TRANSFORMING GROWTH-FACTOR-BETA MODULATES GROWTH AND DIFFERENTIATION OF FETAL HEPATOCYTES IN PRIMARY CULTURE

Fetal hepatocytes in primary culture are cells capable to carry out bo th proliferation and differentiation processes simultaneously. Previou s studies have shown that these cells respond to mitogens, such as hep atocyte growth factor (HGF) or epidermal growth factor (EGF), inducing the expression of early genes, such as fos and myc. The transforming growth factor-beta (TCF-beta) family is one of the most influential gr oups of growth and differentiation factors. In this report, we show th at TGF-beta 1 inhibits fetal hepatocyte proliferation, arresting these cells at G1 phase of the cell cycle. In addition, TGF-beta down-regul ates the mitogen-induced myc early expression. However, TGF-beta has n o effect on the expression of other protooncogenes, such as fos and H- ras. In addition to its inhibitory role on fetal hepatocyte growth, TG F-beta increases the mRNA levels of fibronectin, an extracellular matr ix protein, and maintains the expression of same liver specific genes, such as albumin and alfafetoprotein, above control values. The analys is of the expression of some hepatocyte transcriptional factors has sh own that TGF-beta increases HNF1 alpha and HNF1 beta mRNA levels. We c onclude that TGF-beta may modulate liver growth and differentiation th roughout fetal development. (C) 1995 Wiley-Liss, Inc.