Non-canonical Wnt signalling initiates scarring in biliary disease

Abstract

Cholangiopathies, or biliary diseases, account for a significant proportion of adult and paediatric liver disease. In these pathologies, iterative cycles of damage and repair result in the development of a regenerative microenvironment surrounding the bile ducts, which orchestrates both epithelial proliferation and also biliary fibrosis. Ultimately, fibrosis at the cost of repair results in cholestasis and liver failure, necessitating liver transplantation. Whilst the fibrogenic mechanisms in hepatocellular disease have been widely studied, little is known about the processes that regulate biliary scarring. We sought to determine how the injured biliary epithelium communicates to adjacent stromal cells to regulate scar formation, and to identify therapeutically targetable pathways that could be inhibited to reduce biliary scarring, whilst maintaining the pro--regenerative stroma.Using human tissue, bile duct organoids and animal models of biliary disease, we show that non--canonical Wnt signalling is important in initiating biliary scarring. This process is driven by myeloid Wnt5a and acts through epithelial Vangl2, which is upstream of Jnk/cJun signalling. Activation of this pathway drives a pro--fibrotic signalling process which instructs portal fibroblasts to synthesise collagen. Finally, we determine that therapeutic Wnt ligand inhibition reduces biliary scarring, identifying non--canonical Wnt signalling as a novel target for anti--fibrotic therapy in cholestatic biliary disease.

Planar cell polarity is essential for the architectural patterning of the mammalian biliary tree

“…Similarly, the level of Mapk8 is increased after ductular lineage commitment and during ductular morphogenesis (Figure 5E). In the adult regenerating bile duct JNK signalling is lost following functional Vangl2 -loss 37 similarly, in FLOs the levels of pJNK T183/Y185 are significantly decreased (Figure 5F). Furthermore, when we specifically look for levels of RHOC we found that this is significantly reduced in FLOs derived from Vangl2 S464N mutant mice (Figure 5G).…”