Investigating the roles of Notch and Vascular Endothelial Growth Factor in Hepatic Cell Fate Decisions and Architectural Establishment in Development and Disease.

Abstract

During liver development, precise signaling is required to direct cell fate decisions and architectural establishment. It is hypothesized that the same signaling pathways are important in directing liver regeneration. To examine the signals important in liver development and disease, we genetically manipulated Recombination signaling binding protein J kappa (Rbpj) and Hepatocyte nuclear factor 6 (Hnf6), or Vascular endothelial growth factor (Vegf) within the liver epithelium embryonically in mice. Along with these genetic models, we also examined several non-genetic rodent liver injury models and assessed the protein localization and tissue architecture of both epithelial and endothelial structures in the liver. We find that Rpbj and Hnf6 are together required for the embryonic formation of the intrahepatic bile duct, but dispensable for its regeneration postnatally. In both genetic and non-genetic cholestatic liver injuries in rodent models and in human liver disease, the expression of Sry-related HMG box 9 (Sox9) was found to be a marker of non-proliferative hepatobiliary intermediate cells that may aid the regenerative process. We also determined that the epithelial secretion of Vegf is required for proper endothelial and epithelial cell maturation and tissue architecture. These studies implicate a number of signaling relationships required for proper liver development and regeneration.