Determining how CD4+ T cells regulate adult liver stem cells during regeneration

The liver normally recovers after injury in most situations through the division of hepatocytes, but this is fundamentally impaired during chronic liver injury. During chronic liver injury, bile ducts in the liver react in response to liver damage. This process is important for liver regeneration as some cells of the bile ducts can become hepatocytes when the liver is severely injured. However, the factors that control this process remain unknown. Immune cells infiltrate the liver and are observed close to the bile cuts during chronic liver injury and my initial data suggest that these immune cells control can affect how the liver regenerate. In this project I will use multiple models of human liver disease to investigate what type of immune cells are involved and how they interact with bile ducts to control liver regeneration. This research will enable the design of new therapies to treat chronic liver diseases which is currently a major issue worldwide.

The liver regenerates mainly through hepatocyte proliferation during acute liver injury but this
process is fundamentally impaired during chronic liver injury. Ductular Reaction (DR), the compensatory remodelling of bile ducts occurs during chronic liver injury and is essential for liver regeneration. My research has revealed that cholangiocytes can act as liver stem cells during DR when hepatocyte regeneration is inhibited, and proximate lymphocytic infiltration was observed. CD4 T-cells infiltrate the liver during DR and my preliminary data show that CD4 T-cells can regulate DR, but the type of CD4 T-cells which regulate this process and the mechanisms are unknown. I hypothesize that CD4 T-cell subsets act concurrently to regulate the regenerative capacity of cholangiocytes alongside modulating the immune response. Through this fellowship, I will use multiple transgenic mouse models to determine
1) the dynamics of CD4 T-cell infiltration during liver regeneration and its effects on DR and epithelial plasticity; 2) the molecular interactions and mechanisms at play that control the differentiation capacity of potential resident liver stem cells. These advances will result in the identification of novel factors that control DR, cellular differentiation and facilitate the development of new treatment for chronic liver injury.

Liver disease affects around 2 million people in the UK and 844 million people worldwide and is the only major cause of death that is still increasing compared to other major diseases with Nonalcoholic fatty liver disease (NAFLD) remain one of the most common chronic liver diseases. Improving the knowledge regarding the link between the imbalance in T-cell populations and epithelial regeneration may provide novel targetable pathways for interventions. I will use models of NAFLD and chronic liver disease to investigate the dynamics of T-cell infiltration and its effect on epithelial regeneration. The output of this research includes the mechanistic insights of how liver regeneration is controlled by immune cells and the identification of druggable targets for promoting epithelial regeneration.

Scientific and Educational Impact: Besides the scientific outputs generated from this project will identify key regulators and pathways of liver regeneration, I will pass down my experimental skills and research knowledge to Post-docs, students, colleagues and members of the lab, training the next generation of scientists.

Economic Impact: Identified molecular targets for intervention will lead to drug screening projects with existing small molecule libraries. The mechanistic targets identified and tools generated in this study have the potential to be applicable to other areas of research such as stem cell differentiation and immune-mediated diseases such as PSC and Colitis.

Societal Impact: in the long term, results from this work will inform the design of new cell therapies for liver disease. This will lead to better targeted treatments which in turn will lead to improved patient outcomes. I will also work with charities to communicate our research finding and raise public awareness regarding liver disease.