Zhang Pengpeng, Li Hao, Zhou Chen, Liu Kai, Peng Bo, She Xingguo, Cheng Ke, Liu Hong, Ming Yingzi
The Transplantation Center of the Third Xiangya Hospital, Central South University, Changsha 410013, China.
Engineering & Technology Research Center for Transplantation Medicine of National Ministry of Health, Changsha 410013, China.
J Clin Med. 2022 May 20;11(10):2910. doi: 10.3390/jcm11102910.
Acute-on-chronic liver failure (ACLF) is an acutely decompensated cirrhosis syndrome with high short-term mortality. Very little is known about the relationship between the lymphatic system and ACLF. We explored the role of hepatic lymphatic vessels (LVs) and lymphatic endothelial cells (LyECs) in ACLF using human liver samples with the help of single-cell RNA-sequencing (scRNA-seq) technology. Here, ACLF exhibited more severe liver injury and inflammation than cirrhosis, as indicated by significant increases in plasma levels of alanine/aspartate aminotransferases and total bilirubin. Compared with cirrhosis cases, the number of intrahepatic LVs was decreased significantly in ACLF patients. ScRNA-seq revealed that many monocyte/macrophages infiltrated into the liver of ACLF cases. Meanwhile, scRNA-seq revealed a group of apoptotic and dysfunctional LyECs, which were the result of secreted phosphoprotein 1 (SPP1) released from infiltrating monocyte/macrophages. In vitro, SPP1 increased the proportion of dead LyECs significantly and impaired the ability of tube formation of LyECs in a dose- and time-dependent manner. In conclusion, ACLF is associated with less LV and LyEC dysfunction, at least in part mediated by SPP1 released from infiltrating monocyte/macrophages. Hepatic LVs and LyECs can be a novel therapeutic strategy for ACLF.
慢加急性肝衰竭（ACLF）是一种急性失代偿性肝硬化综合征，短期死亡率高。关于淋巴系统与ACLF之间的关系，人们知之甚少。我们借助单细胞RNA测序（scRNA-seq）技术，利用人类肝脏样本探索了肝淋巴管（LVs）和淋巴管内皮细胞（LyECs）在ACLF中的作用。在此，如丙氨酸/天冬氨酸转氨酶和总胆红素血浆水平显著升高所示，ACLF比肝硬化表现出更严重的肝损伤和炎症。与肝硬化病例相比，ACLF患者肝内LVs数量显著减少。scRNA-seq显示，许多单核细胞/巨噬细胞浸润到ACLF病例的肝脏中。同时，scRNA-seq揭示了一组凋亡和功能失调的LyECs，这是浸润的单核细胞/巨噬细胞释放的分泌磷蛋白1（SPP1）的结果。在体外，SPP1显著增加了死亡LyECs的比例，并以剂量和时间依赖性方式损害了LyECs的管形成能力。总之，ACLF与较少的LV和LyEC功能障碍有关，至少部分由浸润的单核细胞/巨噬细胞释放的SPP1介导。肝LVs和LyECs可能是ACLF的一种新的治疗策略。
