Liver Development
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| This research on liver development was published on StemBook by Dr. Zorn and his laboratory. |
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Figure 1. Liver cell lineage. |
| The cell lineage steps during hepatic development (red) from uncommitted endoderm to functional adult hepatocytes and biliary epithelium. |
Figure 2. Time line of mouse liver development. |
| The schematic shows mouse embryos at different stages of development with the endoderm tissue highlighted in yellow, the liver in red and the gall bladder in green. The major developmental events are listed below. The endoderm germ layer is formed during gastrulation (e6.5-e7.5). Throughout gastrulation and early somite stages of development (e7-e8.5) the endoderm is patterned along the A-P axis into foregut (fg) midgut (mg) and hindgut (hg) progenitor domains. Morphogenesis forms foregut and hindgut pockets as the endodermal cup is transformed into a gut tube. By e8.5 hepatic fate specified in a portion of the ventral foregut endoderm adjacent to the heart. As the embryo grows the endoderm forms a gut tube and the liver domain moves to the midgut. The liver diverticulum (ld) forms by e9 and expands into an obvious liver bud (lb) by e10. The liver grows, and by e15 hepatoblasts are differentiating into hepatocyte and biliary cells. Final maturation of the liver is gradual and continues into the postnatal period. |
Figure 3. Cellular architecture of the liver. |
(A) The schematic shows an adult liver (red), with the gall bladder and extra hepatic ducts (green), in relation to the stomach and intestine (yellow). The extra hepatic duct system consists of the hepatic ducts (hd), which drain bile from the liver into the common hepatic duct (chd) to the gall bladder via the cystic duct (cd) and into the duodenum through the common bile duct (cbd).
(B) A schematic of the cellular architecture of the liver showing the hepatocytes (pink) arranged in hepatic plates separated by sinusoid spaces radiating around a central vein. Bile canaliculi on the surface of adjoining hepatocytes drain bile into the bile ducts (green), which run parallel to portal veins (blue) and hepatic arteries (red) to form the “portal triad”. (Panel B is adapted with permission from Bloom and Fawcett: A Text Book of Histology 10th Edition). |
Introduction | Overview | Cellular Architecture
The liver is the largest internal organ and it provides many essential metabolic, exocrine and endocrine functions. Hepatocytes are the principal cell type in the liver and these along with biliary epithelial cells are derived from the embryonic endoderm. Embryological experiments in animal models have demonstrated that liver development occurs through a progressive series of reciprocal tissue interactions between the embryonic endoderm and nearby mesoderm. In the last ten years many of the genes and molecular pathways that regulate hepatogenesis have been identified. Recently application of this knowledge has enabled researchers to produce “hepatic-like” tissue from embryonic stem (ES) cells in vitro, which may ultimately lead to therapeutically useful tissue for transplantation. This review summarizes the current understanding of the molecular pathways controlling liver and biliary system development focusing on studies in the mouse embryo where this process is best understood.
Introduction
The liver is the largest internal organ providing essential metabolic, exocrine and endocrine functions. These include production of bile, metabolism of dietary compounds, detoxification, regulation of glucose levels through glycogen storage and control of blood homeostasis by secretion of clotting factors and serum proteins such as Albumin.
Hepatocytes are the principal cell type in the liver accounting for ∼70% of the mass of the adult organ. Hepatocytes, along with biliary epithelial cells (BECs; also known as cholangyocytes) are derived from the embryonic endoderm, while the stromal cells, stellate cells, kuppfer cells and blood vessels, are of mesodermal origin (see Fig. 1). The use of animal models, such as the mouse, chicken, zebrafish and Xenopus, as well as primary cell cultures has identified many of the genes and molecular pathways regulating embryonic liver development. These studies show that much of hepatogenesis is evolutionarily conserved and occurs through a progressive series of reciprocal tissue interactions between the embryonic endoderms and nearby mesoderm (see Fig. 2; Zaret, 2008; Zhao and Duncan, 2005). The application of this information has recently enabled researchers to produce “hepatic-like” tissue from embryonic stem (ES) cells in vitro, which may ultimately lead to therapeutically useful tissue for transplantation. This review summarizes the current understanding of liver and biliary system development focusing on studies the in mouse embryo where this process is best understood.
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Overview
The endoderm germ layer is established during gastrulation and forms a primitive gut tube that is subdivided into foregut, midgut and hindgut regions (see Fig. 2). Fate mapping studies in the mouse embryo at embryonic day 8.0 of gestation (e8.0) indicate that the embryonic liver originates from the ventral foregut endoderm (Tremblay and Zaret, 2005). The first morphological sign of the embryonic liver is the formation of the hepatic diverticulum, an out-pocket of thickened ventral foregut epithelium adjacent to the developing heart at e9.0 (see Fig. 2). The anterior portion of the hepatic diverticulum gives rise to the liver and intrahepatic biliary tree, while the posterior portion forms the gall bladder and extrahepatic bile ducts. At e9.5, the hepatic endoderm cells, known as hepatoblasts delaminate from the epithelium and invade the adjacent septum transversum mesenchyme (STM) to form the liver bud (Houssaint, 1980; Le Douarin, 1975; Medlock and Haar, 1983). The STM contributes fibroblasts and stellate cells of the liver. Between e10–15 the liver bud undergoes a period of accelerated growth as it is vascularized and colonized by hematopoietic cells to become the major fetal hematopoietic organ.
The hepatoblasts are bi-potential and those residing next to the portal veins become BECs that will line the lumen of the intrahepatic bile ducts (IHBD), while the majority of hepatoblasts in the parenchyma differentiate into hepatocytes (Lemaigre, 2003; Shiojiri, 1984). The maturation of functional hepatocytes and the formation of a biliary network connected to the extrahepatic bile ducts (EHBD) are gradual. Beginning at e13 this process continues until after birth to generate the characteristic tissue architecture of the liver.
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Cellular Architecture of the Liver
Within the adult liver, the IHBD, portal vein and hepatic artery run in parallel and are referred to as the “portal triad” (see Fig. 3). The portal triad is surrounded by hepatocytes arranged in single cell sheets known as hepatic plates, separated by sinusoid spaces that are connected to a network of blood vessels capillaries. Blood plasma from the portal vein enters the sinusoid space and comes into direct contact with the basal surface of hepatocytes, which absorb metabolites and toxins. Bile is secreted from the apical surface of adjoining hepatocytes into the bile canaliculi (grooves in the cell surface), and then flows though the IHBD to the extrahepatic bile ducts (EHBD), and into the gall bladder where it is stored before release into the duodenum. This cellular architecture is essential for proper hepatic function.
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