EXPRESSION OF HEPATIC TRANSCRIPTION FACTORS DURING LIVER DEVELOPMENT AND OVAL CELL-DIFFERENTIATION

The oval cells are thought to be the progeny of a liver stem cell comp artment and strong evidence now exists indicating that these cells can participate in liver regeneration by differentiating into different h epatic lineages. To better understand the regulation of this process w e have studied the expression of liver-enriched transcriptional factor s (HNF1 alpha and HNF1 beta, HNF3 alpha, HNF3 beta, and HNF3 gamma, HN F4, 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. T he steady-state mRNA levels of four (HNF1 alpha, HNF3 alpha, HNF4, and C/EBP beta) ''liver-enriched'' transcriptional factors gradually decr ease during the late period of embryonic liver development while three factors (HNF1 beta, HNF3 beta, and DBP) increase. In the normal adult rat liver the expression of all the transcription factors are restric ted to the hepatocytes. However, during early stages of oval cell prol iferation both small and large bile ducts start to express HNF1 alpha and HNF1 beta, HNF3 gamma, C/EBP, and DBP but not HNF4. At the later s tages all of these factors are also highly expressed in the proliferat ing oval cells. Expression of HNF4 is first observed when the oval cel ls differentiate morphologically and functionally into hepatocytes and form basophilic foci. At that time the expression of some of the othe r factors is also further increased. Based on these data we suggest th at the upregulation of the ''establishment'' factors (HNF1 and -3) may be an important step in oval cell activation. The high levels of thes e factors in the oval cells and embryonic hepatoblasts further substan tiates 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 hepatocyte s which form the basophilic foci and eventually regenerate the liver p arenchyma.