The discovery of Hepatocyte Growth Factor (HGF) and its significance for cell biology, life sciences and clinical medicine

Abstract

It has been more than 25 years since HGF was discovered as a mitogen of hepatocytes. HGF is produced by stromal cells, and stimulates epithelial cell proliferation, motility, morphogenesis and angiogenesis in various organs via tyrosine phosphorylation of its receptor, c-Met. In fetal stages, HGF-neutralization, or c-Met gene destruction, leads to hypoplasia of many organs, indicating that HGF signals are essential for organ development. Endogenous HGF is required for self-repair of injured livers, kidneys, lungs and so on. In addition, HGF exerts protective effects on epithelial and non-epithelial organs (including the heart and brain) via anti-apoptotic and anti-inflammatory signals. During organ diseases, plasma HGF levels significantly increased, while anti-HGF antibody infusion accelerated tissue destruction in rodents. Thus, endogenous HGF is required for minimization of diseases, while insufficient production of HGF leads to organ failure. This is the reason why HGF supplementation produces therapeutic outcomes under pathological conditions. Moreover, emerging studies delineated key roles of HGF during tumor metastasis, while HGF-antagonism leads to anti-tumor outcomes. Taken together, HGF-based molecules, including HGF-variants, HGF-fragments and c-Met-binders are available as regenerative or anti-tumor drugs. Molecular analysis of the HGF-c-Met system could provide bridges between basic biology and clinical medicine.

Improvement of metabolic syndrome by irbesartan via the PPARγ/HGF pathway in apolipoprotein E knockout mice

“…However, another downstream effector of PPARγ, HGF, is also likely to act as a 'guardian' in MS, in addition to adiponectin. Previous studies suggested that HGF mediates multiple various biological effects in various cells including anti-fibrotic, anti-inflammatory and anti-apoptotic activities (14). The present study clearly demonstrated that the anti-metabolic effects of irbesartan were largely mediated by the PPARγ-HGF pathway, with the exception of Ang II blockade.…”

Pharmacokinetic Modeling of Hepatocyte Growth Factor in Experimental Animals and Humans

“…1,2 Systemic administration of HGF has various beneficial effects in renal failure models in experimental animals. In a mouse model of obstructive nephropathy, for example, HGF attenuates the progression of interstitial fibrosis with a concomitant reduction in tubular apoptosis and an increase in tubular proliferation.…”

“…1,2 This receptor is also proposed to be involved in systemic clearance of HGF. For example, after down-regulation, i.e., reduction of the receptor density on the cell surface, induced by the injection of a relatively high dose of HGF, the total body clearance of 125 I-HGF first decreased, but subsequently increased due to recruitment of c-Met/HGF receptor to the cell surface.…”

BMPS and Liver: More Questions than Answers

“…Expression of these miRNAs is required for the mesenchymal to epithelial transition, a key component of the initiation phase of reprogramming [46]. On this regard, it has been reported that BMP4 regulates the expression level of miR210 and this effect contributes to osteoblastic differentiation [47]. miR199a(*) is an early responsive target of BMP2 during chondrogenesis [48] and several miRNAs are regulated in the BMP2 induced osteogenesis [49].…”