Single-cell spatial transcriptomics reveals a dynamic control of metabolic zonation and liver regeneration by endothelial cell Wnt2 and Wnt9b.

Shikai Hu, Silvia Liu, Yu Bian, Minakshi Poddar, Sucha Singh, Catherine Cao, Jackson McGaughey, Aaron Bell, Levi L Blazer, Jarret J Adams, Sachdev S Sidhu, Stephane Angers, Satdarshan P Monga

Journal: Cell reports. Medicine 2022;3(10):100754

PMID: 36220068

Free Full Text on Elsevier Science View on PubMed

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.

Address: School of Medicine, Tsinghua University, Beijing, China; Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.; Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.; Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.; Donnelly Centre, University of Toronto, Toronto, ON, Canada.; Donnelly Centre, University of Toronto, Toronto, ON, Canada; Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada.; Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Electronic address: [email protected].

DOI: 10.1016/j.xcrm.2022.100754

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MeSH Terms: Humans, Liver Regeneration, beta Catenin, Endothelial Cells, Transcriptome, Wnt Proteins, Acetaminophen, Focal Nodular Hyperplasia, Wnt2 Protein