Hepatocyte growth factor twenty years on: Much more than a growth factor

Abstract

Liver regeneration depends on the proliferation of mature hepatocytes. In the 1980s, the method for the cultivation of mature hepatocytes provided an opportunity for the discovery of hepatocyte growth factor (HGF) as a protein that is structurally and functionally different from other growth factors. In 1991, the scatter factor, tumor cytotoxic factor, and 3-D epithelial morphogen were identified as HGF, and Met tyrosine kinase was identified as the receptor for HGF. Thus, the connection of apparently unrelated research projects rapidly enriched the research on HGF in different fields. The HGF-Met pathway plays important roles in the embryonic development of the liver and the placenta, in the migration of myogenic precursor cells, and in epithelial morphogenesis. The use of tissue-specific knockout mice demonstrated that in mature tissues the HGF-Met pathway plays a critical role in tissue protection and regeneration, and in providing less susceptibility to chronic inflammation and fibrosis. In various injury and disease models, HGF promotes cell survival, regeneration of tissues, and suppresses and improves chronic inflammation and fibrosis. Drug development using HGF has been challenging, but extensive preclinical studies to address its therapeutic effects have provided significant results sufficient for the development of HGF as a biological drug in the regeneration-based therapy of diseases. Clinical trials using recombinant human HGF protein, or HGF genes, are in progress for the treatment of diseases.

Bronchioalveolar morphogenesis of human bronchial epithelial cells depending upon hepatocyte growth factor

“…As a possible reason, Met activation may require cell–cell or cell–matrix adhesions, and thus may be less efficient in poorly differentiated tumours 28. The HGF–Met system is involved in branching tubulogenesis of the lung 22 and other origins 28. In the present study, we found that the HGF–Met pathway induces HBE135 cells into a highly morphogenic, bronchioalveolar structure in 3D culture.…”

Repair of segmental bone defects in rabbit tibia promoted by a complex of β-tricalcium phosphate and hepatocyte growth factor

“…Previous studies have demonstrated therapeutic actions of HGF in different disease models in different tissues, including the liver, kidney, lung, and nervous tissue [9,18]. Consistently, tissue-selective disruption of the Met gene in the liver, kidney, or epidermis indicated impairment in regeneration and healing and/or an increase in epithelial apoptosis [26,27].…”

“…On the basis of this biological activity, HGF and its receptor Met are involved in the development, repair, and protection of tissues [9]. Administration of HGF or expression of the HGF gene promotes tissue regeneration and improves the pathology of a variety of disease models of different tissues [9,10].…”

“…On the basis of this biological activity, HGF and its receptor Met are involved in the development, repair, and protection of tissues [9]. Administration of HGF or expression of the HGF gene promotes tissue regeneration and improves the pathology of a variety of disease models of different tissues [9,10]. A recent study demonstrated that administration of recombinant HGF enhances tendon healing in the bone tunnel and leads to improved biomechanical fixation within a shorter period postoperatively [11].…”

EGFR is dispensable for c-Met-mediated proliferation and survival activities in mouse adult liver oval cells

“…Among others, the well-known receptor tyrosine kinase (RTK) signaling systems, HGF/c-Met, and EGF/EGFR (also known as ErbB1), are certainly interesting targets for experimental studies. Both signalling pathways have a remarkably pleiotropic nature and share common intracellular signalling molecules and biological effects, playing fundamental roles during development and oncogenesis [5][6][7][8]. The HGF actions, namely proliferation, survival, motility, and morphogenesis, are driven by ligand bindingdependent autophosphorylation of c-Met on specific tyrosine residues in the tyrosine kinase and C-terminal domains, followed by either adapter-mediated or direct recruitment and activation of multiple signal transducers, including Ras-ERK 1/2 mitogen activated protein kinases (MAPKs), phosphatidylinositol-3 kinase (PI3K)-AKT, phospholipase C-γ (PLC-γ), p38, and STAT3 [9].…”