Huang Lin-Xiang, Qiu Zi-Xuan, Wang Xiao-Xiao, Wang Zi-Long, Feng Bo
Peking University People's Hospital, Peking University Hepatology Institute, Infectious Disease and Hepatology Center of Peking University People's Hospital, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, 100044, China.
Sci Rep. 2025 Jul 2;15(1):22640. doi: 10.1038/s41598-025-07311-z.
Primary biliary cholangitis (PBC) is an immune-mediated, non-suppurative cholestatic liver disease. Liver sinusoidal endothelial cells (LSECs) play a pivotal role in maintaining hepatic immune tolerance. Emerging research indicates that under certain stimuli, LSECs can transition from a tolerogenic to an immunogenic role. We hypothesize that LSECs may be implicated in the pathogenesis of PBC. Single-cell RNA sequencing (scRNA-seq) data were initially analyzed using R statistical software and Cell Ranger. Differentially expressed genes and marker genes were identified using Seurat. Preliminary cell type identification was conducted with SingleR cell clustering. Differential gene expression was determined using t-tests, and significance analysis was performed with the Limma package. Pseudotime analysis was conducted with Monocle2. Compared to the control (CTR) group, the number of endothelial cells in the PBC group was significantly reduced (P < 0.05). Further analysis of these endothelial cells revealed seven distinct subpopulations, including a newly defined CPE vWF endothelial cell type. Interaction between CPE vW endothelial cells and bile duct cells was mediated through the APP-CD74 axis. Expression levels of CD74 and MIF were significantly higher in patients with PBC compared to CTR. CD74, serving as a receptor for the pro-inflammatory cytokine MIF, may counteract the anti-inflammatory effects of glucocorticoids. Expression levels of PTPRC and CCL5 were positively correlated with hepatic inflammation and fibrosis severity and were elevated in patients with PBC. CPE vWF endothelial cells might play a promising role in contributing to bile duct cell injury in patients with PBC by upregulating the pro-inflammatory factor MIF and interacting with CD74. Additionally, another unidentified endothelial cell type was suggested to exacerbate biliary damage and fibrosis by upregulating PTPRC and CCL5 expression.
原发性胆汁性胆管炎（PBC）是一种免疫介导的非化脓性胆汁淤积性肝病。肝窦内皮细胞（LSEC）在维持肝脏免疫耐受中起关键作用。新出现的研究表明，在某些刺激下，LSEC可从促耐受性作用转变为免疫原性作用。我们推测LSEC可能与PBC的发病机制有关。最初使用R统计软件和Cell Ranger分析单细胞RNA测序（scRNA-seq）数据。使用Seurat鉴定差异表达基因和标记基因。用SingleR细胞聚类进行初步细胞类型鉴定。使用t检验确定差异基因表达，并使用Limma软件包进行显著性分析。用Monocle2进行伪时间分析。与对照组（CTR）相比，PBC组内皮细胞数量显著减少（P < 0.05）。对这些内皮细胞的进一步分析揭示了七个不同的亚群，包括一种新定义的CPE vWF内皮细胞类型。CPE vW内皮细胞与胆管细胞之间的相互作用是通过APP-CD74轴介导的。与CTR相比，PBC患者中CD74和MIF的表达水平显著更高。CD74作为促炎细胞因子MIF的受体，可能抵消糖皮质激素的抗炎作用。PTPRC和CCL5的表达水平与肝脏炎症和纤维化严重程度呈正相关，且在PBC患者中升高。CPE vWF内皮细胞可能通过上调促炎因子MIF并与CD74相互作用，在PBC患者胆管细胞损伤中发挥重要作用。此外，另一种未鉴定的内皮细胞类型被认为通过上调PTPRC和CCL5表达加剧胆管损伤和纤维化。
