YAP-Dependent Induction of CD47-Enriched Extracellular Vesicles Inhibits Dendritic Cell Activation and Ameliorates Hepatic Ischemia-Reperfusion Injury
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-associate...
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| creator | Yuan, Zenan Ye, Linsen Feng, Xiao Zhou, Tian Zhou, Yi Zhu, Shuguang Jia, Changchang Li, Haibo Qiu, Dongbo Li, Kun Liu, Wei Li, Yang Tang, Hui Wang, Guoying Zhang, Qi Yang, Yang Chen, Guihua Li, Hua |
| description | 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. |
| doi_str_mv | 10.1155/2021/6617345 |
| format | Article |
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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.</description><identifier>ISSN: 1942-0900</identifier><identifier>EISSN: 1942-0994</identifier><identifier>DOI: 10.1155/2021/6617345</identifier><identifier>PMID: 34239692</identifier><language>eng</language><publisher>United States: Hindawi</publisher><subject>Adaptive immunity ; Adult ; Aged ; Animals ; Bone marrow ; CD47 Antigen - metabolism ; Dendritic Cells - metabolism ; Experiments ; Extracellular vesicles ; Extracellular Vesicles - metabolism ; Female ; Humans ; Inflammation ; Ischemia ; Liver ; Liver - blood supply ; Liver - metabolism ; Liver - pathology ; Male ; Mice ; Mice, Knockout ; Middle Aged ; Plasmids ; Proteins ; Reperfusion Injury - genetics ; Reperfusion Injury - metabolism ; YAP-Signaling Proteins - metabolism ; Young Adult</subject><ispartof>Oxidative medicine and cellular longevity, 2021, Vol.2021 (1), p.6617345-6617345</ispartof><rights>Copyright © 2021 Zenan Yuan et al.</rights><rights>Copyright © 2021 Zenan Yuan et al. This is an open access article distributed under the Creative Commons Attribution License (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. https://creativecommons.org/licenses/by/4.0</rights><rights>Copyright © 2021 Zenan Yuan et al. 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c448t-aa5f3b69c114546763a463a6fb3eb0220303810d88f4def6ad3c9b9a0b84a0243</citedby><cites>FETCH-LOGICAL-c448t-aa5f3b69c114546763a463a6fb3eb0220303810d88f4def6ad3c9b9a0b84a0243</cites><orcidid>0000-0002-3875-2473 ; 0000-0002-0318-8892 ; 0000-0001-9776-8515</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241504/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241504/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,4024,27923,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34239692$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Pechanova, Olga</contributor><contributor>Olga Pechanova</contributor><creatorcontrib>Yuan, Zenan</creatorcontrib><creatorcontrib>Ye, Linsen</creatorcontrib><creatorcontrib>Feng, Xiao</creatorcontrib><creatorcontrib>Zhou, Tian</creatorcontrib><creatorcontrib>Zhou, Yi</creatorcontrib><creatorcontrib>Zhu, Shuguang</creatorcontrib><creatorcontrib>Jia, Changchang</creatorcontrib><creatorcontrib>Li, Haibo</creatorcontrib><creatorcontrib>Qiu, Dongbo</creatorcontrib><creatorcontrib>Li, Kun</creatorcontrib><creatorcontrib>Liu, Wei</creatorcontrib><creatorcontrib>Li, Yang</creatorcontrib><creatorcontrib>Tang, Hui</creatorcontrib><creatorcontrib>Wang, Guoying</creatorcontrib><creatorcontrib>Zhang, Qi</creatorcontrib><creatorcontrib>Yang, Yang</creatorcontrib><creatorcontrib>Chen, Guihua</creatorcontrib><creatorcontrib>Li, Hua</creatorcontrib><title>YAP-Dependent Induction of CD47-Enriched Extracellular Vesicles Inhibits Dendritic Cell Activation and Ameliorates Hepatic Ischemia-Reperfusion Injury</title><title>Oxidative medicine and cellular longevity</title><addtitle>Oxid Med Cell Longev</addtitle><description>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.</description><subject>Adaptive immunity</subject><subject>Adult</subject><subject>Aged</subject><subject>Animals</subject><subject>Bone marrow</subject><subject>CD47 Antigen - metabolism</subject><subject>Dendritic Cells - metabolism</subject><subject>Experiments</subject><subject>Extracellular vesicles</subject><subject>Extracellular Vesicles - metabolism</subject><subject>Female</subject><subject>Humans</subject><subject>Inflammation</subject><subject>Ischemia</subject><subject>Liver</subject><subject>Liver - blood supply</subject><subject>Liver - metabolism</subject><subject>Liver - pathology</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Middle Aged</subject><subject>Plasmids</subject><subject>Proteins</subject><subject>Reperfusion Injury - genetics</subject><subject>Reperfusion Injury - metabolism</subject><subject>YAP-Signaling Proteins - metabolism</subject><subject>Young Adult</subject><issn>1942-0900</issn><issn>1942-0994</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>RHX</sourceid><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp9kU9rFDEYhwex2Fq9eZaAF0HH5v9OLsKyu9qFgiIqeArvJBk3y0xmTWaq_SJ-XjPd7VI9eAgJ5Hmf5H1_RfGM4DeECHFBMSUXUpIZ4-JBcUYUpyVWij88njE-LR6ntMVYMsrJo-KUccqUVPSs-P1t_rFcup0L1oUBrYMdzeD7gPoGLZZ8Vq5C9GbjLFr9GiIY17ZjCxF9dcmb1qVcsfG1HxJaZkX0gzdokSE0z5pruFVBsGjeudb3EYZccul2MHHrlMWdh_JTfj82Y5rgddiO8eZJcdJAm9zTw35efHm3-ry4LK8-vF8v5lel4bwaSgDRsFoqQwgXXM4kA56XbGrmakwpZphVBNuqarh1jQTLjKoV4LrigCln58XbvXc31p2zJs8gQqt30XcQb3QPXv99E_xGf--vdZUHKfAkeHkQxP7H6NKgO5-mKUFw_Zg0FQJTSQmmGX3xD7rtxxhye5niFVVcEJKp13vKxD6l6JrjZwjWU-B6ClwfAs_48_sNHOG7hDPwag9sfLDw0_9f9wcEcLRx</recordid><startdate>2021</startdate><enddate>2021</enddate><creator>Yuan, Zenan</creator><creator>Ye, Linsen</creator><creator>Feng, Xiao</creator><creator>Zhou, Tian</creator><creator>Zhou, Yi</creator><creator>Zhu, Shuguang</creator><creator>Jia, Changchang</creator><creator>Li, Haibo</creator><creator>Qiu, Dongbo</creator><creator>Li, Kun</creator><creator>Liu, Wei</creator><creator>Li, Yang</creator><creator>Tang, Hui</creator><creator>Wang, Guoying</creator><creator>Zhang, Qi</creator><creator>Yang, Yang</creator><creator>Chen, Guihua</creator><creator>Li, Hua</creator><general>Hindawi</general><general>Hindawi Limited</general><scope>RHU</scope><scope>RHW</scope><scope>RHX</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-3875-2473</orcidid><orcidid>https://orcid.org/0000-0002-0318-8892</orcidid><orcidid>https://orcid.org/0000-0001-9776-8515</orcidid></search><sort><creationdate>2021</creationdate><title>YAP-Dependent Induction of CD47-Enriched Extracellular Vesicles Inhibits Dendritic Cell Activation and Ameliorates Hepatic Ischemia-Reperfusion Injury</title><author>Yuan, Zenan ; Ye, Linsen ; Feng, Xiao ; Zhou, Tian ; Zhou, Yi ; Zhu, Shuguang ; Jia, Changchang ; Li, Haibo ; Qiu, Dongbo ; Li, Kun ; Liu, Wei ; Li, Yang ; Tang, Hui ; Wang, Guoying ; Zhang, Qi ; Yang, Yang ; Chen, Guihua ; Li, Hua</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c448t-aa5f3b69c114546763a463a6fb3eb0220303810d88f4def6ad3c9b9a0b84a0243</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Adaptive immunity</topic><topic>Adult</topic><topic>Aged</topic><topic>Animals</topic><topic>Bone marrow</topic><topic>CD47 Antigen - metabolism</topic><topic>Dendritic Cells - metabolism</topic><topic>Experiments</topic><topic>Extracellular vesicles</topic><topic>Extracellular Vesicles - metabolism</topic><topic>Female</topic><topic>Humans</topic><topic>Inflammation</topic><topic>Ischemia</topic><topic>Liver</topic><topic>Liver - blood supply</topic><topic>Liver - metabolism</topic><topic>Liver - pathology</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Middle Aged</topic><topic>Plasmids</topic><topic>Proteins</topic><topic>Reperfusion Injury - genetics</topic><topic>Reperfusion Injury - metabolism</topic><topic>YAP-Signaling Proteins - metabolism</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yuan, Zenan</creatorcontrib><creatorcontrib>Ye, Linsen</creatorcontrib><creatorcontrib>Feng, Xiao</creatorcontrib><creatorcontrib>Zhou, Tian</creatorcontrib><creatorcontrib>Zhou, Yi</creatorcontrib><creatorcontrib>Zhu, Shuguang</creatorcontrib><creatorcontrib>Jia, Changchang</creatorcontrib><creatorcontrib>Li, Haibo</creatorcontrib><creatorcontrib>Qiu, Dongbo</creatorcontrib><creatorcontrib>Li, Kun</creatorcontrib><creatorcontrib>Liu, Wei</creatorcontrib><creatorcontrib>Li, Yang</creatorcontrib><creatorcontrib>Tang, Hui</creatorcontrib><creatorcontrib>Wang, Guoying</creatorcontrib><creatorcontrib>Zhang, Qi</creatorcontrib><creatorcontrib>Yang, Yang</creatorcontrib><creatorcontrib>Chen, Guihua</creatorcontrib><creatorcontrib>Li, Hua</creatorcontrib><collection>Hindawi Publishing Complete</collection><collection>Hindawi Publishing Subscription Journals</collection><collection>Hindawi Publishing Open Access Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>ProQuest research library</collection><collection>Research Library (Corporate)</collection><collection>Access via ProQuest (Open Access)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Oxidative medicine and cellular longevity</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yuan, Zenan</au><au>Ye, Linsen</au><au>Feng, Xiao</au><au>Zhou, Tian</au><au>Zhou, Yi</au><au>Zhu, Shuguang</au><au>Jia, Changchang</au><au>Li, Haibo</au><au>Qiu, Dongbo</au><au>Li, Kun</au><au>Liu, Wei</au><au>Li, Yang</au><au>Tang, Hui</au><au>Wang, Guoying</au><au>Zhang, Qi</au><au>Yang, Yang</au><au>Chen, Guihua</au><au>Li, Hua</au><au>Pechanova, Olga</au><au>Olga Pechanova</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>YAP-Dependent Induction of CD47-Enriched Extracellular Vesicles Inhibits Dendritic Cell Activation and Ameliorates Hepatic Ischemia-Reperfusion Injury</atitle><jtitle>Oxidative medicine and cellular longevity</jtitle><addtitle>Oxid Med Cell Longev</addtitle><date>2021</date><risdate>2021</risdate><volume>2021</volume><issue>1</issue><spage>6617345</spage><epage>6617345</epage><pages>6617345-6617345</pages><issn>1942-0900</issn><eissn>1942-0994</eissn><abstract>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.</abstract><cop>United States</cop><pub>Hindawi</pub><pmid>34239692</pmid><doi>10.1155/2021/6617345</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0002-3875-2473</orcidid><orcidid>https://orcid.org/0000-0002-0318-8892</orcidid><orcidid>https://orcid.org/0000-0001-9776-8515</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Oxidative medicine and cellular longevity, 2021, Vol.2021 (1), p.6617345-6617345 |
| issn | 1942-0900 1942-0994 |
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| source | MEDLINE; Wiley Online Library (Open Access Collection); PubMed Central; Alma/SFX Local Collection; EZB Electronic Journals Library; PubMed Central Open Access |
| subjects | Adaptive immunity Adult Aged Animals Bone marrow CD47 Antigen - metabolism Dendritic Cells - metabolism Experiments Extracellular vesicles Extracellular Vesicles - metabolism Female Humans Inflammation Ischemia Liver Liver - blood supply Liver - metabolism Liver - pathology Male Mice Mice, Knockout Middle Aged Plasmids Proteins Reperfusion Injury - genetics Reperfusion Injury - metabolism YAP-Signaling Proteins - metabolism Young Adult |
| title | YAP-Dependent Induction of CD47-Enriched Extracellular Vesicles Inhibits Dendritic Cell Activation and Ameliorates Hepatic Ischemia-Reperfusion Injury |
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