Altered biodistribution of deglycosylated extracellular vesicles through enhanced cellular uptake
Altered biodistribution of deglycosylated extracellular vesicles through enhanced cellular uptake
复制标题
通过增强细胞摄取改变去糖基化细胞外囊泡的生物分布
DOI：
10.1080/20013078.2020.1713527
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发表时间：
2020-01-01
影响因子：
16
通讯作者：
Ochiya, Takahiro
中科院分区：
文献类型：
--
作者：
Nishida-Aoki, Nao;Tominaga, Naoomi;Ochiya, Takahiro
来自癌症的细胞外囊泡 (EV) 被输送到近端和远端器官。 EV 在与细胞相互作用的表面高度糖基化，因此对其特性和生物功能产生影响。癌症中的异常糖基化与癌症进展和转移有关。然而，EV表面糖基化的生物学功能尚未被揭示。我们首先通过凝集素印迹证明了 EV 及其起源细胞的差异糖基化谱，以及脑转移亚系 BMD2a 与其亲代人乳腺癌细胞系 MDA-MB-231-luc-D3H2LN 中不同的糖基化谱。然后我们研究了表面糖复合物对 EV 摄取的作用。荧光标记的 BMD2a EV 的 N-和/或 O-糖基化去除增强了内皮细胞的细胞摄取，表明表面糖基化对细胞摄取具有抑制作用。使用近红外亲脂性染料进一步分析静脉注射给小鼠的糖基化剥夺的 BMD2a EV 的生物分布。注射24小时后，用O-去糖基化酶处理的EV增强了EV在肺部的积累，而N-去糖基化并没有显着改变生物分布。由于肺部是静脉血液流动的第一个器官，我们建议癌症来源的 EV 的表面糖基化避免了与近端组织的混杂粘附，从而被输送到远端器官。
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.