Function of Cholangiocytes in chronic liver diseases

Cholangiocytes are the mCholangiocytes are the main cell type lining the epithelium of the biliary tree, a network of conduits which drain the liver from bile produced by hepatocytes.

While the role of cholangiocytes have been broadly studied in the context of cholangiopathies, their role in chronic liver disease affecting hepatocytes is often overlooked despite growing evidence that they play a central role in disease progression, regeneration, and cancer.

Thus, understanding the mechanisms controlling the regenerative potential of cholangiocytes is essential to develop new therapies promoting tissue repair or blocking tumour formation.

However, the study of these mechanisms has been restricted by technical and conceptual barriers especially in human.Here, we propose to bypass these limitations by developing an innovative program of research combining functional experiments in organoids, single cell analyses on human primary tissue and preclinical studies in animal models.

We will use this approach to specifically address the role of cholangiocytes in chronic liver disease. More precisely, we aim to uncover the mechanisms driving cholangiocytes activation, plasticity and transformation. Importantly, we hypothesise that these different processes are interlinked and share common factors.

The FunChol program will systematically address these questions in the context of Non-Alcoholic Fatty Liver Disease (NAFLD).

This chronic disease and its progressive form Non-alcoholic Steatohepatitis (NASH) represent the most rapidly rising cause of liver cirrhosis worldwide and there is currently no therapy for this major health care challenge.

Overall, this multidisciplinary proposal will reveal the molecular interplays by which liver injuries can affect cholangiocytes and how in turn cholangiocytes react to improve tissue repair or to aggravate disease.

This research will pave the way for the development of new therapeutics controlling regeneration to limit disease progression.