WNT5A Inhibits Hepatocyte Proliferation and Concludes β-Catenin Signaling in Liver Regeneration

Abstract

Activation of Wnt/b-catenin signaling during liver regeneration (LR) after partial hepatectomy (PH) is observed in several species. However, how this pathway is turned off when hepatocyte proliferation is no longer required is unknown. We assessed LR in liver-specific knockouts of Wntless (Wls-LKO), a protein required for Wnt secretion from a cell. When subjected to PH, Wls-LKO showed prolongation of hepatocyte proliferation for up to 4 days compared with littermate controls. This coincided with increased b-catenineT-cell factor 4 interaction and cyclin-D1 expression. Wls-LKO showed decreased expression and secretion of inhibitory Wnt5a during LR. Wnt5a expression increased between 24 and 48 hours, and Frizzled-2 between 24 and 72 hours, after PH in normal mice. Treatment of primary mouse hepatocytes and liver tumor cells with Wnt5a led to a notable decrease in b-catenineT-cell factor activity, cyclin-D1 expression, and cell proliferation. Intriguingly, Wnt5a-LKO did not display any prolongation of LR because of compensation by other cells. In addition, Wnt5a-LKO hepatocytes failed to respond to exogenous Wnt5a treatment in culture because of a compensatory decrease in Frizzled-2 expression.In conclusion, we demonstrate Wnt5a to be, by default, a negative regulator of b-catenin signaling and hepatocyte proliferation, both in vitro and in vivo. We also provide evidence that the Wnt5a/Frizzled-2 axis suppresses b-catenin signaling in hepatocytes in an autocrine manner, thereby contributing to timely conclusion of the LR process. (Am J Pathol 2015, 185: 2194e2205; http:// dx

Noncanonical Wnt signaling plays an important role in modulating canonical Wnt-regulated stemness, proliferation and terminal differentiation of hepatic progenitors

“…Interestingly, a recent study examined the important role of Wnt5a in hepatocyte proliferation and liver regeneration [26]. Using the liver-specific knockout models of Wntless (Wls-LKO), Yang et al showed that when subjected to partial hepatectomy the Wls-LKO showed prolongation of hepatocyte proliferation for up to 4 days compared with littermate controls, which coincided with increased β-catenin/TCF activity and decreased expression and secretion of Wnt5a [26].…”

Wnt/β-Catenin Signaling in Liver Development, Homeostasis, and Pathobiology

“…Interestingly, noncanonical Wnt signaling was shown to be involved in the conclusion of liver regeneration post-PHx. Wnt5a was found to inhibit canonical Wnt/β-catenin signaling in cultured primary hepatocytes, and mice with liver-specific deletion of Wntless displayed continued hepatocyte proliferation for up to 4 days longer than control littermates, owing to the reduced expression of inhibitory Wnt5a 24–48 h post-PHx (90) (Figure 5). This suggests an autocrine mechanism of proliferation termination following the acquisition of required hepatocyte mass during regeneration.…”

Combination of cord blood‐derived human hepatic progenitors and hepatogenic factors strongly improves recovery after acute liver injury in mice through modulation of the Wnt/β‐catenin signaling

“…The termination of liver regeneration in fact requires a transition from positive to negative regulation within a signaling pathway. In this path, Wnt5a seems to play a crucial role (Fan et al, ; Yang et al, ). In our model, Wnt5a showed an increase in both transplanted groups, more pronounced in iBHPs–HM group and only moderate in iBHPs–saline group, compared with sham.…”

“…The termination of liver regeneration in fact requires a transition from positive to negative regulation within a signaling pathway. In this path, Wnt5a seems to play a crucial role Yang et al, 2015).…”