HGF Function

Summary of HGF Function

HGF regulates cell growth, cell motility, and morphogenesis by activating a tyrosine kinase signaling cascade after binding to the c-Met receptor. HGF is secreted by mesenchymal cells and acts as a multi-functional cytokine on cells of mainly epithelial origin. Its ability to stimulate mitogenesis, cell motility, and matrix invasion gives it a central role in angiogenesis, tumorogenesis, and tissue regeneration.

HGF Function in Organ Regeneration

Liver regeneration is recognized as an example of controlled tissue growth. Originally, HGF was identified in the sera of 70%-hepatectomized rats, as a mitogen of adult rat hepatocytes. Indeed, during hepatic injuries, blood and liver HGF levels markedly increased, via both extra-hepatic and intra-hepatic pathways. Animal studies using either anti-HGF antibody or c-Met gene destruction techniques revealed that both the endocrine and paracrine effects of HGF are involved in liver growth after 70%-hepatectomy, and for recovery from hepatitis, respectively. Several lines of in vitro studies have revealed that HGF has regenerative effects on epithelium in the kidney, lung and other tissues. Indeed, plasma HGF levels are elevated in patients during organ injuries. Endogenous HGF is important for inducing self-repair responses in numerous organs. The paracrine or endocrine pathway that is predominantly involved in tissue repair depends on the degree, or kind, of injury. Regardless of the pathway, HGF is secreted as a pro-HGF and then converted to the active form only at the injury sites by HGF-activators.

HGF Function in Organ Failure

Apoptotic events are one of the key pathogenic causes for the manifestation of organ injury. HGF prohibits apoptotic signals via inhibition of caspase-3 activity or induction of anti-apoptotic molecules, such as Bcl-xL. Furthermore, HGF prohibits Fas-mediated apoptosis signals via sequestration of Fas and c-Met on cell surfaces. These effects of HGF protect the epithelium, neurons and cardiomyocytes during organ diseases. During chronic organ injuries, TGF-βplays a pivotal role in tissue fibrosis via converting HGF-producing fibroblasts to ECM-producing myofibroblasts (MyoFBs). HGF inhibits TGF-- production in cultures of MyoFBs and intercepts the TGF--1-mediated signal pathway by inhibiting nuclear smad2/3 activation. Moreover, HGF reduced the TGF---receptor and induced decorin, an inhibitor of TGF--1, all of which might lead to anti-fibrotic outcomes in vivo. In addition, HGF inhibits the functions of other fibrogenic cytokines, including platelet-derived growth factor (PDGF), connective tissue growth factor (CTGF) and monocyte chemoattractant peptide-1 (MCP-1).

HGF Function as an Angiogenic Factor

HGF is an angiogenic factor in vitro, in addition to vascular endothelium growth factor (VEGF) and basic fibroblast growth factor (b-FGF). Induction of angiogenesis by HGF supplementation resulted in improved local hypoxia. HGF had an anti-apoptotic effect on endothelium via Bcl-2 induction. In contrast to other angiogenic factors, HGF has benefits, such as antithrombosis. VEGF enhanced endothelial permeability and edema, whereas HGF inhibited endothelial permeability. In contrast to the fibrotic effects of b-FGF, HGF is anti-fibrotic. These benefits lead to "therapeutic angiogenesis", even under hypoxic conditions.

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