Molecular mechanisms of organ regeneration and homeoslasis by injurin/HGF system.

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(1) Roles of HGF as an organotrophic factor : Recombinant HGF suppressed the onset of liver fibrosis/cirrhosis and fatty liver caused by chronic hepatic injury. We found that HGF functions as renotrophic and pulmotrophic factor for regeneration of the kidney and lung. HGF may well become a new therapeutic drug for the treatment of various organ diseases, including liver fibrosis/cirrhosis, acute renal failure, and lung fibrosis.(2) HGF as a neurotrophic factor : HGF stimulated survival of hippocampal neurons in vitro. Importantly, the infused recombinant HGF markedly prevented neuronal death caused by ischemic injury in rats.(3) HGF as a mediator in epithelial-mesenchymal interactions : Epithelial-mesenchymal interaction is a critical tissue interaction for organogenesis. HGF is expressed in mesenchymal tissue, while c-Met/HGF receptor in epithelial tissue during development of the liver, kidney, lung tooth, limb, etc. HGF supports organogenesis of various organs, such as the liver, kidney, lung, tooth, mammary gland, as a mesenchymal-derived factor.(4) HGF is tumor-stromal interactions : Malignant phenotypes of tumor cells are regulated through their interactions with host stromal cells. We found that various tumor cells produce HGF-inducer (injurin) and stromal-derived HGF enhanced the invation of tumor cells. Matual interaction between tumor cells and host stromal cells mediate tumor-stromal interactions.(5) Identification of injurin (HGF-inducer) : We purified injurin (s) from lung tissue extract and found that these are IL-1, PDGF,and bFGF.Likewise, we identified tumor-derived injurins as IL-1, PDGF,and bFGF.But mouse mammary tumor cells produced novel HGF-inducer. In contrast, we found that TGF-beta and glucocorticoids are negative regulator of HGF expression.