Exosomes from hypoxic endothelial cells have increased collagen crosslinking activity through up-regulation of lysyl oxidase-like 2.
Exosomes from hypoxic endothelial cells have increased collagen crosslinking activity through up-regulation of lysyl oxidase-like 2.
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来自缺氧内皮细胞的外泌体通过上调赖氨酰氧化酶样 2 增加了胶原交联活性。
DOI：
10.1111/jcmm.12730
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发表时间：
2016-02
影响因子：
5.3
通讯作者：
Verhaar MC
中科院分区：
文献类型：
--
作者：
de Jong OG;van Balkom BW;Gremmels H;Verhaar MC
外泌体是细胞间通讯的重要介质。此外，它们含有多种能够与细胞外基质（ECM）相互作用的成分，包括整合素、基质金属蛋白酶和免疫球蛋白超家族成员。尽管有这些观察结果，外泌体- ECM相互作用的研究是有限的。在这里，我们研究了外泌体相关赖氨酸氧化酶家族成员赖氨酸氧化酶样2 （LOXL2）是否参与ECM重塑。我们发现LOXL2存在于内皮细胞（EC）来源的外泌体的外部，使其直接靠近ECM。在缺氧条件下培养的EC衍生外泌体中，其上调两倍。缺氧EC和LOXL2过表达EC的完整外泌体在赖氨酸氧化酶酶活性测定和胶原凝胶收缩测定中显示活性增加。同时，在正常和缺氧条件下，在产生EC的外泌体中，LOXL2的敲低会降低外泌体的活性。我们的研究结果首次表明，在缺氧的调节下，EC衍生的外泌体通过LOXL2介导ECM交联，并暗示外泌体在缺氧调节的局灶性ECM重塑中发挥作用，这是纤维化和伤口愈合的关键过程。
Exosomes are important mediators of intercellular communication. Additionally, they contain a variety of components capable of interacting with the extracellular matrix (ECM), including integrins, matrix metalloproteinases and members of the immunoglobin superfamily. Despite these observations, research on exosome‐ECM interactions is limited. Here, we investigate whether the exosome‐associated lysyl oxidase family member lysyl oxidase‐like 2 (LOXL2) is involved in ECM remodelling. We found that LOXL2 is present on the exterior of endothelial cell (EC)‐derived exosomes, placing it in direct vicinity of the ECM. It is up‐regulated twofold in EC‐derived exosomes cultured under hypoxic conditions. Intact exosomes from hypoxic EC and LOXL2 overexpressing EC show increased activity in a fluorometric lysyl oxidase enzymatic activity assay as well as in a collagen gel contraction assay. Concordantly, knockdown of LOXL2 in exosome‐producing EC in both normal and hypoxic conditions reduces activity of exosomes in both assays. Our findings show for the first time that ECM crosslinking by EC‐derived exosomes is mediated by LOXL2 under the regulation of hypoxia, and implicate a role for exosomes in hypoxia‐regulated focal ECM remodelling, a key process in both fibrosis and wound healing.