Mechanisms of Liver Development: Concepts for Understanding Liver Disorders and Design of Novel Therapies

Initiation of liver development in the mouse embryo. (A) The left panel shows a mouse embryo at E8.25 (10 somites). The dashed line indicates the foregut delineated by the endoderm. The gut is still open at that stage; the arrow points to the anterior ventral opening (anterior intestinal portal). The right panel schematizes a slightly younger embryo with a ventral view on the anterior intestinal portal. The blue areas correspond to the hepatic progenitor domains in the ventral endoderm. (B) Schematic representation (profile view) of the respective position of liver, heart, and septum transversum at 2 stages of liver development. When FGF production by the heart increases, the liver moves away from the heart and becomes adjacent to the septum transversum to ensure that the liver cells are exposed to the appropriate FGF concentrations.

Budding of the liver out of the endoderm. The upper panel schematizes the changes in morphology of the liver when it buds out of the endoderm. The lower panel summarizes the control of key regulatory events by transcription factors and extracellular signaling.

Regulation of liver growth during development. The signaling factors and downstream cascades that control proliferation and apoptosis of hepatoblasts are illustrated. Liver growth depends on the coordinated control of these biological processes.

Mechanisms of cell fate determination in the liver. Hepatoblasts give rise to either hepatocytes or cholangiocytes. Transcription factors and extracellular regulators that operate in the 3 cell types and during the transition from one cell type to the other are illustrated. The orange dashed oval integrates biliary differentiation mechanisms, and the green dashed oval delineates hepatocyte-inducing mechanisms. In cholangiocytes, HNF-6 controls a gradient of TGF-β signaling that is active at higher levels in the periportal cholangiocytes than in the rest of the parenchyma. The question mark refers to in vitro data not confirmed by in vivo experiments (Notch signaling).

Dynamic organization of a hepatic transcriptional network. (A) Changes in interactions between the core hepatocyte-enriched transcription factors at 2 stages of development and in the adult. Green arrows, unidirectional regulations; blue double arrows, reciprocal interactions. Adapted with permission from Kyrmizi et al.⁷⁷ (B) Model for time-specific gene activation during development. The concentration of 3 transcription factors (TF1, TF2, and TF3) and of 2 coactivators (CoAct1 and CoAct2) rises during development. When threshold concentration levels are reached, these proteins can interact interdependently and synergistically to induce specific genes at specific time points during development.

Morphogenesis of the intrahepatic bile ducts. During bile duct development, the cholangiocytes first form a ring of cells (ductal plate) around the branches of the portal vein. Hepatoblasts then come into contact with the ductal plate and delineate the lumen of transiently asymmetrical ducts. When the hepatoblasts on the parenchymal side of the asymmetrical ducts differentiate to cholangiocytes, the ducts become symmetrical (totally delineated by cholangiocytes) and surrounded by portal mesenchyme. The ducts grow from the hilum toward the periphery of the liver lobes, which is reflected by the observation that sections at different levels along the hilum-periphery axis reveal different levels of duct maturation. Adapted with permission from Antoniou et al.⁵⁹