YAP-Dependent Induction of CD47-Enriched Extracellular Vesicles Inhibits Dendritic Cell Activation and Ameliorates Hepatic Ischemia-Reperfusion Injury.
YAP-Dependent Induction of CD47-Enriched Extracellular Vesicles Inhibits Dendritic Cell Activation and Ameliorates Hepatic Ischemia-Reperfusion Injury.
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YAP 依赖性诱导富含 CD47 的细胞外囊泡抑制树突状细胞活化并改善肝缺血再灌注损伤
DOI：
10.1155/2021/6617345
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发表时间：
2021
影响因子：
--
通讯作者：
Li H
中科院分区：
文献类型：
--
作者：
Yuan Z;Ye L;Feng X;Zhou T;Zhou Y;Zhu S;Jia C;Li H;Qiu D;Li K;Liu W;Li Y;Tang H;Wang G;Zhang Q;Yang Y;Chen G;Li H
肝缺血再灌注损伤（IRI）是导致肝切除术和肝移植手术失败的最常见原因。据报道，广泛的炎症反应和氧化反应是加剧IRI的主要过程。yes相关蛋白（YAP）参与了这两个过程，但YAP在IRI中的作用和机制尚不清楚。在本研究中，我们构建了肝细胞特异性YAP敲除（YAP- hko）小鼠并诱导肝脏IRI模型。令人惊讶的是，与WT小鼠相比，YAP-HKO小鼠在肝脏IRI期间血清EVs数量减少。然后，我们发现YAP的激活通过F-actin增加了EV的分泌，增加了膜的形成，同时抑制了肝细胞中多泡体（multivesicular body， MVB）和溶酶体的融合。此外，为了探索yap诱导的ev的基本要素，我们应用质谱分析发现CD47是肝细胞源性ev高表达的主要靶点之一。因此，我们利用微珠富集CD47+ ev，并将分离的CD47+ ev应用于IRI小鼠。我们发现，在这些小鼠中，CD47+ EV治疗后IRI症状得到改善，CD47+ EV与树突状细胞（DC）表面的CD172α结合，抑制DC激活和炎症反应级联。我们的数据显示，富含cd47的EVs以yap依赖的方式由肝细胞释放，这可以抑制DC激活并有助于改善肝脏IRI。CD47+ ev可能是治疗肝脏IRI的潜在策略。
Hepatic ischemia-reperfusion injury (IRI) is the most common cause of liver damage leading to surgical failures in hepatectomy and liver transplantation. Extensive inflammatory reactions and oxidative responses are reported to be the major processes exacerbating IRI. The involvement of Yes-associated protein (YAP) in either process has been suggested, but the role and mechanism of YAP in IRI remain unclear. In this study, we constructed hepatocyte-specific YAP knockout (YAP-HKO) mice and induced a hepatic IRI model. Surprisingly, the amount of serum EVs decreased in YAP-HKO compared to WT mice during hepatic IRI. Then, we found that the activation of YAP increased EV secretion through F-actin by increasing membrane formation, while inhibiting the fusion of multivesicular body (MVB) and lysosomes in hepatocytes. Further, to explore the essential elements of YAP-induced EVs, we applied mass spectrometry and noticed CD47 was among the top targets highly expressed on hepatocyte-derived EVs. Thus, we enriched CD47+ EVs by microbeads and applied the isolated CD47+ EVs on IRI mice. We found ameliorated IRI symptoms after CD47+ EV treatment in these mice, and CD47+ EVs bound to CD172α on the surface of dendritic cells (DCs), which inhibited DC activation and the cascade of inflammatory responses. Our data showed that CD47-enriched EVs were released in a YAP-dependent manner by hepatocytes, which could inhibit DC activation and contribute to the amelioration of hepatic IRI. CD47+ EVs could be a potential strategy for treating hepatic IRI.
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DOI：
10.1038/nrm2867
发表时间：
2010-04
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
64.5
作者：
Puthenveedu MA;Lauffer B;Temkin P;Vistein R;Carlton P;Thorn K;Taunton J;Weiner OD;Parton RG;von Zastrow M
通讯作者：
von Zastrow M
影响因子：
4.8
作者：
Chan, Siew Wee;Lim, Chun Jye;Hong, Wanjin
通讯作者：
Hong, Wanjin
DOI：
10.1002/hep.29276
发表时间：
2017-10
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Kolachala VL;Palle S;Shen M;Feng A;Shayakhmetov D;Gupta NA
通讯作者：
Gupta NA
影响因子：
16.8
作者：
Kaisho, T;Akira, S
通讯作者：
Akira, S