Extracellular vesicles derived from GMSCs stimulated with TNF-α and IFN-α promote M2 macrophage polarization via enhanced CD73 and CD5L expression.
Extracellular vesicles derived from GMSCs stimulated with TNF-α and IFN-α promote M2 macrophage polarization via enhanced CD73 and CD5L expression.
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用TNF-α和IFN-α刺激的GMSC衍生的细胞外囊泡通过增强CD 73和CD 5L表达促进M2巨噬细胞极化。
DOI：
10.1038/s41598-022-17692-0
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发表时间：
2022-08-03
影响因子：
4.6
通讯作者：
Nishimura, Fusanori
中科院分区：
文献类型：
--
作者：
Watanabe, Yukari;Fukuda, Takao;Hayashi, Chikako;Nakao, Yuki;Toyoda, Masaaki;Kawakami, Kentaro;Shinjo, Takanori;Iwashita, Misaki;Yamato, Hiroaki;Yotsumoto, Karen;Taketomi, Takaharu;Uchiumi, Takeshi;Sanui, Terukazu;Nishimura, Fusanori
间充质干细胞（MSC）衍生的细胞外囊泡（EV）的免疫调节特性是有前途的。牙龈组织来源的间充质干细胞（GMSC）具有独特的免疫调节能力，并分泌大量的EV。最近的研究结果表明，用炎症刺激物引发MSC是无细胞治疗的有效策略。然而，EV内容定制的精确机制尚未完全阐明。在这里，我们表明，来自GMSC的EV与两种促炎细胞因子，肿瘤坏死因子-α（TNF-α）和干扰素-α（IFN-α）的组合，协同促进抗炎M2巨噬细胞极化通过增加分化簇73（CD73）和CD5分子样（CD5L）的表达。TNF-α/IFN-α刺激的CD73表达通过激活哺乳动物雷帕霉素靶信号和低氧诱导因子1 α在GMSC中的核转位而转录上调。TNF-α/IFN-α处理还通过转录因子DNA结合蛋白抑制剂ID3和肝X受体显著增加CD5L mRNA的表达。有趣的是，外泌体CD5L是EV介导的M2巨噬细胞极化的协同效应的先决条件。这些结果表明，在GMSC中联合预许可TNF-α和IFN-α对于增强EV的抗炎功能是理想的，这有助于建立一种治疗工具。
Immunoregulatory properties of mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) are promising. Gingival tissue-derived MSCs (GMSCs) have unique immunoregulatory capacity and secrete large amounts of EVs. Recent findings suggest that priming MSCs with inflammatory stimuli is an effective strategy for cell-free therapy. However, the precise mechanism by which the contents of EVs are customized has not been fully elucidated. Here, we show that EVs derived from GMSCs primed with a combination of two pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α) and interferon-α (IFN-α), synergistically promote anti-inflammatory M2 macrophage polarization by increasing the expression of cluster of differentiation 73 (CD73) and CD5 molecule-like (CD5L). Expression of CD73 by TNF-α/IFN-α stimulation was transcriptionally upregulated by the activation of mammalian target of rapamycin signaling and nuclear translocation of hypoxia-inducible factor 1α in GMSCs. TNF-α/IFN-α treatment also significantly increased the expression of CD5L mRNA via the transcription factor DNA-binding protein inhibitor ID3 and liver X receptor. Interestingly, exosomal CD5L is a prerequisite for the synergistic effect of EVs-mediated M2 macrophage polarization. These results indicate that combined pre-licensing with TNF-α and IFN-α in GMSCs is ideal for enhancing the anti-inflammatory function of EVs, which contributes to the establishment of a therapeutic tool.
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影响因子：
7.5
作者：
Lin T;Pajarinen J;Nabeshima A;Lu L;Nathan K;Jämsen E;Yao Z;Goodman SB
通讯作者：
Goodman SB
影响因子：
64.5
作者：
Joseph, SB;Bradley, MN;Tontonoz, P
通讯作者：
Tontonoz, P
影响因子：
17.1
作者：
Kou X;Xu X;Chen C;Sanmillan ML;Cai T;Zhou Y;Giraudo C;Le A;Shi S
通讯作者：
Shi S
影响因子：
3.4
作者：
Mathivanan, Suresh;Simpson, Richard J.
通讯作者：
Simpson, Richard J.
DOI：
10.4049/jimmunol.181.2.1052
发表时间：
2008-07-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Gerber SA;Pober JS
通讯作者：
Pober JS