Extracellular vesicles containing GAS6 protect the liver from ischemia-reperfusion injury by enhancing macrophage efferocytosis via MerTK-ERK-COX2 signaling

IF 6.1 2区生物学 Q1 CELL BIOLOGY Cell Death Discovery Pub Date : 2024-09-10 DOI:10.1038/s41420-024-02169-y

Longyu Miao, Chaoqun Yu, Ge Guan, Xiaoyu Luan, Xiaoshuang Jin, Meiqi Pan, Yuzhen Yang, Jiaoyang Yan, Peng Chen, Guohu Di

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Abstract

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.

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.

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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

肝脏缺血再灌注损伤（HIRI）是肝脏移植和手术过程中的一个重要问题，会导致肝功能衰竭甚至死亡。尽管间充质干细胞衍生的细胞外囊泡在各种器官缺血再灌注损伤（IRI）的细胞替代疗法中显示出巨大潜力，但其确切机制仍不清楚。在这项研究中，我们证明了全身给药间充质干细胞-EVs主要被巨噬细胞吸收，并验证了它能显著减轻缺血再灌注损伤小鼠的肝损伤和炎症反应。此外，间充质干细胞-EVs还能诱导巨噬细胞向抗炎表型极化。从机理上讲，蛋白质组学分析表明，间充质干细胞-EVs中富含生长停滞特异性6（GAS6），能显著促进巨噬细胞中髓-上皮-还原性酪氨酸激酶/细胞外调节蛋白激酶/环氧化酶2（MerTK/ERK/COX2）信号通路的激活，并进一步提高它们的排泄效率。通过慢病毒转染敲除GAS6或使用UNC2025（一种MerTK小分子抑制剂）抑制MerTK可部分消除间充质干细胞-EV对巨噬细胞渗出和肝损伤的保护作用。总之，我们的研究结果支持富含GAS6的间充质干细胞-EVs具有抗炎作用，突出表明基于间充质干细胞-EVs调节巨噬细胞功能的治疗是一种治疗IRI的有前景的方法。在小鼠HIRI模型中，富含GAS6的间充质干细胞-EVs通过GAS6/MerTK/ERK/COX2信号通路，有效增强巨噬细胞在体内和体外的排泄功能，显著减轻肝损伤。本图由作者绘制。

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来源期刊

Cell Death Discovery Biochemistry, Genetics and Molecular Biology-Cell Biology

CiteScore

8.30

自引率

1.40%

发文量

468

审稿时长

9 weeks

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.