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Hepatectomy-induced apoptotic extracellular vesicles stimulate neutrophils to secrete regenerative growth factors
Journal of Hepatology ( IF 25.7 ) Pub Date : 2022-08-17 , DOI: 10.1016/j.jhep.2022.07.027
Victoria Brandel 1 , Vanessa Schimek 2 , Samantha Göber 2 , Thomas Hammond 3 , Laura Brunnthaler 4 , Waltraud Cornelia Schrottmaier 4 , Marion Mussbacher 5 , Monika Sachet 2 , Ying Yu Liang 2 , Siegfried Reipert 6 , Gregor Ortmayr 2 , David Pereyra 1 , Jonas Santol 7 , Marlene Rainer 2 , Natalie Walterskirchen 2 , Cristiano Ramos 2 , Vasileios Gerakopoulos 2 , Carina Rainer 2 , Andreas Spittler 2 , Tamara Weiss 8 , Renate Kain 9 , Barbara Messner 10 , Thomas Gruenberger 11 , Alice Assinger 4 , Rudolf Oehler 2 , Patrick Starlinger 12
Affiliation  

Background & Aims

Surgical resection of the cancerous tissue represents one of the few curative treatment options for neoplastic liver disease. Such partial hepatectomy (PHx) induces hepatocyte hyperplasia, which restores liver function. PHx is associated with bacterial translocation, leading to an immediate immune response involving neutrophils and macrophages, which are indispensable for the priming phase of liver regeneration. Additionally, PHx induces longer-lasting intrahepatic apoptosis. Herein, we investigated the effect of apoptotic extracellular vesicles (aEVs) on neutrophil function and their role in this later phase of liver regeneration.

Methods

A total of 124 patients undergoing PHx were included in this study. Blood levels of the apoptosis marker caspase-cleaved cytokeratin-18 (M30) and circulating aEVs were analyzed preoperatively and on the first and fifth postoperative days. Additionally, the in vitro effects of aEVs on the secretome, phenotype and functions of neutrophils were investigated.

Results

Circulating aEVs increased at the first postoperative day and were associated with higher concentrations of M30, which was only observed in patients with complete liver recovery. Efferocytosis of aEVs by neutrophils induced an activated phenotype (CD11bhighCD16highCD66bhighCD62Llow); however, classical inflammatory responses such as NETosis, respiratory burst, degranulation, or secretion of pro-inflammatory cytokines were not observed. Instead, efferocytosing neutrophils released various growth factors including fibroblast growth factor-2 and hepatocyte growth factor (HGF). Accordingly, we observed an increase of HGF-positive neutrophils after PHx and a correlation of plasma HGF with M30 levels.

Conclusions

These data suggest that the clearance of PHx-induced aEVs leads to a population of non-inflammatory but regenerative neutrophils, which may support human liver regeneration.

Lay summary

In this study, we show that the surgical removal of a diseased part of the liver triggers a specific type of programmed cell death in the residual liver tissue. This results in the release of vesicles from dying cells into the blood, where they are cleared by circulating immune cells. These respond by secreting hepatocyte growth factors that could potentially support the regeneration of the liver remnant.



中文翻译:

肝切除术诱导的凋亡细胞外囊泡刺激中性粒细胞分泌再生生长因子

背景与目标

癌组织的手术切除代表了肿瘤性肝病的少数治愈性治疗选择之一。这种部分肝切除术 (PHx) 诱导肝细胞增生,从而恢复肝功能。PHx 与细菌易位相关,导致涉及中性粒细胞和巨噬细胞的即时免疫反应,这对于肝再生的启动阶段是必不可少的。此外,PHx 诱导更持久的肝内细胞凋亡。在此,我们研究了凋亡细胞外囊泡 (aEV) 对中性粒细胞功能的影响及其在肝再生后期的作用。

方法

本研究共纳入 124 名接受 PHx 治疗的患者。术前和术后第一天和第五天分析了细胞凋亡标志物 caspase-cleaved cytokeratin-18 (M30) 和循环 aEV 的血液水平。此外,还研究了 aEV 对中性粒细胞分泌蛋白组、表型和功能的体外影响。

结果

循环 aEVs 在术后第一天增加,并且与更高浓度的 M30 相关,这仅在肝脏完全恢复的患者中观察到。中性粒细胞对 aEV 的胞吐作用诱导了活化表型(CD11bCD16CD66bCD62L);然而,没有观察到典型的炎症反应,如 NETosis、呼吸爆发、脱颗粒或促炎细胞因子的分泌。相反,胞吐性中性粒细胞释放各种生长因子,包括成纤维细胞生长因子 2 和肝细胞生长因子 (HGF)。因此,我们观察到 PHx 后 HGF 阳性中性粒细胞的增加以及血浆 HGF 与 M30 水平的相关性。

结论

这些数据表明,PHx 诱导的 aEV 的清除会导致大量非炎症但可再生的中性粒细胞,这可能支持人类肝脏再生。

外行总结

在这项研究中,我们表明手术切除肝脏的病变部分会在残留的肝组织中引发特定类型的程序性细胞死亡。这导致囊泡从垂死的细胞中释放到血液中,在那里它们被循环的免疫细胞清除。它们通过分泌肝细胞生长因子做出反应,这些因子可能支持残余肝脏的再生。

更新日期:2022-08-17
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