Wnt-driven communication between macrophages and hepatic stellate cells within the ductular reaction - Pro-fibrotic or pro-regenerative?

• Applicant: Dr. Berit Genz
• Subject Area: Gastroenterology ; Public Health, Healthcare Research, Social and Occupational Medicine
• Term: from 2015 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 280670045

Chronic liver diseases like chronic hepatitis C virus infection, alcoholic and non-alcoholic fatty liver disease and biliary diseases represent a worldwide health problem with a persistently high incidence. According to the data of the World Health Organisation 800.000 people per year worldwide die from cirrhosis, beside organ failure and hepatocellular carcinoma one of the main consequences of chronic liver-injury and the resulting progressive liver fibrosis. However, till today no promising therapeutics for the treatment of liver fibrosis besides organ transplantation are available. Therefore, a better understanding of the molecular mechanisms underlying progression of chronic liver diseases is required to identify new therapeutic opportunities. Regardless of the aetiology, chronic or overwhelming liver cell damage leads via continuing inflammation, cytokine-secretion and oxidative stress to the misdirection of regenerative processes. In this environment, hepatic stellate cells, known as main initiators of fibrotic processes, activate and transform to matrix-secreting myofibroblasts. Furthermore, if hepatocyte regeneration is impaired progenitor cell proliferation and differentiation can be stimulated. As a result, a bile ductular reaction at the periphery of portal tracts arises. The ductular reaction represents a complex of biliary differentiated progenitor and stem cells, an inflammatory niche containing leukocytes (particularly macrophages), myofibroblasts and extracellular matrix. Experiments in mice revealed that during liver-injury and regeneration hepatic stellate cells or myofibroblasts can function as hepatocellular progenitors. Progenitor cell activation and fate is influenced by factors secreted within the ductular niche, which in turn may determine the balance between liver repair and fibrogenesis. Those factors include macrophage-derived Wnt ligands. Wnt signaling is thought to drive hepatocellular differentiation and is also involved in stellate cell activation. Whether Wnt-signaling mediates the communication and interaction between macrophages and stellate cells within the ductular reaction and whether it drives fibrotic or regenerative processes is not well examined.Aim of this study is therefore (I) to characterize the human ductular niche, with a focus on understanding how macrophages and especially their interaction with HSC contribute to fibrosis progression, (II) to determine the mechanism/s by which Wnt-mediated communication between macrophages and HSC participates in protection and/or resolution from fibrosis and (III) to examine whether inflammatory liver macrophages can be re-programmed in situ to adopt pro-regenerative functions and stimulate HSC towards epithelial transdifferentiation. These investigations will generate new knowledge that is crucial to our understanding of liver fibrogenesis and how to target it therapeutically.

• DFG Programme: Research Fellowships
• International Connection: Australia
• Hosts: Dr. Kathrine Irvine; Professorin Dr. Elizabeth Powell