Single-cell spatial transcriptomics reveals a dynamic control of metabolic zonation and liver regeneration by endothelial cell Wnt2 and Wnt9b.
IF: 16.988
Cited by: 14


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.


Spatial Transcriptomics
Wnt signaling
endothelial cells
hepatocyte proliferation
liver injury
liver regeneration
metabolic zonation
single cell spatial transcriptomics

MeSH terms

Liver Regeneration
beta Catenin
Endothelial Cells
Wnt Proteins
Focal Nodular Hyperplasia
Wnt2 Protein


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