PERCHOL

Cholangiopathies are a significant cause of morbidity and mortality and a major indication for liver transplant. They affect cholangiocytes, the cells lining the biliary system, a tree-shaped network of biliary ducts which carry the bile out of the liver. Due to its complex organization and entanglement with other hepatic cells, biliary tissue specific functions are difficult to assess, making the etiology of several cholangiopathies still elusive. Therefore, the production of bioengineered biliary tissue appears critical. However, neither 2D cultures nor 3D biliary spheres already produced can constitute a relevant model to question among the most important physio-pathological processes like the increase in biliary pressure, the alteration of the epithelial permeability, the exposure to shifted bile acid composition, inflammation or toxic drugs such as some antibiotics. Preliminary work within the consortium resulted in the bioprinting of bile tubes lined with rat cholangiocytes. Based on this breakthrough, our project aims to produce a model to study the pathogenesis of the biliary epithelium, by connecting bile tubes bio-printed with rat or human cholangiocytes differentiated from iPSCs, to an external microfluidic system where the flow can be measured and finely regulated. The effects of pathological conditions such as increased fluid pressure, the introduction of toxic bile compounds or antibiotics, or the invalidation of tight junction genes will be evaluated in terms of functionality, permeability, homeostasis. and regeneration of the biliary epithelium. The consortium relies on complementary expertise in biliary bioengineering, microfluidics, clinical hepatology, differentiation of hiPSCs into hepatic cells, biliary homeostasis and pathophysiology in vitro and in mouse models.