Imbalanced Activation of Wnt-/β-Catenin-Signaling in Liver Endothelium Alters Normal Sinusoidal Differentiation

Philipp-Sebastian Koch; Kajetan Sandorski; Joschka Heil; Christian D Schmid; Sina W Kürschner; Johannes Hoffmann; Manuel Winkler; Theresa Staniczek; Carolina de la Torre; Carsten Sticht; Kai Schledzewski; Makoto Mark Taketo; Felix A Trogisch; Joerg Heineke; Cyrill Géraud; Sergij Goerdt; Victor Olsavszky

doi:10.3389/fphys.2021.722394

Imbalanced Activation of Wnt-/β-Catenin-Signaling in Liver Endothelium Alters Normal Sinusoidal Differentiation

Front Physiol. 2021 Sep 29:12:722394. doi: 10.3389/fphys.2021.722394. eCollection 2021.

Authors

Philipp-Sebastian Koch^{1

2}, Kajetan Sandorski^{1

2}, Joschka Heil^{1

2}, Christian D Schmid^{1

2}, Sina W Kürschner^{1

2}, Johannes Hoffmann^{1

2}, Manuel Winkler^{1

2}, Theresa Staniczek^{1

2}, Carolina de la Torre³, Carsten Sticht³, Kai Schledzewski^{1

2}, Makoto Mark Taketo⁴, Felix A Trogisch^{2

5}, Joerg Heineke^{2

5}, Cyrill Géraud^{1

2

6}, Sergij Goerdt^{1

2}, Victor Olsavszky^{1

2}

Affiliations

¹ Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University and Center of Excellence in Dermatology, Mannheim, Germany.
² European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
³ Next Generation Sequencing Core Facility, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
⁴ Division of Experimental Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
⁵ Department of Cardiovascular Physiology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
⁶ Section of Clinical and Molecular Dermatology, Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

Abstract

Endothelial wingless-related integration site (Wnt)-/β-catenin signaling is a key regulator of the tightly sealed blood-brain barrier. In the hepatic vascular niche angiokine-mediated Wnt signaling was recently identified as an important regulator of hepatocyte function, including the determination of final adult liver size, liver regeneration, and metabolic liver zonation. Within the hepatic vasculature, the liver sinusoidal endothelial cells (LSECs) are morphologically unique and functionally specialized microvascular endothelial cells (ECs). Pathological changes of LSECs are involved in chronic liver diseases, hepatocarcinogenesis, and liver metastasis. To comprehensively analyze the effects of endothelial Wnt-/β-catenin signaling in the liver, we used endothelial subtype-specific Clec4g-iCre mice to generate hepatic ECs with overexpression of Ctnnb1. In the resultant Clec4g-iCre ^tg/wt ;Ctnnb1(Ex3) ^fl/wt (Ctnnb1 ^OE-EC ) mice, activation of endothelial Wnt-/β-catenin signaling resulted in sinusoidal transdifferentiation with disturbed endothelial zonation, that is, loss of midzonal LSEC marker lymphatic vessel endothelial hyaluronic acid receptor 1 (Lyve1) and enrichment of continuous EC genes, such as cluster of differentiation (CD)34 and Apln. Notably, gene set enrichment analysis revealed overrepresentation of brain endothelial transcripts. Activation of endothelial Wnt-/β-catenin signaling did not induce liver fibrosis or alter metabolic liver zonation, but Ctnnb1 ^OE-EC mice exhibited significantly increased plasma triglyceride concentrations, while liver lipid content was slightly reduced. Ctnnb1 overexpression in arterial ECs of the heart has been reported previously to cause cardiomyopathy. As Clec4g-iCre is active in a subset of cardiac ECs, it was not unexpected that Ctnnb1 ^OE-EC mice showed reduced overall survival and cardiac dysfunction. Altogether, balanced endothelial Wnt-/β-catenin signaling in the liver is required for normal LSEC differentiation and for maintenance of normal plasma triglyceride levels.

Keywords: endothelial cells; liver; liver sinusoidal endothelial cells; mice; triglycerides.