Impaired hepatocyte regeneration confers lineage plasticity in the biliary epithelium: a study of the transcriptional heterogeneity within the biliary epithelium following injury

Abstract

Chronic liver disease is a major global health burden, accounting for approximately 2 million deaths per year and the prevalence in the United Kingdom is ever-increasing. Currently the only definitive treatment option for patients suffering from chronic liver disease is orthotopic liver transplant. The shortage of suitable donor organs prompts the search for novel disease-modifying and curative therapies. Despite the varying aetiology, chronic liver disease is always characterised by compromised regenerative capacity of hepatocytes – the main functional cell types of the liver. Recent studies highlight the capacity for lineage plasticity of the biliary cells which can act as facultative liver progenitor cells and differentiate into hepatocytes to repair the damaged liver parenchyma. However, it is still unknown whether all biliary cells have a similar regenerative capacity, or a population of pre-committed progenitors exist in the liver. I hypothesise that in the damaged liver the biliary cells are transcriptionally heterogeneous and that differentiation of biliary cells into hepatocytes is underpinned by a modulation of a unique set of genes and signalling pathways. I utilised two established clinically relevant murine models of chronic liver disease to study the mechanisms that underpin the differential regenerative response following diet induced liver injury, depending on the proliferative capacity of the native hepatocytes. I employed bulk transcriptomic and scRNA-Seq technologies to study the transcriptional differences that arise in biliary cells isolated from these models. I identified populations of cells exclusively present in the models in which biliary to hepatocyte differentiation occurs. These results confirm that following liver injury, the biliary cells represent a heterogeneous population and reveal novel potential therapeutic targets that can inform cell therapy and drug discovery campaigns, seeking to develop innovative solutions for the treatment of chronic liver disease by enhancing the endogenous capacity of biliary cells to differentiate into hepatocytes on demand