Generation and regeneration of cells of the liver and pancreas

Abstract

Liver and pancreas progenitors develop from endoderm cells in the embryonic foregut. Shortly after their specification, liver and pancreas progenitors rapidly acquire markedly different cellular functions and regenerative capacities. These changes are elicited by inductive signals and genetic regulatory factors that are highly conserved among vertebrates. Interest in the development and regeneration of the organs has been fueled by the intense need for hepatocytes and pancreatic beta cells in the therapeutic treatment of liver failure and type I diabetes. Studies in diverse model organisms have revealed evolutionarily conserved inductive signals and transcription factor networks that elicit the differentiation of liver and pancreatic cells and provide guidance for how to promote hepatocyte and beta cell differentiation from diverse stem and progenitor cell types.

Fig. 1

Cell domains and signals for embryonic liver and pancreas specification. A. Fate map of progenitor cell domains prior to tissue induction; view is into the foregut of an idealized mouse embryo at E8.25 (3-4 somite stage). Green arrows indicate movement of lateral progenitor regions toward the ventral-medial region. B. Sagittal view of a mouse embryo several hours later than in A, showing the positions of the newly specified liver and pancreas tissue domains. Signals and cell sources that pattern the endoderm are shown. Dashed blue line indicates plane of view in A.

Fig. 2

Stages of liver bud organogenesis. Hepatoblasts are stained blue (Hex^LacZ+); cells with orange nuclei are gut endoderm (FoxA2⁺); and all nuclei were stained green by DAPI. White arrows point to the hepatic cells. Genes and signals that promote each transition are indicated. Similar morphogenetic stages occur during pancreas bud organogenesis. Images are adapted from (36). S, pair somite stage; E, embryonic day.

Fig. 3

Regulatory factors controlling cell type lineages within the liver and pancreas. Transcription factor genes are shown in bold; their functions have been reviewed in the text and elsewhere (23, 55-57), except for vHnf1 in hepatic development (81). Note that Pdx1 initially marks duodenum and caudal stomach progenitors (not shown) as well as the pancreatic domains (28).

Fig. 4

Progenitor lineage relationships in adult liver and pancreas. The thickness of the arrows indicates the dominant mode of regeneration. Dashed lines delineate rare or hypothetical cell fate transitions that occur only under specific experimental conditions.