Hepatocyte growth factor: Molecular structure and implications for a central role in liver regeneration

Hepatocyte growth factor (HGF) is a most potent factor for mature parenchymal hepatocytes in primary culture and may act as a trigger for liver regeneration. We purified HGF from rat platelets to homogeneity and cloned both human and rat HGF cDNA. HGF is a heterodimer molecule composed of the 69 kDa alpha-subunit and the 34 kDa beta-subunit. HGF has no amino acid sequence homology with other known peptide growth factors and possesses the highest potential among known growth factors to stimulate proliferation of hepatocytes in primary culture. HGF is derived from a single chain precursor of 728 amino acid residues and the precursor is proteolytically processed to form a two-chain mature HGF. The alpha-subunit of HGF contains 4 kringle structures and HGF has a homology (38%) with plasmin. Biologically active recombinant human HGF could be expressed from COS-1 cells and CHO cells transfected with cloned cDNA. HGF activity and the HGF mRNA level are markedly increased in the liver following insult such as hepatitis, by the administration of hepatotoxins, ischaemia, physical damage and partial hepatectomy. Moreover, HGF mRNA is induced in the lung and kidney, in the presence of liver injury. In situ hybridization revealed that HGF-producing cells in liver are non-parenchymal liver cells, presumably Kupffer and sinusoidal endothelial cells. Therefore, HGF from neighbouring cells (Kupffer and sinsuoidal endothelial cells) and distal organs (lung and kidney) may function as a trigger for liver regeneration by both a paracrine mechanism and an endocrine mechanism. HGF has mitogenic activity for renal tubular epithelial cells, epidermal melanocytes and keratinocytes as well as mature hepatocytes, and has the potential to promote cell migration for some epithelial cells, including normal human keratinocytes. Since cell growth and cell motility are relevant to tissue repair and embryogenesis, HGF may well have important roles in tissue repair and embryogenesis as well as in liver regeneration.