Rbpj deletion in hepatic progenitor cells attenuates endothelial responses in a mouse model of cholestatic liver disease
Rbpj deletion in hepatic progenitor cells attenuates endothelial responses in a mouse model of cholestatic liver disease
ABSTRACT Background and AimsSince the role of hepatic progenitor cells (HPCs) constituting ductular reactions in pathogenesis remains ambiguous, we aimed to establish the in vivo cause-and-effect relationship between HPCs and angiogenesis, a process associated with chronic liver disease progression. We previously demonstrated that peritumoral ductules are associated with angiogenesis in liver tumors and forkhead box L1 (Foxl1)- expressing murine HPCs secrete angiogenic factors in vitro. Therefore, we hypothesized that HPCs are capable of remodeling the vascular microenvironment and this function of HPCs is dependent on recombination signal binding protein for immunoglobulin kappa J region (RBPJ), a key effector of the Notch signaling pathway. Approach and ResultsWe generated HPC-specific Rbpj conditional knockout mice using Foxl1-Cre and treated them with the 3,5-diethoxycarbonyl-1,4-dihydrocollidine-supplemented diet to induce cholestatic liver disease. Knockout mice displayed significant reduction of HPC proliferation and ductular reactions as well as attenuated vascular and fibrotic areas compared to control mice. Assessment of vascular endothelial growth factor A-positive areas in vivo and the effects of Rbpj shRNAs in vitro indicated that Rbpj knockout in HPCs reduces the total number of angiogenic factor-expressing cells rather than affecting angiogenic factor expression within HPCs. Single-nucleus RNA sequencing analysis indicated that conditional Rbpj knockout in HPCs induces transcriptional changes in endothelial cells and alters expression of genes involved in various functions of the endothelium. ConclusionOur findings indicate that HPCs regulate endothelial responses to cholestatic liver disease and Rbpj deletion in HPCs attenuates these responses, identifying novel targets for modulating angiogenesis during disease progression.
Huppert Stacey S.、Shin Soona、Ren Lu、Zhou Ping、Potter Andrew、Lee Sanghoon、Paranjpe Aditi
Division of Gastroenterology, Hepatology & Nutrition, Cincinnati Children?ˉs Hospital Medical Center||Department of Pediatrics, University of Cincinnati College of MedicineDivision of Pediatric General and Thoracic Surgery, Cincinnati Children?ˉs Hospital Medical Center||Department of Surgery, University of Cincinnati College of MedicineDivision of Pediatric General and Thoracic Surgery, Cincinnati Children?ˉs Hospital Medical CenterDivision of Pediatric General and Thoracic Surgery, Cincinnati Children?ˉs Hospital Medical CenterCardiology Clinic, Cincinnati Children?ˉs Hospital Medical CenterDivision of Pediatric General and Thoracic Surgery, Cincinnati Children?ˉs Hospital Medical CenterDepartment of Information Services, Cincinnati Children?ˉs Hospital Medical Center
基础医学内科学分子生物学
Hepatic progenitor cellsendothelial cellsductular reactionliver diseaseRbpj
Huppert Stacey S.,Shin Soona,Ren Lu,Zhou Ping,Potter Andrew,Lee Sanghoon,Paranjpe Aditi.Rbpj deletion in hepatic progenitor cells attenuates endothelial responses in a mouse model of cholestatic liver disease[EB/OL].(2025-03-28)[2025-08-25].https://www.biorxiv.org/content/10.1101/2024.04.13.589277.点此复制
评论