WNT7B Regulates Cholangiocyte Proliferation and Function During Murine Cholestasis

Area of Science:

• Hepatology
• Gastroenterology
• Molecular Biology

Background:

• Wnt proteins are upregulated in cholestatic liver injury.
• Wnt7b promotes cholangiocyte proliferation and inflammation in vitro.
• Wnt7b loss was hypothesized to impair biliary repair in cholangiopathies.

Purpose of the Study:

• To investigate the role of Wnt7b in cholangiocytes and hepatocytes during cholestatic liver injury.
• To determine if Wnt7b depletion exacerbates or ameliorates cholestatic liver disease complications.

Main Methods:

• Generated Wnt7b-deficient mice in cholangiocytes (CC KO) and in hepatocytes/cholangiocytes (HC+CC KO).
• Administered a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet to induce cholestatic liver injury.
• Evaluated biliary injury, cellular senescence, bile acid accumulation, and hepatocyte reprogramming.

Main Results:

• Wnt7b KO mice showed reduced biliary injury, senescence, and bile acid accumulation.
• Wnt7b suppression decreased inflammatory cytokine expression.
• Hepatocytes in Wnt7b KO mice expressed cholangiocyte markers, indicating reprogramming, despite fewer proliferating cholangiocytes.

Conclusions:

• Wnt7b drives a proproliferative, proinflammatory program in cholangiocytes during cholestasis.
• Loss of Wnt7b is compensated by hepatocyte reprogramming into a biliary phenotype, improving outcomes in cholestatic injury.