Cell‐specific Wnts regulate liver zonation and regeneration

Our lab has previously shown that β‐catenin regulates liver regeneration in a partial hepatectomy (Phx) model, under the control of Wnt and the canonical signaling pathway. This is true at early timepoints up to 40–72 hours. Using cell‐specific Wntless (Wls) knockout mouse models, we have previously determined epithelial cells are not the source of these Wnts. However, macrophage‐specific Wls knockouts (MP‐KO) have a regeneration deficit at 40 hours that is not seen earlier, suggesting they are a contributing source of Wnts in a temporal manner. We sought to further elucidate the source, identity, and initiation of Wnts using a Tamoxifen‐inducible endothelial cell‐specific Wls knockout model (EC‐KO). At basline, EC‐KO showed decrease in pericentral b‐catenin target genes such as GS, Cyp2e1, and notably Cyclin D1, suggesting a contribution to zonation and potentially regeneration. Since b‐catenin activation occurs early during regeneration, we also wanted to investigate the most proximal event that could be stimulating Wnt expression and secretion from relevant cells after hepatectomy. We hypothesized that shear stress immediately after Phx may initiate Wnt expression and secretion. Using an in vitro system, a preliminary analysis demonstrates that shear stress can initiate Wnt expression in EC, but not in MP or hepatocytes. In vivo , MP and EC demonstrate high levels of Wnt2 and 9b at baseline, which significantly increases after Phx. Taken together, we predict shear stress initiates secretion of Wnt2 and Wnt9b from EC at early timepoints, and MP secrete Wnt2 and Wnt9b at later timepoints, thus temporally regulating b‐catenin and contributing to liver regeneration. Support or Funding Information 5T32HL094295‐05