes may be concomitantly or reciprocally regulated, depending on the cellular conditions. Given that increased levels of autophagy are required to activate HSCs, it is important to investigate whether autophagy levels decrease at later stages of hepatic stellate cell activation, leading to increased release of exosomes and further propagation of hepatic fibrosis.

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          Most cited references137

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          Shedding light on the cell biology of extracellular vesicles

          Extracellular vesicles are a heterogeneous group of cell-derived membranous structures comprising exosomes and microvesicles, which originate from the endosomal system or which are shed from the plasma membrane, respectively. They are present in biological fluids and are involved in multiple physiological and pathological processes. Extracellular vesicles are now considered as an additional mechanism for intercellular communication, allowing cells to exchange proteins, lipids and genetic material. Knowledge of the cellular processes that govern extracellular vesicle biology is essential to shed light on the physiological and pathological functions of these vesicles as well as on clinical applications involving their use and/or analysis. However, in this expanding field, much remains unknown regarding the origin, biogenesis, secretion, targeting and fate of these vesicles.
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            Extracellular vesicles: Exosomes, microvesicles, and friends

            Cells release into the extracellular environment diverse types of membrane vesicles of endosomal and plasma membrane origin called exosomes and microvesicles, respectively. These extracellular vesicles (EVs) represent an important mode of intercellular communication by serving as vehicles for transfer between cells of membrane and cytosolic proteins, lipids, and RNA. Deficiencies in our knowledge of the molecular mechanisms for EV formation and lack of methods to interfere with the packaging of cargo or with vesicle release, however, still hamper identification of their physiological relevance in vivo. In this review, we focus on the characterization of EVs and on currently proposed mechanisms for their formation, targeting, and function.
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              mTOR Signaling in Growth, Metabolism, and Disease.

              The mechanistic target of rapamycin (mTOR) coordinates eukaryotic cell growth and metabolism with environmental inputs, including nutrients and growth factors. Extensive research over the past two decades has established a central role for mTOR in regulating many fundamental cell processes, from protein synthesis to autophagy, and deregulated mTOR signaling is implicated in the progression of cancer and diabetes, as well as the aging process. Here, we review recent advances in our understanding of mTOR function, regulation, and importance in mammalian physiology. We also highlight how the mTOR signaling network contributes to human disease and discuss the current and future prospects for therapeutically targeting mTOR in the clinic.
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                Author and article information

                Contributors
                Journal
                Front Physiol
                Front Physiol
                Front. Physiol.
                Frontiers in Physiology
                Frontiers Media S.A.
                1664-042X
                03 February 2022
                2021
                : 12
                : 801340
                Affiliations
                [1] 1Department of Anatomy-Histology-Embryology, Faculty of Medicine, School of Health Sciences, University of Ioannina , Ioannina, Greece
                [2] 2Department of Pathology, Faculty of Medicine, School of Health Sciences, University of Ioannina , Ioannina, Greece
                [3] 3Hepato-Pancreatico-Biliary Unit, Department of Surgery, University General Hospital of Ioannina and School of Medicine, University of Ioannina , Ioannina, Greece
                Author notes

                Edited by: Hiroshi Nakase, Sapporo Medical University, Japan

                Reviewed by: Jordi Muntané, Institute of Biomedicine of Seville, Spanish National Research Council (CSIC), Spain; Savneet Kaur, The Institute of Liver and Biliary Sciences (ILBS), India

                *Correspondence: Antonia V. Charchanti, acharcha@ 123456uoi.gr

                This article was submitted to Gastrointestinal Sciences, a section of the journal Frontiers in Physiology

                Article
                10.3389/fphys.2021.801340
                8850693
                35185602
                96067c65-31a4-4c40-bd79-4fdc8762a7ec
                Copyright © 2022 Mastoridou, Goussia, Glantzounis, Kanavaros and Charchanti.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 25 October 2021
                : 27 December 2021
                Page count
                Figures: 3, Tables: 0, Equations: 0, References: 137, Pages: 15, Words: 12838
                Categories
                Physiology
                Review

                Anatomy & Physiology
                autophagy,exosomes,hepatic stellate cells,liver,fibrosis
                Anatomy & Physiology
                autophagy, exosomes, hepatic stellate cells, liver, fibrosis

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