Shikai Hu1,2, Silvia Liu2,5, Yu Bian2, Minakshi Poddar2, Sucha Singh2, Catherine Cao2, Jackson McGaughey2, Aaron Bell2,5, Levi L Blazer3, Jarret J Adams3, Sachdev S Sidhu3, Stephane Angers3,4, Satdarshan P. Monga2,5,6
1 School of Medicine, Tsinghua University, Beijing, China
2 Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA USA
3 Donnelly Centre, University of Toronto, Toronto, ON, Canada
4 Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada
5 Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA USA
6 Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA USA
Abstract
The conclusive identity of Wnts regulating liver zonation (LZ) and regeneration (LR) remains unclear despite an undisputed role of β-catenin. Using single-cell analysis, we identified a conserved Wnt2 and Wnt9b expression in endothelial cells (ECs) in zone 3. EC-elimination of Wnt2 and Wnt9b led to both loss of β-catenin targets in zone 3, and re-appearance of zone 1 genes in zone 3, unraveling dynamicity in the LZ process. Impaired LR observed in the knockouts phenocopied models of defective hepatic Wnt signaling. Administration of a tetravalent antibody to activate Wnt signaling rescued LZ and LR in the knockouts and induced zone 3 gene expression and LR in controls. Administration of the agonist also promoted LR in acetaminophen overdose acute liver failure (ALF) fulfilling an unmet clinical need. Overall, we report an unequivocal role of EC-Wnt2 and Wnt9b in LZ and LR and show the role of Wnt activators as regenerative therapy for ALF.
