Cell Lineage Analysis during Liver Development Using the spfash-Heterozygous Mouse

Abstract

SUMMARY:Biliary epithelial cells differentiate from periportal hepatoblasts during fetal mouse liver development. It remains to be determined whether each hepatoblast is equivalent for differentiation into hepatocytes and biliary epithelial cells in normal liver development. To resolve this question, the mosaic pattern of ornithine transcarbamylase (OTC) expression was analyzed in the hepatoblast population of spf ash (sparse-fur with abnormal skin and hair)-heterozygous fetal mouse livers, in which random inactivation of either the X chromosome carrying the spf ash gene (causing OTC deficiency) or its wild-type gene occurs. Aggregates (patches) of OTC-positive hepatoblasts showed very complex patterns, and their shapes and size distributions were similar in sections from periportal regions and nonperiportal regions of the fetal liver in which bile duct differentiation by periportal hepatoblasts occurred. Average sizes of periportal patches were larger than those of nonperiportal patches because of the presence of more hemopoietic cells in the latter region. The OTC mosaicism in periportal bile duct progenitors and hepatoblast islands of other liver parenchyma was also similar. These results suggest that the growth patterns of hepatoblasts are similar in both periportal and nonperiportal regions. Isolated three-dimensional patches comprising hepatoblasts giving rise to only biliary epithelial cells or hepatoblasts giving rise to both hepatocytes and biliary epithelial cells were observed in periportal regions. In nonperiportal regions, patches consisting of hepatoblasts differentiating into hepatocytes were also seen. Thus, it is likely that there are three lineages for the developmental fates of hepatoblasts: hepatoblasts giving rise to only biliary epithelial cells, hepatoblasts giving rise to only hepatocytes, and hepatoblasts giving rise to both of them. (Lab Invest 2001, 81:17-25).

A mouse model for cystic biliary dysgenesis in autosomal recessive polycystic kidney disease (ARPKD)†

“…Thereby, the ductal plate becomes physically separated from the periportal hepatocellular parenchyme. 15 Then, the ductal plate duplicates through continued cholangioblast proliferation to form a primitive cylindric bile duct encircling almost the entire portal tract. It is assumed that physical separation of the ductal plate provides a signal to the cholangioblasts to undergo apoptosis and a series of subsequent architectural remodeling steps to form mature bile ducts longitudinally orientated along the portal veins.…”

“…For reverse transcription, 1 g total RNA was primed with 1 g oligo d(T) [12][13][14][15][16][17][18] , and transcription was performed by Superscript II RT following the manufacturer's description (Invitrogen). PCR was run with 35 cycles (1 minute at 94°C, 45 seconds at 53°C to 55°C, and 1 to 2 minutes at 72°C).…”

The stem cell niche of human livers: Symmetry between development and regeneration

“…14,20,21 Recently, this paracrine signaling has been shown to derive from angioblasts and their progeny, endothelia, which provide multiple signals, including a subset of fibroblast growth factors. 22,23 HNF1 and HNF6b signaling in a highly localized response are hypothesized also to be critical regulators of the process.…”

Inhibition of Jagged-mediated Notch signaling disrupts zebrafish biliary development and generates multi-organ defects compatible with an Alagille syndrome phenocopy

“…How Notch signaling regulates mammalian biliary development is not known. Mammalian cholangiocytes and hepatocytes appear to develop from a common precursor, the hepatoblast (reviewed by Lemaigre, 2003;Rogler, 1997;Shiojiri, 1984;Shiojiri et al, 2001). Expression of jagged 1, and notch 2 and notch 3 genes within portal vein endothelia and mesenchyme, and adjacent hepatoblasts is compatible with an inductive mechanism (Loomes et al, 2002;Louis et al, 1999;McCright et al, 2002).…”