Longyu Miao, Chaoqun Yu, Ge Guan, Xiaoyu Luan, Xiaoshuang Jin, Meiqi Pan, Yuzhen Yang, Jiaoyang Yan, Peng Chen, Guohu Di
{"title":"含有GAS6的细胞外囊泡通过MerTK-ERK-COX2信号传导增强巨噬细胞的排泄功能,从而保护肝脏免受缺血再灌注损伤的影响","authors":"Longyu Miao, Chaoqun Yu, Ge Guan, Xiaoyu Luan, Xiaoshuang Jin, Meiqi Pan, Yuzhen Yang, Jiaoyang Yan, Peng Chen, Guohu Di","doi":"10.1038/s41420-024-02169-y","DOIUrl":null,"url":null,"abstract":"<p>Hepatic ischemia-reperfusion injury (HIRI) is a significant issue during liver transplantation and surgery, contributing to the liver failure or even mortality. Although extracellular vesicles derived from mesenchymal stem cells (MSC-EVs) have shown substantial potentials in cell replacement therapy of various organ ischemia reperfusion injuries (IRIs), the precise mechanisms remain unclear. In this study, we demonstrate that systemic MSC-EVs administration is predominantly absorbed by macrophages, and verified that it could significantly reduce the liver injury and inflammatory response in mice suffering from HIRI. Furthermore, treatment with MSC-EVs induces macrophage polarization toward an anti-inflammatory phenotype. Mechanistically, proteomic profiling reveals an enrichment of growth arrest-specific 6 (GAS6) in MSC-EVs, significantly promoting the activation of myeloid-epithelial-reproductive tyrosine kinase/extracellular regulated protein kinases/cyclooxygenase 2 (MerTK/ERK/COX2) signaling pathway in macrophages and further enhancing their efferocytosis efficiency. Knockdown of GAS6 via lentiviral transfection or inhibition of MerTK using UNC2025 (a MerTK small molecule inhibitor) partially eliminates the protective effects of MSC-EVs on macrophage efferocytosis and liver injury. Overall, our findings support that MSC-EVs enriched GAS6 execute an anti-inflammation effect, highlighting that treatment based on the modulation of macrophage function by MSC-EVs as a promising approach in IRI.</p><figure><p>HIRI is a thorny problem after liver surgery such as liver transplantation. In a murine model of HIRI, MSC-EVs enriched GAS6 effectively enhance macrophage efferocytosis both in vivo and in vitro through the GAS6/MerTK/ERK/COX2 signaling pathway and significantly mitigate liver injury. This image was drawn by the authors.</p></figure>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":null,"pages":null},"PeriodicalIF":6.1000,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Extracellular vesicles containing GAS6 protect the liver from ischemia-reperfusion injury by enhancing macrophage efferocytosis via MerTK-ERK-COX2 signaling\",\"authors\":\"Longyu Miao, Chaoqun Yu, Ge Guan, Xiaoyu Luan, Xiaoshuang Jin, Meiqi Pan, Yuzhen Yang, Jiaoyang Yan, Peng Chen, Guohu Di\",\"doi\":\"10.1038/s41420-024-02169-y\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Hepatic ischemia-reperfusion injury (HIRI) is a significant issue during liver transplantation and surgery, contributing to the liver failure or even mortality. Although extracellular vesicles derived from mesenchymal stem cells (MSC-EVs) have shown substantial potentials in cell replacement therapy of various organ ischemia reperfusion injuries (IRIs), the precise mechanisms remain unclear. In this study, we demonstrate that systemic MSC-EVs administration is predominantly absorbed by macrophages, and verified that it could significantly reduce the liver injury and inflammatory response in mice suffering from HIRI. Furthermore, treatment with MSC-EVs induces macrophage polarization toward an anti-inflammatory phenotype. Mechanistically, proteomic profiling reveals an enrichment of growth arrest-specific 6 (GAS6) in MSC-EVs, significantly promoting the activation of myeloid-epithelial-reproductive tyrosine kinase/extracellular regulated protein kinases/cyclooxygenase 2 (MerTK/ERK/COX2) signaling pathway in macrophages and further enhancing their efferocytosis efficiency. Knockdown of GAS6 via lentiviral transfection or inhibition of MerTK using UNC2025 (a MerTK small molecule inhibitor) partially eliminates the protective effects of MSC-EVs on macrophage efferocytosis and liver injury. Overall, our findings support that MSC-EVs enriched GAS6 execute an anti-inflammation effect, highlighting that treatment based on the modulation of macrophage function by MSC-EVs as a promising approach in IRI.</p><figure><p>HIRI is a thorny problem after liver surgery such as liver transplantation. In a murine model of HIRI, MSC-EVs enriched GAS6 effectively enhance macrophage efferocytosis both in vivo and in vitro through the GAS6/MerTK/ERK/COX2 signaling pathway and significantly mitigate liver injury. This image was drawn by the authors.</p></figure>\",\"PeriodicalId\":9735,\"journal\":{\"name\":\"Cell Death Discovery\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":6.1000,\"publicationDate\":\"2024-09-10\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cell Death Discovery\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1038/s41420-024-02169-y\",\"RegionNum\":2,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Death Discovery","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41420-024-02169-y","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
Extracellular vesicles containing GAS6 protect the liver from ischemia-reperfusion injury by enhancing macrophage efferocytosis via MerTK-ERK-COX2 signaling
Hepatic ischemia-reperfusion injury (HIRI) is a significant issue during liver transplantation and surgery, contributing to the liver failure or even mortality. Although extracellular vesicles derived from mesenchymal stem cells (MSC-EVs) have shown substantial potentials in cell replacement therapy of various organ ischemia reperfusion injuries (IRIs), the precise mechanisms remain unclear. In this study, we demonstrate that systemic MSC-EVs administration is predominantly absorbed by macrophages, and verified that it could significantly reduce the liver injury and inflammatory response in mice suffering from HIRI. Furthermore, treatment with MSC-EVs induces macrophage polarization toward an anti-inflammatory phenotype. Mechanistically, proteomic profiling reveals an enrichment of growth arrest-specific 6 (GAS6) in MSC-EVs, significantly promoting the activation of myeloid-epithelial-reproductive tyrosine kinase/extracellular regulated protein kinases/cyclooxygenase 2 (MerTK/ERK/COX2) signaling pathway in macrophages and further enhancing their efferocytosis efficiency. Knockdown of GAS6 via lentiviral transfection or inhibition of MerTK using UNC2025 (a MerTK small molecule inhibitor) partially eliminates the protective effects of MSC-EVs on macrophage efferocytosis and liver injury. Overall, our findings support that MSC-EVs enriched GAS6 execute an anti-inflammation effect, highlighting that treatment based on the modulation of macrophage function by MSC-EVs as a promising approach in IRI.
期刊介绍:
Cell Death Discovery is a multidisciplinary, international, online-only, open access journal, dedicated to publishing research at the intersection of medicine with biochemistry, pharmacology, immunology, cell biology and cell death, provided it is scientifically sound. The unrestricted access to research findings in Cell Death Discovery will foster a dynamic and highly productive dialogue between basic scientists and clinicians, as well as researchers in industry with a focus on cancer, neurobiology and inflammation research. As an official journal of the Cell Death Differentiation Association (ADMC), Cell Death Discovery will build upon the success of Cell Death & Differentiation and Cell Death & Disease in publishing important peer-reviewed original research, timely reviews and editorial commentary.
Cell Death Discovery is committed to increasing the reproducibility of research. To this end, in conjunction with its sister journals Cell Death & Differentiation and Cell Death & Disease, Cell Death Discovery provides a unique forum for scientists as well as clinicians and members of the pharmaceutical and biotechnical industry. It is committed to the rapid publication of high quality original papers that relate to these subjects, together with topical, usually solicited, reviews, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.