Co-Mitogenic Effect of Pancreatic Polypeptide on Adult Rat Hepatocytes in Primary Culture

Abstract

Proliferation of hepatocytes in liver regeneration is regulated by humoral and neuronal factors. Humoral factors include hormones and growth factors (mitogens). The neuronal factors, however, have not yet been identified. Factors that amplify the effect of complete mitogens (epidermal growth factor, transforming growth factor a and hepatocyte growth factor) are termed co-mitogens, which include vasopressin, angiotensin II, noradrenaline, neurotensin and neuropeptide-y. We have surveyed various other neuropeptides and gastrointestinal hormones that may have a co-mitogenic effect on rat hepatocytes using a complete serum-free primary culture system. Pancreatic polypeptide at 10 - 9 to 10 - 6 M amplified DNA synthesis stimulated by a low concentration of EGF (1 ng/mL) by 4- to 5-fold. Neuropeptide Y or peptide YY that have a structural similarity to pancreatic polypeptide did not amplify DNA synthesis. A similar amplification was found for secretin (10 - 1 0 to 10 - 7 M). These results indicate that pancreatic polypeptide and secretin can be regarded as novel co-mitogens, and suggest that these peptides and other co-mitogenic neuropeptides, most of them are found also in neurons, are candidate neuronal factors in hepatocyte proliferation in vivo, i.e. liver regeneration.