Department of Dermatology, Venereology, and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, and Center of Excellence in Dermatology, Mannheim, Germany.
German Cancer Research Center (DKFZ), Division of Signaling and Functional Genomics and Heidelberg University, Faculty of Medicine Mannheim, Department of Cell and Molecular Biology, Heidelberg, Germany.
Hepatology. 2018 Aug;68(2):707-722. doi: 10.1002/hep.29613. Epub 2018 Feb 1.
Postnatal liver development is characterized by hepatocyte growth, proliferation, and functional maturation. Notably, canonical Wnt signaling in hepatocytes has been identified as an important regulator of final adult liver size and metabolic liver zonation. The cellular origin of Wnt ligands responsible for homeostatic liver/body weight ratio (LW/BW) remained unclear, which was also attributable to a lack of suitable endothelial Cre driver mice. To comprehensively analyze the effects of hepatic angiocrine Wnt signaling on liver development and metabolic functions, we used endothelial subtype-specific Stab2-Cre driver mice to delete Wls from hepatic endothelial cells (HECs). The resultant Stab2-Cre ;Wls (Wls-HECKO) mice were viable, but showed a significantly reduced LW/BW. Specifically, ablation of angiocrine Wnt signaling impaired metabolic zonation in the liver, as shown by loss of pericentral, β-catenin-dependent target genes such as glutamine synthase (Glul), RhBg, Axin2, and cytochrome P450 2E1, as well as by extended expression of periportal genes such as arginase 1. Furthermore, endothelial subtype-specific expression of a c-terminally YFP-tagged Wls fusion protein in Wls-HECKO mice (Stab2-Cre ;Wls ;Rosa26:Wls-YFP [Wls-rescue]) restored metabolic liver zonation. Interestingly, lipid metabolism was altered in Wls-HECKO mice exhibiting significantly reduced plasma cholesterol levels, while maintaining normal plasma triglyceride and blood glucose concentrations. On the contrary, zonal expression of Endomucin, LYVE1, and other markers of HEC heterogeneity were not altered in Wls-HECKO livers.
Angiocrine Wnt signaling controls liver growth as well as development of metabolic liver zonation in mice, whereas intrahepatic HEC zonation is not affected. (Hepatology 2017).
出生后肝脏的发育以肝细胞的生长、增殖和功能成熟为特征。值得注意的是，肝实质细胞中的经典 Wnt 信号已被确定为调节终末成人肝脏大小和代谢性肝区带的重要调控因子。负责维持肝/体重比（LW/BW）平衡的 Wnt 配体的细胞来源仍不清楚，这也归因于缺乏合适的内皮细胞特异性 Cre 驱动小鼠。为了全面分析肝血管生成 Wnt 信号对肝脏发育和代谢功能的影响，我们使用内皮细胞亚型特异性 Stab2-Cre 驱动小鼠删除肝内皮细胞（HECs）中的 Wls。结果产生的 Stab2-Cre ; Wls (Wls-HECKO) 小鼠是存活的，但 LW/BW 显著降低。具体而言，血管生成 Wnt 信号的缺失损害了肝脏的代谢区带，表现为中央区、β-连环蛋白依赖性靶基因如谷氨酰胺合成酶（Glul）、RhBg、Axin2 和细胞色素 P450 2E1 的缺失，以及门周基因如精氨酸酶 1 的表达延长。此外，在 Wls-HECKO 小鼠中内皮细胞亚型特异性表达 C 端 YFP 标记的 Wls 融合蛋白（Stab2-Cre ; Wls ; Rosa26:Wls-YFP [Wls 挽救]）恢复了代谢性肝区带。有趣的是，Wls-HECKO 小鼠的脂质代谢发生改变，表现为血浆胆固醇水平显著降低，而血浆甘油三酯和血糖浓度正常。相反，Wls-HECKO 肝脏中内皮细胞异质性的 Endomucin、LYVE1 和其他标记物的区带表达没有改变。
血管生成 Wnt 信号控制着小鼠肝脏的生长和代谢性肝区带的发育，而肝内 HEC 区带未受影响。（《肝脏病学》2017 年）。
