Notch signaling in liver cell plasticity, development, and regeneration

• Applicant: Privatdozent Dr. Fabian K. Geisler
• Subject Area: Gastroenterology
• Term: from 2011 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 194010126

The liver has a unique capacity to regenerate. After acute loss of liver mass (i.e. after resection) a sequence of well orchestrated cellular events is initiated which leads to proliferation of mature hepatocytes and biliary cells of the normally quiescent organ to ultimately restore liver function and size within few days. However, in many cases of chronic liver and biliary disease, when hepatocyte and cholangiocyte proliferation is impaired, an expansion of progenitors with stem cell properties is observed (ductular reaction or oval cell response). Oval cells are part of the biliary compartment and reside in a niche close to the terminal bile ducts (Canals of Hering), and are believed to give rise to both, hepatocytes and bile ducts. The functional relevance of this progenitor response to injury repair is controversially debated. Moreover, the molecular mechanisms driving expansion, morphogenesis and cellular allocation of adult progenitors to hepatocytes or mature biliary cells are not well defined. However, emerging concepts derived from morphological and in vitro studies propose that liver progenitor cell-mediated repair mechanisms in adult livers recapitulate developmental processes using identical molecular pathways, morphogens, and growth factors usually active during embryonic development.We have previously established the central role of the Notch-signaling pathway in cell fate decisions and morphogenesis during embryonic liver development as well as in mediating cellular reprogramming of adult liver cells. For our current project we have characterized a new mouse strain (R26TomHNF1betaCreER), that allows highly effective and compartment-specific inducible genetic labelling of adult liver progenitors with a fluorescent dye (tdTomato) in order to trace the cellular destiny of these cells in mice subjected to various exogenous and endogenous genetic regeneration protocols. By simultaneously combining this lineage tracing approach with conditional gain- and loss-of-function mouse models for the Notch- and Notch-related (Wnt/beta-Catenin) pathways we will determine not only the functional role and prospective cellular potency of ductular reactions in liver regeneration; we will also systematically characterize the role of Notch in regulating progenitor cell expansion, morphogenesis, and lineage allocation. Our study will provide fundamental new insights into the biology and regulation of progenitor-mediated liver repair that may have a wide-ranging impact on the development of new therapeutical strategies for acute and chronic liver failure.

• DFG Programme: Research Grants
• Participating Persons: Professor Dr. Mathias Heikenwälder; Professor Dr. Jens T. Siveke