In the liver, hepatic stem/progenitor cells (HPCs) represent a facultative stem/progenitor cell compartment located within canals of Hering and bile ductules. HPCs are bipotent stem cells characterized by the capability to differentiate towards mature hepatocytes and cholangiocytes. In human Non Alcoholic Fatty Liver Disease (NAFLD), HPCs can activate and proliferate as a consequence of impaired proliferation of mature hepatocyes due to lipotoxicity. Recently, a niche of stem cells endowed within peribiliary glands (PBGs) has been described along extrahepatic and large intrahepatic bile ducts. This heterogeneous population of stem and progenitor cells has been collectively named Biliary Tree Stem Cells (BTSCs) and is implicated in the pathogenesis of human cholangiopathies.
The general aim of the present project will be to define the role and the activation mechanisms of HPCs and BTSCs in human liver diseases. Specific objectives of the present project will be: i) to investigate the activation of HPCs in the progression of NAFLD and the relationship with levels of Lipopolysaccharide (LPS), platelets and macrophage activation; ii) to study the signaling pathways driving the BTSC activation in human Primary Sclerosing Cholangitis (PSC) and Non anastomotic strictures (NAS) in transplanted livers; iii) to individuate the role of peribiliary glands (PBGs) in biliary regeneration and in the pathogenesis of biliary damage by a lineage tracing approach in mice.
Data obtained from this project will lead i) to understand cellular mechanisms at the basis of NAFLD progression; ii) to characterize the anatomy and physiology of PBG stem cell niche, its behavior in regenerative response, and the signals involved in niche activation; iii) to clarify the pathogenesis of cholangiopathies and biliary fibrosis; iv) to individuate novel molecular tools and therapeutic approaches targeting stem cell niches.
