Wnt5a inhibits beta-catenin signaling and proliferation in hepatocyte cultures: Implications in liver regeneration

Liver regeneration (LR) occurs when part of the liver is damaged or surgically removed by partial hepatectomy (PH). The organ responds by cell division to restore the lost mass. Determining the mechanism by which hepatocytes stop proliferating once LR is complete may provide insight into termination of LR. Several pathways can induce hepatocyte proliferation after PH, including ?-Catenin, which stimulates cyclin-D1 expression. However, it is unclear how ?-catenin is inhibited once LR is accomplished. Using LR samples from different times after PH in mice, we identified Wnt-5a increase at 24-72h post-PH, only subsequent to ?-catenin activation. To determine its role, primary mouse hepatocytes were cultured in the presence of Wnt-5a. A significant decrease in thymidine incorporation was observed with Wnt-5a. Western blots using lysates from Wnt-5a treated hepatocytes revealed a decrease in canonical Wnt pathway components and targets such as ?-catenin, cyclin D-1, ser9-GSK3?, and Frizzled-4 levels, while an increase was detected in Ror2, an inhibitory Wnt receptor. Additionally, Wnt-5a treated hepatoma cells showed decreased ?-catenin reporter activity. In conclusion, we have identified Wnt-5a to inhibit ?-catenin activity in liver cells by inducing its degradation and may be terminating ?-catenin signaling following adequate hepatocyte proliferation during LR.