Wilson, D. H. | Search bioRxiv

bioRxiv2025

Tissue scarring provides a biomechanical framework to promote mammalian bile duct regeneration through the activation of integrin-SRC/FAK signalling.

Following chronic injury, the adult mammalian bile duct regenerates by forming new branches, essentially replumbing the ductular system to overcome blockages and breaks. To regenerate effectively, biliary epithelial cells (BECs) receive a range of pro-mitogenic signals from myofibroblasts, which concurrently deposit a collagen-rich scar around the duct as it regrows. Despite epithelial regeneration and scarring occurring side-by-side, whether the deposition of scar tissue regulates ductular regeneration per se remains unclear. By inducing ductular fibrosis and regeneration in vivo, we show that the formation of collagen-I-rich scars around regenerating ducts changes the local biomechanical properties of these tissues, promoting the growth of ducts. Critically, this changing structural landscape is perceived by a spatially restricted population of biliary epithelial cells which forms a "leading-tip" of integrin-2-high cells. This leading-tip undergoes partial-EMT-type reprogramming, allowing it to become migratory and coordinate ductular regeneration. We show that this process is directly driven through an integrin-2-SRC/FAK signalling axis; thereby connecting epithelial regeneration directly to the changing fibrotic environment in chronic ductular disease. HighlightsO_LIChronic liver disease results in the formation of stiff, collagen scars around ducts. C_LIO_LINew ducts acquire high levels of integrin-2 which is spatially localised to a "leading-tip", which loses epithelial features. C_LIO_LIIntegrin-2{beta}1-SRC/FAK signalling regulates ductular migration by linking changes in the bio-structural composition of the liver with ductular cells. C_LI

cell biology↗

bioRxiv2018

Non-canonical Wnt signalling initiates scarring in biliary disease

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.

physiology↗