Hepatocyte growth factor as mitogen, motogen and morphogen, and its roles in organ regeneration

Hepatocyte growth factor (HGF) has been discovered, purified, and molecularly cloned as a potent mitogen for mature hepatocytes. HGF is a heterodimeric molecule composed of a 69 kDa alpha-subunit and a 34 kDa subunit. It contains four kringle domains in the alpha-subunit. It is produced by mesenchymal cells and predominantly acts on a wide variety of epithelial cells as a mitogen (stimulation of cell growth), a motogen (stimulation of cell motility), and a morphogen (induction of multicellular tissue-like structure). These pleiotropic functions of HGF are essential biological activities for the construction of normal tissue architecture. HGF may be one of the long-sought paracrine mediators of morphogenetic epithelial-mesenchymal interactions. On the other hand, HGF receptor was identified as the product of the c-met proto-oncogene, which encodes a 190-kDa transmembrane protein possessing tyrosine kinase domain. HGF mRNA and HGF protein are rapidly and markedly increased in the liver and plasma of rats with various types of liver injuries. HGF receptors on plasma membranes of the liver were almost completely down-regulated due to HGF binding and subsequent internalization. Therefore, HGF acts as a hepatotropic factor for liver regeneration. Recombinant HGF, intravenously injected into mice, remarkably enhances liver regeneration. After various renal and lung injuries, HGF mRNA, HGF protein, and HGF receptors in the kidney and lung are also rapidly altered prior to the onset of replication of renal tubular cells and lung alveolar epithelial cells Recombinant HGF intravenously injected into rats also remarkably enhances renal and lung regeneration. Thus, HGF acts as a renotropic factor in renal regeneration and as a plumotropic factor in lung regeneration. It is considered a key molecule for the construction of normal tissue structure during embryogenesis, organogenesis, and organ regeneration.