Liver regeneration. 2. Role of growth factors and cytokines in hepatic regeneration.

During liver regeneration quiescent hepatocytes undergo one or two rounds of replication and then return to a nonproliferative state. Growth factors regulate this process by providing both stimulatory and inhibitory signals for cell proliferation. EGF, TGFα, and HGF stimidate DNA synthesis in hepatocytes in vivo and in culture but the sensitivity of cidtured hepatocytes to the mitogenic effects of these factors is much higher than that of quiescent hepatocytes in intact livers. We have proposed that after partial hepatectomy, hepatocytes enter a state of replicative competence (“priming”) before they can fully respond to growth factors. The priming step is an initiating event in liver regeneration that involves the activation and DNA binding of NF-κB and other transcription factors, which could be induced by TNF or other cytokines. EGF, TGFα, and HGF have major effects on liver growth. TGFα expression correlates with hepatocyte DNA synthesis during liver development and growth and the constitutive expression of the factor confers proliferative activity to adult hepatocytes in vivo and in culture. The data indicate that the activity of stimulatory and inhibitory growth factors such as TGFβl and activin is low in normal livers but that the expression of both types of factors increase during liver regeneration.—Fausto, N., Laird, A. D., Webber, E. M. Role of growth factors and cytokines in hepatic regeneration. FASEB J. 9, 1527-1536 (1995)