Peribiliary Glands in Biliary Regeneration: providing Mechanistic Insights into the Pathogenesis of Post-transplant Cholangiopathy and Biliary Atresia

Stem cell properties have only recently been assigned to the epithelial cells residing in the bile duct wall in small pouches, called peribiliary glands (PBGs). These glands are particularly important when the bile duct suffers from injury; they contribute to repair of the bile duct in a process called biliary regeneration or: wound healing.
In this thesis, a novel model to study biliary regeneration from the PBGs ex vivo was presented. Using this model, it was shown that PBGs proliferate, migrate, and differentiate to replace the lost epithelial cells after damage. Placing this basic principle of biliary regeneration in context of bile duct diseases, we identified critical mechanisms underlying post-transplant non-anastomotic strictures and biliary atresia.
Non-anastomotic strictures are a complication after liver transplantation, characterized by scarring (i.e., fibrosis) of the bile duct. We found that persistent damage of the microvasculature around PBGs led to ongoing hypoxia after transplantation, impeding regeneration from the PBGs. This was paralleled by fibrosis of the bile duct yielding the typical image of non-anastomotic strictures.
Furthermore, the development of biliary atresia, an obstructive cholangiopathy affecting newborns, was studied by examining fetal sheep bile ducts after injury. As a response to prenatal injury, we observed excessive PBG growth, increased hyaluronic acid production, and mucus production which resulted in narrowing of the bile duct lumen and increased bilirubin levels, mimicking biliary atresia.
Together, the elucidated mechanisms have important implications for the clinical practice and guide future studies towards potential therapeutic interventions in biliary atresia.