ADAMTS18-fibronectin interaction regulates the morphology of liver sinusoidal endothelial cells
Liya Wang,
Li He,
Weijia Yi,
Min Wang,
Fangmin Xu,
Hanlin Liu,
Jiahui Nie,
Yi-Hsuan Pan,
Suying Dang,
Wei Zhang
Affiliations
Liya Wang
Key Laboratory of Brain Functional Genomics (Ministry of Education and Shanghai), School of Life Sciences, East China Normal University, Shanghai, China
Li He
Key Laboratory of Brain Functional Genomics (Ministry of Education and Shanghai), School of Life Sciences, East China Normal University, Shanghai, China
Weijia Yi
Key Laboratory of Brain Functional Genomics (Ministry of Education and Shanghai), School of Life Sciences, East China Normal University, Shanghai, China
Min Wang
Key Laboratory of Brain Functional Genomics (Ministry of Education and Shanghai), School of Life Sciences, East China Normal University, Shanghai, China
Fangmin Xu
Key Laboratory of Brain Functional Genomics (Ministry of Education and Shanghai), School of Life Sciences, East China Normal University, Shanghai, China
Hanlin Liu
Key Laboratory of Brain Functional Genomics (Ministry of Education and Shanghai), School of Life Sciences, East China Normal University, Shanghai, China
Jiahui Nie
Key Laboratory of Brain Functional Genomics (Ministry of Education and Shanghai), School of Life Sciences, East China Normal University, Shanghai, China
Yi-Hsuan Pan
Key Laboratory of Brain Functional Genomics (Ministry of Education and Shanghai), School of Life Sciences, East China Normal University, Shanghai, China
Suying Dang
Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Corresponding author
Wei Zhang
Key Laboratory of Brain Functional Genomics (Ministry of Education and Shanghai), School of Life Sciences, East China Normal University, Shanghai, China; Corresponding author
Summary: 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 Adamts18-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.
