Wang Liya, He Li, Yi Weijia, Wang Min, Xu Fangmin, Liu Hanlin, Nie Jiahui, Pan Yi-Hsuan, Dang Suying, Zhang Wei
Key Laboratory of Brain Functional Genomics (Ministry of Education and Shanghai), School of Life Sciences, East China Normal University, Shanghai, China.
Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
iScience. 2024 Jun 14;27(7):110273. doi: 10.1016/j.isci.2024.110273. eCollection 2024 Jul 19.
Liver sinusoidal endothelial cells (LSECs) have a unique morphological structure known as "fenestra" that plays a crucial role in liver substance exchange and homeostasis maintenance. In this study, we demonstrate that ADAMTS18 protease is primarily secreted by fetal liver endothelial cells. ADAMTS18 deficiency leads to enlarged fenestrae and increased porosity of LSECs, microthrombus formation in liver vessels, and an imbalance of liver oxidative stress. These defects worsen carbon tetrachloride (CCl4)-induced liver fibrosis and diethylnitrosamine (DEN)/high-fat-induced hepatocellular carcinoma (HCC) in adult -deficient mice. Mechanically, ADAMTS18 functions as a modifier of fibronectin (FN) to regulate the morphological acquisition of LSECs via the vascular endothelial growth factor A (VEGFA) signaling pathways. Collectively, a mechanism is proposed for LSEC morphogenesis and liver homeostasis maintenance via ADAMTS18-FN-VEGFA niches.
肝窦内皮细胞（LSECs）具有一种独特的形态结构，称为“窗孔”，其在肝脏物质交换和内环境稳态维持中起着关键作用。在本研究中，我们证明ADAMTS18蛋白酶主要由胎儿肝脏内皮细胞分泌。ADAMTS18缺乏会导致LSECs的窗孔扩大和孔隙率增加、肝脏血管中形成微血栓以及肝脏氧化应激失衡。在成年ADAMTS18缺陷小鼠中，这些缺陷会加重四氯化碳（CCl4）诱导的肝纤维化以及二乙基亚硝胺（DEN）/高脂诱导的肝细胞癌（HCC）。从机制上讲，ADAMTS18作为纤连蛋白（FN）的修饰因子，通过血管内皮生长因子A（VEGFA）信号通路调节LSECs的形态形成。总的来说，我们提出了一种通过ADAMTS18-FN-VEGFA生态位进行LSEC形态发生和肝脏内环境稳态维持的机制。
