Single-Cell RNA Transcriptomics Reveals the State of Hepatic Lymphatic Endothelial Cells in Hepatitis B Virus-Related Acute-on-Chronic Liver Failure

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.