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      Modification of the glycosylation of extracellular vesicles alters their biodistribution in mice

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          Abstract

          Positron emission tomography allows in vivo tracking of EVs and reveals changes in their biodistribution after glycosylation modification.

          Abstract

          Extracellular vesicles (EVs) are considered sophisticated vehicles for cell-to-cell communication, thanks to the possibility of handling a variable cargo in a shell with multiple types of decoders. Surface glycosylation of EVs is a method that could be used to control their interaction with different cells and, consequently, the biodistribution of the vesicles in the body. Herein, we produced EVs derived from mouse liver proliferative cells, and we treated them with neuraminidase, an enzyme that digests the terminal sialic acid residues from glycoproteins. Afterwards, we labeled the EVs directly with [ 124I]Na and injected them in mice intravenously or into the hock. The amount of radioactivity in major organs was measured at different time points after administration both in vivo using positron emission tomography and ex vivo (after animal sacrifice) using dissection and gamma counting. The results showed that intravenous injection leads to the rapid accumulation of EVs in the liver. Moreover, after some hours the distribution led to the presence of EVs in different organs including the brain. Glycosidase treatment induced an accumulation in the lungs, compared with the intact EVs. Furthermore, when the EVs were injected through the hock, the neuraminidase-treated vesicles distributed better at the axillary lymph nodes than the untreated EVs. This result shows that modification of the glycosylated complexes on the EV surface can affect the distribution of these vesicles, and specifically removing the sialic acid residues allows more EVs to reach and accumulate at the lungs.

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          Most cited references26

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          In Vivo Imaging Reveals Extracellular Vesicle-Mediated Phenocopying of Metastatic Behavior

          Summary Most cancer cells release heterogeneous populations of extracellular vesicles (EVs) containing proteins, lipids, and nucleic acids. In vitro experiments showed that EV uptake can lead to transfer of functional mRNA and altered cellular behavior. However, similar in vivo experiments remain challenging because cells that take up EVs cannot be discriminated from non-EV-receiving cells. Here, we used the Cre-LoxP system to directly identify tumor cells that take up EVs in vivo. We show that EVs released by malignant tumor cells are taken up by less malignant tumor cells located within the same and within distant tumors and that these EVs carry mRNAs involved in migration and metastasis. By intravital imaging, we show that the less malignant tumor cells that take up EVs display enhanced migratory behavior and metastatic capacity. We postulate that tumor cells locally and systemically share molecules carried by EVs in vivo and that this affects cellular behavior.
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            Dynamic biodistribution of extracellular vesicles in vivo using a multimodal imaging reporter.

            Extracellular vesicles (EVs) are nanosized vesicles released by normal and diseased cells as a novel form of intercellular communication and can serve as an effective therapeutic vehicle for genes and drugs. Yet, much remains unknown about the in vivo properties of EVs such as tissue distribution, blood levels, and urine clearance, important parameters that will define their therapeutic effectiveness and potential toxicity. Here we combined Gaussia luciferase and metabolic biotinylation to create a sensitive EV reporter (EV-GlucB) for multimodal imaging in vivo, as well as monitoring of EV levels in the organs and biofluids ex vivo after administration of EVs. Bioluminescence and fluorescence-mediated tomography imaging on mice displayed a predominant localization of intravenously administered EVs in the spleen followed by the liver. Monitoring EV signal in the organs, blood, and urine further revealed that the EVs first undergo a rapid distribution phase followed by a longer elimination phase via hepatic and renal routes within six hours, which are both faster than previously reported using dye-labeled EVs. Moreover, we demonstrate systemically injected EVs can be delivered to tumor sites within an hour following injection. Altogether, we show the EVs are dynamically processed in vivo with accurate spatiotemporal resolution and target a number of normal organs as well as tumors with implications for disease pathology and therapeutic design.
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              Characterization and comprehensive proteome profiling of exosomes secreted by hepatocytes.

              Exosomes represent a discrete population of vesicles that are secreted from various cell types to the extracellular media. Their protein and lipid composition are a consequence of sorting events at the level of the multivesicular body, a central organelle which integrates endocytic and secretory pathways. Characterization of exosomes from different biological samples has shown the presence of common as well as cell-type specific proteins. Remarkably, the protein content of the exosomes is modified upon pathological or stress conditions. Hepatocytes play a central role in the body response to stress metabolizing potentially harmful endogenous substances as well as xenobiotics. In the present study, we described and characterized for the first time exosome secretion in nontumoral hepatocytes, and with the use of a systematic proteomic approach, we establish the first extensive proteome of a hepatocyte-derived exosome population which should be useful in furthering our understanding of the hepatic function and in the identification of components that may serve as biomarkers for hepatic alterations. Our analysis identifies a significant number of proteins previously described among exosomes derived from others cell types as well as proteins involved in metabolizing lipoproteins, endogenous compounds and xenobiotics, not previously described in exosomes. Furthermore, we demonstrated that exosomal membrane proteins can constitute an interesting tool to express nonexosomal proteins into exosomes with therapeutic purposes.
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                Author and article information

                Journal
                NANOHL
                Nanoscale
                Nanoscale
                Royal Society of Chemistry (RSC)
                2040-3364
                2040-3372
                January 23 2019
                2019
                : 11
                : 4
                : 1531-1537
                Affiliations
                [1 ]Exosomes Laboratory
                [2 ]CIC bioGUNE
                [3 ]CIBERehd
                [4 ]Derio
                [5 ]Spain
                [6 ]Radiochemistry and Nuclear Imaging Group
                [7 ]CIC biomaGUNE
                [8 ]20014 Donosti
                [9 ]Thenanostic Nanomedicine Laboratory
                Article
                10.1039/C8NR03900C
                30623961
                85caa48e-a9a8-4549-9777-9413419a0692
                © 2019

                http://creativecommons.org/licenses/by-nc/3.0/

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