Control of liver growth.

The liver is an excellent tissue for the study of growth regulation because of its ability to regenerate by a process of compensatory growth following surgical resection or toxic injury. Much of the investigation on the mechanisms of hepatic growth has been done in partially hepatectomized animals in vivo and in hepatocytes in primary culture. Almost immediately after partial hepatectomy there are major changes in the binding capacity of transcription activators and in the expression of a relatively large number of genes. Many of the immediate early response gene products are themselves transcription activators and thus can multiply and propagate the initial gene activation process. An important issue in the regulation of liver growth is to identify growth factors that may play a role in hepatocyte replication in vivo. In addition to substances that are adjuvants in the mitogenic response at least three growth factors, EGF, TGF alpha, and HGF, are complete mitogens for hepatocytes in culture and appear to play important roles as stimulators of liver growth. We discuss data that indicate that none of these growth factors seems capable of causing a significant increase in DNA synthesis in quiescent hepatocytes in vivo. In contrast, EGF, TGF alpha, and HGF (both the monomer and the heterodimer) increase DNA synthesis in vivo in hepatocytes that have become "competent" to proliferate. We suggest that the competence process involves the activation of transcription factors and protooncogenes, and that during liver regeneration at least some of these changes precede rather than follow growth factor/ligand signaling. The available data suggest that the three growth factors by themselves may not trigger regeneration in strictly quiescent hepatocytes. There is now extensive evidence from work on TGF alpha in developing and regenerating liver as well as studies with transgenic animals to indicate that the factor may act as a cell cycle progression agent. We suggest that "priming" of hepatocytes after partial hepatectomy might have similarities to the widespread activation of genes observed in response to stimuli such as heat shock, ionic imbalances, and changes in redox potentials, and that TGF alpha and also probably the other growth factors act to make primed cells progress through the cycle and undergo DNA synthesis. TGF beta 1 is a potent antagonist to the mitogenic effects of these growth factors on cultured hepatocytes and could be an important factor for terminating the proliferative response of hepatocytes after partial hepatectomy. Although we have moved closer to finding "on" and "off" switches for regeneration, their precise identities and mechanisms remain elusive.