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Hepatology. 2018 Aug;68(2):707-722. doi: 10.1002/hep.29613. Epub 2018 Feb 1.

Angiocrine Wnt signaling controls liver growth and metabolic maturation in mice.

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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.
Molecular Cell Biology and Plant Cell Technology, University of Applied Sciences Weihenstephan-Triesdorf, Freising, Germany.
Division of Vascular Oncology and Metastasis (DKFZ-ZMBH Alliance), DKFZ, Heidelberg, Germany.
Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Department of General Pediatrics, Division of Inherited Metabolic Diseases, University Children's Hospital, Heidelberg, Germany.
European Center for Angioscience, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.


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-Cretg/wt ;Wlsfl/fl (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-Cretg/wt ;Wlsfl/fl ;Rosa26:Wls-YFPfl/wt [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).

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