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

Cell Rep Med. 2022 Oct 18;3(10):100754. doi: 10.1016/j.xcrm.2022.100754. Epub 2022 Oct 10.


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.

Keywords: Wnt signaling; acetaminophen; endothelial cells; hepatocyte; hepatocyte proliferation; liver injury; liver regeneration; metabolic zonation; repair; single cell spatial transcriptomics.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetaminophen / metabolism
  • Endothelial Cells / metabolism
  • Focal Nodular Hyperplasia* / metabolism
  • Humans
  • Liver Regeneration* / genetics
  • Transcriptome
  • Wnt Proteins / genetics
  • Wnt2 Protein / genetics
  • beta Catenin / genetics


  • beta Catenin
  • Wnt Proteins
  • Acetaminophen
  • WNT2 protein, human
  • Wnt2 Protein
  • WNT9B protein, human