Background/aims: In the embryo, rapidly proliferating hepatocytes migrate from the liver primordium into the surrounding mesenchyme, whereas foetal hepatocytes are mitotically quiescent and accumulate hepatocyte-specific enzymes. We investigated the timing and topography of this behavioural switch.
Methods: The expression of the c-met receptor and its ligand, hepatocyte growth factor (HGF), was investigated in prenatal rat liver by in situ hybridization, immunohistochemistry and western-blot analysis.
Results: c-Met was expressed by hepatocytes and HGF by non-parenchymal liver cells. Their mRNA levels peaked during embryonic day (ED) 11-13. c-Met protein was weakly expressed in the entire liver during ED 11 and 12, but more abundantly at ED 13, when its expression withdrew to the hepatic periphery. Simultaneously, the periportal hepatocellular marker carbamoylphosphate synthetase began to accumulate in the centre of the liver. Although the definitive vascular architecture develops simultaneously, the downstream, pericentral hepatocytes began to express glutamine synthetase only 4 days later, suggesting a requirement for prior periportal hepatocyte maturation. Additionally, c-met protein appeared in the connective tissue surrounding the large veins. The c-met protein/mRNA ratio was substantially higher in non-epithelial cells (hepatic connective tissue, heart) than in endoderm-derived epithelia, including hepatocytes, indicating important post-transcriptional regulation.
Conclusions: The decline in c-met expression reflects the end of the embryonic phase and heralds the onset of the fetal, maturational phase of liver development.