The establishment of the hepatic architecture is a prerequisite for the development of a lobular pattern of gene...

We have studied the expression patterns of ammonia-metabolising enzymes and serum proteins in intrasplenically transplanted embryonic rat hepatocytes by in situ hybridisation and immunohistochemical analysis. The enzymic phenotype of individually settled hepatocytes was compared with that of hepatocytes being organised into a three-dimensional hepatic structure. Our results demonstrate that development towards the terminally differentiated state with zonal differences in enzyme content requires the incorporation of hepatocytes into lobular structures. Outside such an architectural context, phenotypic maturation becomes arrested and hepatocytes linger in the protodifferentiated state. These features identify the foetal period as a crucial time for normal liver development and show that the establishment of the terminally differentiated hepatocellular phenotype, beginning with the differentiation of hepatocytes from the embryonic foregut, is realised via a multistep process.