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 8 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.

Persistent elevation of hepatocyte growth factor activator inhibitors in cholangiopathies affects liver fibrosis and differentiation

“…2C, middle) were coexpressed with CK19, a well-known marker for HSCs and cells of the cholangiocyte lineage. 24 Moreover, HAI-1 was also coexpressed with epithelial cell adhesion molecule (EpCAM), Gli-2, and OV6, additional biomarkers for HSCs (Supporting Fig. 3A-C).…”

“…3D), which probably represent a subset of HSCs. 15,24 Thus, we hypothesized that HAI-1 and/ or -2 may also have functions in HSCs. To prove this, we examined HAI expression in the developing livers of legally aborted fetuses.…”

“…We found that both HAIs were highly expressed in mouse hepatoblast-derived bipotential cells and probably expressed in human HSCs in BA livers, whereas in human fetal liver, HAI-1 and -2 were differentially expressed in HSCs and hepatoblasts, respectively, according to the definition and staging of HSCs and hepatoblasts proposed by Dr. Lola M. Reid and colleagues. 24 Thus, both HAIs might function as regulators keeping hepatic precursor cells in a less-differentiated status prior to undergoing differentiation. To link the roles of the HAIs in hepatic differentiation and fibrosis, two seemingly unrelated phenomena, we propose that the key discriminative factor may be the action dose and duration of HAI expression.…”

Notch2 signaling and undifferentiated liver cancers: Evidence of hepatic stem/progenitor cell origin

“…4,5 However, albumin and transthyretin are expressed in cells undergoing liver differentiation from embryoid bodies 6 and in hepatic and biliary tree stem/progenitors in intrahepatic (canals of Hering) and/or extrahepatic (peribiliary glands) niches. 7,8 In the studies by Dill et al, 1 biliary hyperplasia and large biliary cyst formation were induced, even though the albumin gene promoter was targeted to induce selective hepatic N2ICD overexpression. Therefore, albumin-expressing cells in different anatomical sites could have been targeted.…”

Stemness of liver cancer: From hepatitis B virus to Wnt activation

“…Although EpCAM is known to be expressed in a variety of normal epithelial cells, it is strongly overexpressed in human adenocarcinomas [7]. In liver cell lineages, EpCAM is absent in mature hepatocytes but detectable in hepatic stem/progenitor cells and cholangiocytes [8]. Numerous studies have suggested the utility of EpCAM as a marker to identify liver cancer stem cells as well as normal hepatic progenitors [3].…”