Function of Cholangiocytes in chronic liver diseases

Introduction

Cholangiocytes are the main cell type lining the epithelium of the biliary tree, a network of conduits that drain the liver from bile produced by hepatocytes. While the role of cholangiocytes has 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, understanding the mechanisms controlling the regenerative potential of cholangiocytes is essential to develop new therapies promoting tissue repair or blocking tumor formation.

Research Limitations

The study of these mechanisms has been restricted by technical and conceptual barriers, especially in humans. Here, we propose to bypass these limitations by developing an innovative program of research combining:

1. Functional experiments in organoids
2. Single-cell analyses on human primary tissue
3. Preclinical studies in animal models

Research Objectives

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:

• Cholangiocyte activation
• Cholangiocyte plasticity
• Cholangiocyte transformation

Importantly, we hypothesize that these different processes are interlinked and share common factors.

Focus on NAFLD

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.

Expected Outcomes

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.