Human hepatic stem cell and maturational liver lineage biology

Abstract

Livers are comprised of maturational lineages of cells beginning extrahepatically in the hepato-pancreatic common duct near the duodenum and intrahepatically in zone 1 by the portal triads. The extrahepatic stem cell niches are the peribiliary glands deep within the walls of the bile ducts; those intrahepatically are the canals of Hering in postnatal livers and that derive from ductal plates in fetal livers. Intrahepatically, there are at least eight maturational lineage stages from the stem cells in zone 1 (periportal), through the midacinar region (zone 2), to the most mature cells and apoptotic cells found pericentrally in zone 3. Those found in the biliary tree are still being defined. Parenchymal cells are closely associated with lineages of mesenchymal cells, and their maturation is coordinated. Each lineage stage consists of parenchymal and mesenchymal cell partners distinguishable by their morphology, ploidy, antigens, biochemical traits, gene expression, and ability to divide. They are governed by changes in chromatin (e.g., methylation), gradients of paracrine signals (soluble factors and insoluble extracellular matrix components), mechanical forces, and feedback loop signals derived from late lineage cells. Feedback loop signals, secreted by late lineage stage cells into bile, flow back to the periportal area and regulate the stem cells and other early lineage stage cells in mechanisms dictating the size of the liver mass. Recognition of maturational lineage biology and its regulation by these multiple mechanisms offers new understandings of liver biology, pathologies, and strategies for regenerative medicine and treatment of liver cancers.

Figure 1

Schematic image of liver, the biliary tree and panceas and their connections with the duodenum. The blue stars indicate sites at which there are high numbers of peribiliary glands, the stem cell niches of the biliary tree.

Figure 2

Schematic image of intrahepatic maturational lineages.

Figure 3

Human hepatic stem cell and hepatoblast phenotypes in vivo. a,b) EpCAM expression in fetal liver: EpCAM expressed in the ductal plate is not only at the cell surface but also in the cytoplasm. EpCAM expressed in the hepatoblasts is specific to the cell surface. d,e) EpCAM expression in adult liver: One end of the Canal of Hering connects to the bile duct, the other end connects to hepatoblasts (arrow), indicating that the hepatoblasts are derived from primitive hepatic stem cells harbored in Canals of Hering. c) Double staining for CK-19/AFP and f) Ep-CAM/AFP of human fetal liver in the portal triad area and analyzed by confocal microscopy. CK-19 (c, green) is expressed not only by remodeling ductal plate but faintly expressed by some of the hepatoblasst. Ep-CAM (f, green) is detected in all the parenchymal cells and biliary epithelial cells forming bile duct and ductal plate (DP). AFP(red) is expressed by hepatoblasts throughout the fetal liver and undetectable in the ductal plate. (PT: Portal triad; DP: Ductal Plate)

Figure 4

Human hepatic stem cell and hepatoblast phenotypes in culture. a) Morphology of human hepatic stem cells and b) human hepatoblasts in culture on plastic. c) Albumin staining of human hepatic stem cells, transitioning to hepatoblasts. d) hepatic stem cells stained with NCAM (green) and hepatoblasts stained with ICAM (red).

Figure 5

Schematic image indicating the Coordinate Maturation of the Epithelia (Parenchymal cells) and their Mesenchymal Partners and some of the identified extracellular matrix components found at the particular lineage stages. Not shown in the figure are the soluble signals that also are lineage dependent. Some of those identified and that are lineage dependent are: hepatic stem cells are LIF, IL-6, IL-11, and acetylcholine; hepatoblasts are HGF, EGF, bFGF, IL-6, IL-11, and acetylcholine; hepatocytes are HGF, EGF, bFGF, T3, glucagon, and hydrocortisone; cholangiocytes are VEGF, HGF, bFGF. and acetylcholine.