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      Extracellular Vesicles in neural cell interaction and CNS homeostasis

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          Abstract

          Central nervous system (CNS) homeostasis critically depends on the interaction between neurons and glia cells. Extracellular vesicles (EVs) recently emerged as versatile messengers in CNS cell communication. EVs are released by neurons and glia in activity‐dependent manner and address multiple target cells within and outside the nervous system. Here, we summarize the recent advances in understanding the physiological roles of EVs in the nervous system and their ability to deliver signals across the CNS barriers. In addition to the disposal of cellular components via EVs and clearance by phagocytic cells, EVs are involved in plasticity‐associated processes, mediate trophic support and neuroprotection, promote axonal maintenance, and modulate neuroinflammation. While individual functional components of the EV cargo are becoming progressively identified, the role of neural EVs as compound multimodal signaling entities remains to be elucidated. Novel transgenic models and imaging technologies allow EV tracking in vivo and provide further insight into EV targeting and their mode of action. Overall, EVs represent key players in the maintenance of CNS homeostasis essential for the lifelong performance of neural networks and thus provide a wide spectrum of biomedical applications.

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          Most cited references152

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          Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines

          ABSTRACT The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.
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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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              Tumour exosome integrins determine organotropic metastasis

              Ever since Stephen Paget’s 1889 hypothesis, metastatic organotropism has remained one of cancer’s greatest mysteries. Here we demonstrate that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins α6β4 and α6β1 were associated with lung metastasis, while exosomal integrin αvβ5 was linked to liver metastasis. Targeting the integrins α6β4 and αvβ5 decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Finally, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis.
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                Author and article information

                Contributors
                alberse@uni-mainz.de
                Journal
                FASEB Bioadv
                FASEB Bioadv
                10.1096/(ISSN)2573-9832
                FBA2
                FASEB BioAdvances
                John Wiley and Sons Inc. (Hoboken )
                2573-9832
                13 May 2021
                August 2021
                : 3
                : 8 ( doiID: 10.1002/fba2.v3.8 )
                : 577-592
                Affiliations
                [ 1 ] Institute of Developmental Biology and Neurobiology Biology of Extracellular Vesicles University of Mainz Mainz Germany
                Author notes
                [*] [* ] Correspondence

                Eva‐Maria Krämer‐Albers, Institute of Developmental Biology and Neurobiology, Biology of Extracellular Vesicles, University of Mainz, 55099 Mainz, Germany.

                Email: alberse@ 123456uni-mainz.de

                Author information
                https://orcid.org/0000-0001-7994-1185
                Article
                FBA21234
                10.1096/fba.2021-00035
                8332475
                34377954
                a06c5c9c-e6c0-4454-99b1-4265ab034c03
                © 2021 The Authors. FASEB BioAdvances published by the Federation of American Societies for Experimental Biology

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 16 April 2021
                : 06 March 2021
                : 22 April 2021
                Page count
                Figures: 2, Tables: 0, Pages: 16, Words: 11450
                Funding
                Funded by: DFG
                Award ID: KR 3668/1‐1
                Award ID: KR 3668/1‐2
                Award ID: KR 3668/2‐1
                Award ID: KR 3668/2‐2
                Categories
                Review
                Reviews
                Custom metadata
                2.0
                August 2021
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.0.4 mode:remove_FC converted:03.08.2021

                axonal maintenance,blood–brain barrier,exosomes,in vivo imaging,microvesicles,neuroinflammation,neuron–glia interaction,synaptic plasticity

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