The research is focused on defining the cellular and molecular biology of the hepatic and pancreatic stem cell compartments in normal and neoplastic organs. The oval cells are thought to be the progeny of a liver stem cell compartment and strong evidence now exists indicating that these cells can participate in liver regeneration by differentiating into different hepatic lineages. To better understand the regulation of this process, we have studied the expression of liver enriched transcriptional factors (HNF1alpha and -beta, HNF3alpha, -beta and - gamma, HNF4, C/EBP, C/EBP beta, and DBP) in an experimental model of oval cell proliferation and differentiation and compared the expression of these factors to that observed during late stages of hepatic ontogenesis. The steady-state mRNA levels of four (HNF1alpha, HNF3alpha, HNF4 and C/EBPbeta) """"""""liver enriched"""""""" transcriptional factors gradually decrease during the late period of embryonic liver development, while three factors (HNF1beta, HNF3beta, and DBP) increase. In the normal adult rat liver the expression of all the transcription factors are restricted to the hepatocytes. However, during early stages of oval cell proliferation both small and large bile ducts start to express HNF1alpha and beta-, HNF3gamma, C/EBP, and DBP but not HNF4. At the later stages, all of these factors are also highly expressed in the proliferating oval cells. Expression of HNF4 is first observed when the oval cells differentiate morphologically and functionally into hepatocytes and form basophilic foci. At that time, the expression of some of the other factors is also further increased. Based on these data, we suggest that the upregulation of the """"""""establishment"""""""" factors (HNF1 and -3) may be an important step in oval cell activation. The high levels of these factors in the oval cells and embryonic hepatoblasts further substantiates the similarity between the two cell compartments. Furthermore, the data suggest that HNF4 may be responsible for the final commitment of a small portion of the oval cells to differentiate into hepatocytes which form the basophilic foci and eventually regenerate the liver parenchyma.
