Research at the Huppert Lab

The Huppert lab is interested in intercellular signaling pathways that regulate cell fate decisions and lineage restriction during organogenesis and adult cell population renewal. Our projects use genetic mouse models and embryonic stem cell lines as well as pharmacological inhibition both in vivo and in vitro to answer questions related to liver organogenesis and regeneration. The liver is a vital organ for metabolism and homeostasis, and has the highest regenerative capacity of all parenchymal organs. Proper architecture of the liver biliary and vasculature systems is crucial for the overall health of the organ and the ability to carry out endocrine and exocrine functions. Organogenesis and remodeling following liver injury requires finely tuned epithelial-mesenchymal interactions. The goal of our lab is to explore how intercellular signaling pathways are integrated to regulate the cellular interactions during organogenesis and regenerative responses of the liver following injury. We are initially examining the role of the Notch intercellular signaling pathway in coordinating cell fate decisions during liver organogenesis and regeneration. Notch signaling is an evolutionarily conserved, primary regulator of cell lineage diversification and stem/progenitor cell maintenance. Studies in model organisms from invertebrates to vertebrates have established that Notch signaling actively influences cell fate decisions, both during embryogenesis and in adult tissues. Mutations in the Notch ligand JAGGED1 cause 94% of human Alagille syndrome cases, a complex developmental disorder. A common feature of this sporadic genetic disorder is cholestasis due to paucity of bile ducts. However, while there is direct genetic evidence indicating that an abnormality in Notch signaling affects the formation of bile duct structures in the liver we do not yet understand precisely how this occurs. The role of Notch signaling in liver progenitor cell proliferation, maintanence and lineage restriction remains to be accurately defined. It is our hope that by elucidating the molecular mechanisms that guide cell-cell communication, epithelial-mesenchymal interactions and lineage restriction in the liver, we will gain novel insights into how defects in normal processes are mis-regulated in chronic liver diseases and other hepatic pathologies.