Changes in sensitivity of hepatocytes isolated from regenerating rat liver to the growth inhibitory action of transforming growth factor beta.

Transforming growth factor beta (TGFB) is a potent inhibitor of DNA synthesis in adult rat hepatocytes in vitro. In the present study, the response of hepatocytes from normal or regenerating rat liver to TGFB was determined. TGFB inhibited DNA synthesis uniformly in hepatocytes from both groups in the absence of EGF. However, hepatocytes from 3 h regenerating liver maintained for 3 days in the presence of EGF were less sensitive to the growth-inhibitory action of TGFB. [3H]-thymidine incorporation was inhibited at 20 pM TGFB by only 7% in hepatocytes from 3 h regenerating liver compared with 70% in normal hepatocytes. By increasing the dose of TGFB to 100 pM, however, the full inhibitory response was restored. Reduced sensitivity was also found when the nuclear labelling index was determined, but no change was observed in cells from rats 3 h following sham hepatectomy. The change in sensitivity to TGFB required the presence of 5 ng/ml EGF or greater. Within a further 24-48 h in culture, the response to lower doses of TGFB was at least partially restored. While the present experimental design cannot directly confirm the role of TGFB as a paracrine inhibitor of liver growth in vivo, the data are compatible with this hypothesis.