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Altered biodistribution of deglycosylated extracellular vesicles through enhanced cellular uptake.

ABSTRACT: Extracellular vesicles (EVs) from cancer are delivered both proximal and distal organs. EVs are highly glycosylated at the surface where EVs interact with cells and therefore has an impact on their properties and biological functions. Aberrant glycosylation in cancer is associated with cancer progression and metastasis. However, the biological function of glycosylation on the surface of EV is uncovered. We first demonstrated differential glycosylation profiles of EVs and their originated cells, and distinct glycosylation profiles in a brain-metastatic subline BMD2a from its parental human breast cancer cell line, MDA-MB-231-luc-D3H2LN by lectin blot. We then investigated the roles of surface glycoconjugates on EV uptake. N- and/or O-glycosylation removal of fluorescent-labelled BMD2a EVs enhanced cellular uptake to endothelial cells, suggesting that surface glycosylation has inhibitory effects on cellular uptake. Biodistribution of glycosylation-deprived BMD2a EVs administrated intravenously into mice was further analysed ex vivo using near-infrared lipophilic dye. EVs treated with O-deglycosylation enzymes enhanced the accumulation of EVs to the lungs after 24 h from the injection, while N-deglycosylation did not markedly alter biodistribution. As the lungs are first organs in which intravenous blood flows, we suggest that surface glycosylation of cancer-derived EVs avoid promiscuous adhesion to proximal tissues to be delivered to distant organs.

SUBMITTER: Nishida-Aoki N

PROVIDER: S-EPMC7006786 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Altered biodistribution of deglycosylated extracellular vesicles through enhanced cellular uptake.

Nishida-Aoki Nao N Tominaga Naoomi N Kosaka Nobuyoshi N Ochiya Takahiro T

Journal of extracellular vesicles 20200113 1

Extracellular vesicles (EVs) from cancer are delivered both proximal and distal organs. EVs are highly glycosylated at the surface where EVs interact with cells and therefore has an impact on their properties and biological functions. Aberrant glycosylation in cancer is associated with cancer progression and metastasis. However, the biological function of glycosylation on the surface of EV is uncovered. We first demonstrated differential glycosylation profiles of EVs and their originated cells, ...[more]

PMID: 32082512

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Project description:Bariatric surgery is the most effective treatment for obesity and its comorbidities. However, our understanding of the molecular mechanisms behind its beneficial effects is limited. Extracellular vesicles (EVs) comprise an important mode of intercellular communication. They carry nucleic acids, hormones, and signaling molecules and regulate multiple processes. Our aim was to test the role of EVs in the effects of vertical sleeve gastrectomy (VSG) using a mouse model. Small intestinal EVs were obtained from the mice that underwent VSG or control surgery and were on chow or high-fat diet or diet-restricted, and then they were subjected to the proteomic analysis. Enteroid and bacterial cultures were treated with EVs to evaluate their survival effect. A mouse cohort received intraduodenal administration of EVs from VSG or Sham mice for 10 days. Body weight, glucose metabolism, and intestinal morphology were evaluated. EVs were enriched in the intestinal lumen and mucus of VSG compared with Sham mice. Protein composition of VSG and Sham-derived EVs was highly distinct. When introduced into culture, VSG EVs decreased survival of intestinal enteroids and, conversely, promoted proliferation of bacteria. Mice administered with EVs obtained from VSG and Sham groups did not show differences in body weight, food intake, or glucose metabolism. Intestinal morphology was altered, as VSG EVs caused reduction of ileal villi length and decreased epithelial proliferation in the jejunum and ileum. VSG causes remodeling of intestinal EVs, which results in unique protein composition. VSG-derived EVs exhibit cytotoxic effects on epithelial cells and reduce proliferation of intestinal progenitor cells in mice.NEW & NOTEWORTHY This is the first study that investigates the impact of bariatric surgery on protein composition of intestinal extracellular vesicles. Extracellular vesicle composition is greatly altered after vertical sleeve gastrectomy and may potentially modulate various signaling pathways. In our study, extracellular vesicles from vertical sleeve gastrectomy-treated mice promote bacterial proliferation but exhibit cytotoxic effect on epithelial cells and reduce proliferation of intestinal progenitor cells in mice.

Dataset Information

Altered biodistribution of deglycosylated extracellular vesicles through enhanced cellular uptake.

Publications

Altered biodistribution of deglycosylated extracellular vesicles through enhanced cellular uptake.

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