Specification of Liver from Embryonic Endoderm

Abstract

During organogenesis, how do endoderm cells acquire their multipotency, become specified to different cell types, and give rise to tissue buds? The liver derives from the definitive gut endoderm, which expresses many genes in common with the visceral endoderm, which give rise to the yolk sac. The gut endoderm forms from epithelial sheets which form the foregut and hindgut, which elongate and converge at the midsection. During determination, different domains of endoderm are dependent on different groups of transcription factors, which appear to be controlled partially by preprogramming and partially by the influence of overlying mesoderm. When progenitor cells become specified, they proliferate more extensively, forming a tissue bud that extends into the surrounding mesenchymal domain. The liver tissue bud interacts with the adjacent septum transversum mesenchyme between the liver tissue bud and the developing heart (cardiogenic mesoderm). Coordinate signaling from both the cardiogenic mesoderm and septum transversum mesenchyme is required to induce liver differentiation in the ventral foregut endoderm. On the other hand, dorsal-posterior mesenchyme inhibits the induction of liver gene expression in endoderm outside the ventral foregut region. Liver progenitor cells in the ventral foregut also have the potential to undergo pancreatic differentiation. At the time of hepatic specification, there is a burst of expression of fibroblast growth factor-1 (FGF-1) and FGF-2 and persistent expression of FGF-8 in the cardiac mesoderm, and the adjacent ventral foregut expresses FGF receptor genes (FGF-R1 and FGF-R4). Inhibition of this signaling results in failure of hepatic gene expression; FGF signaling is sufficient to induce a hepatic fate, while suppressing a pancreatic fate. Bone morphogenetic proteins from the septum transversum, in conjunction with FGF signaling from the cardiogenic mesoderm, pattern the ventral foregut endoderm into liver and pancreatic cell domains. The induction of expression of liver genes is tightly coupled to morphological changes in the cells from cuboidal to columnar and increased proliferation resulting in formation of the liver bud. The bud expands into the surrounding mesenchyme of the septum transversum with subsequent appearance of endothelial cells that will define the sinusoidal paths. Isolation and culture of uncommitted foregut endodermal cells of the mouse between the 2- and 6-somite stage is described.