Potential Of Hepatocyte Growth Factor Research Articles

Revealing the heterogeneity of plasma protein and cognitive decline trajectory among Mild Cognitive Impairment patients by clustering of brain atrophy features

Alzheimer's disease (AD) is suggested to be a heterogeneous disorder, but limited studies explore the heterogeneity of the Mild Cognitive Impairment (MCI) stage. This study aimed to tackle such problems using the CIMLR (Cancer Integration via Multikernel Learning) algorithm to cluster brain structural features extracted from T1-weighted Magnetic Resonance Images of MCI patients from Alzheimer's Disease Neuroimaging Initiative. The demographic and cognitive results, characteristics of brain structural features, plasma biomarkers, and longitudinal cognitive trajectory were analyzed for each cluster. The CIMLR clustering analysis revealed four distinct clusters. Cluster 1 is the oldest group but has had mild atrophy and moderate progression with elevated Tumor Necrosis Factor Receptor 2 level; and low Brain-Derived Neurotrophic Factor and CD40 Ligand levels. Cluster 2 showed the highest risk for aggressive MCI progression, with abnormal Leptin, Adiponectin, and Creatine kinase-MB values. Cluster 3 exhibited a low level of Monokine Induced by Gamma Interferon and mild atrophy that shared similar patterns with Cluster 1. Cluster 4 represented the healthiest group during longitudinal tracking, with the mildest Parahippocampal atrophy, which was found to be positively correlated with cognitive impairment and amino acid levels. The longitudinal analyses showed the potential of Hepatocyte Growth Factor as a marker for slow cognitive impairment; Cortisol and Neurofilament Light Polypeptide as prognosis markers for aggressive MCI progression. These findings may lay out new suggestions for further research contributing to the accurate diagnosis and precision medicine for dementia and AD.

Therapeutic potential of hepatocyte growth factor against cerebral ischemia (Review).

The effective treatment for cerebral ischemia has not yet been established. Hepatocyte growth factor (HGF) is a potent pleiotropic cytokine that is involved in cell and tissue regeneration, including in the central nervous system. Studies have demonstrated that an exogenous administration of HGF protects brain tissue from ischemic damage. In response to binding to the receptor c-Met, HGF activates the downstream signaling pathways (including the phosphatidylinositol 3-kinase/Akt, Ras/MAPK and signal transducer and activator of transcription pathways) which leads to various cellular responses involved in angiogenesis, glial scar formation, anti-apoptosis and neurogenesis. The purpose of this review is to summarize the present understanding of the therapeutic potential of HGF in cerebral ischemia.

IL-1β-stimulated urokinase plasminogen activator expression through NF-κB in gastric cancer after HGF treatment

The potential of hepatocyte growth factor (HGF) to regulate the expression of urokinase plasminogen activator (uPA) in a gastric cancer cell is not widely acknowledged. To identify the genes associated with the plasminogen activator proteolytic axis by HGF, we used cDNA microarray technology and selected genes upregulated or downregulated in two gastric cell lines (NUGC-3 and MKN-28). First, IL-1β RNA and protein were confirmed to be upregulated. Then, we investigated the effect of IL-1β induced by HGF on the uPA system, facilitating the migration and invasion of cancer cells in the metastatic process. The role for IL-1β in HGF-induced upregulation of uPA was determined by knockdown of IL-1β with IL-1β shRNA and a chromatin immune precipitation assay. The levels of IL-1β and uPA were upregulated in cells treated with HGF in a dose-dependent manner. HGF-induced upregulation of uPA was suppressed by IL-1β knockdown. HGF enhanced the binding activity of NF-κB to the uPA promoter in control cells, but not in the IL-1β shRNA cells. We confirmed the functional role of HGF inactivation of the uPA promoter by a reporter gene assay. Downregulation of IL-1β using IL-1β shRNA also decreased cell proliferation and in vitro cell invasion. IL-1β stimulated uPA expression through ERK and NF-κB in gastric cancer, which may therefore be promising targets for gastric cancer therapy.

Therapeutic Potential of Hepatocyte Growth Factor for Treating Neurological Diseases

This review summarizes recent findings on the therapeutic potential of hepatocyte growth factor (HGF) for a variety of neurological diseases. HGF, originally identified and molecularly cloned as a potent mitogen for hepatocytes, exhibits multiple biological effects, including mitogenic, motogenic, morphogenic, and anti-apoptotic activities in a wide variety of cells by binding to the c-Met/HGF receptor tyrosine kinase (c-Met). HGF is thus potentially a powerful tool as an organotropic factor for protection and regeneration of a variety of organs, and has an ability to exert the multipotent activities under pathophysiological conditions. In the nervous system, HGF and c-Met are expressed in not only developing brain but also adult mature brain, indicating that HGF-c-Met system plays a functional role in the central nervous system. Indeed, many studies have demonstrated that HGF shows neurotrophic activities in the hippocampal, cerebral cortical, midbrain dopaminergic, motor, sensory, sympathetic, parasympathetic, and cerebellar granule neurons in vitro. In in vivo studies, HGF exerted neuroprotective effects by preventing neuronal cell death in animal models of cerebrovascular diseases including ischemic brain injuries and neurodegenerative diseases including Alzheimers disease, Parkinsons disease, and amyotrophic lateral sclerosis (ALS). These reports suggested that HGF is an effective therapeutic agent for the treatment of various neurological diseases. Keywords: HGF, c-Met, neurotrophic, amyotrophic lateral sclerosis (ALS), spinal cord injury (SCI), hepatocyte growth factor (HGF), nervous system, glial cellline derived neurotrophic factor, angiogenic activity, organotropic factor, neurological diseases

Recombinant hepatocyte growth factor treatment in a canine model of congenital liver hypoplasia

Although the liver has a large regenerative capacity, in many hepatopathies, these repair mechanisms fail. The therapeutic potential of hepatocyte growth factor (HGF) has been proven in numerous toxin-induced liver failure models in rodents, but never in spontaneously occurring liver diseases in larger animal models. The aim of this study was to induce liver growth in a hypoplastic liver by the administration of exogenous recombinant HGF. The natural hypoplastic liver model used is the canine congenital portosystemic shunt (CPSS) characterized by strongly reduced liver growth and function. Recombinant HGF (rHGF), 200 μg/kg, was given twice daily during 3 weeks by an intravenous injection in six dogs with CPSS. Liver volumes were determined by computed tomography before and at 1, 2, 3 and 7 weeks after the initiation of treatment. Portosystemic shunting was evaluated with an ammonia tolerance test and liver portal perfusion was quantified with scintigraphy. Simultaneously, blood parameters for liver function were assayed and liver biopsies were taken for histology, immunohistochemistry and gene-expression measurements. During 3 weeks of HGF treatment, hepatocyte proliferation increased and an increase in liver volume up to 44% was seen, persisting in two dogs up to 4 weeks after the termination of treatment. Ki-67 expression, gene expression of E2F1 and CDC6, phosphorylated-c-MET and phosphorylated-ERK1/2 protein levels confirmed increased hepatocyte proliferation and HGF signalling. The aberrant portal perfusion did not change during treatment. Transient in vivo liver growth is shown using CPPS as a naturally occurring large animal model, indicating the therapeutic potential of HGF in liver disease.

Growth factor modulation of hepatic inflammation: a novel approach to the management of total parenteral nutrition–associated liver disease

Purpose Dependence on total parenteral nutrition in intestinal failure or short bowel syndrome patients can lead to many complications. The most significant complication is progressive liver injury leading to liver failure. This study assesses the potential of hepatocyte growth factor (HGF) in modulating the hepatic response in a rat cholestatic liver injury model. Methods Female Sprague-Dawley rats were divided into 3 groups: control (n = 5), chronic liver injury ( α-naphtylisocyocyanate [ANIT] every 3.5 days at 75 mg/kg; n = 5), and chronic liver injury plus HGF (ANIT + HGF at 250 μg kg −1 d −1; n = 5). The rats initially underwent massive (80%) small bowel resections. Seven days later, they were given intraperitoneal injections of saline (control) or ANIT and implantation of an osmotic minipump for continuous intravenous saline or HGF. Intraperitoneal saline or ANIT injections were subsequently administered every 3.5 days to create a chronic cholestatic model. After 14 days, the animals were euthanized, and liver biopsies were obtained. The liver biopsies were evaluated by histology, immunofluorescence staining for interleukin-6 and tumor necrosis factor α, and assessment of apoptosis by terminal dUTP-transferase-mediated nick end labeling (TUNEL) technique. Results In this chronic liver injury model, HGF did not effect the grade of inflammation. However, HGF did induce retention of the ductal structures and avoided ductal proliferation, damage, and evidence of primary sclerosing cholangitis ( P < .05). Hepatocyte growth factor induced less interleukin-6 ( P < .011) and tumor necrosis factor α ( P < .01) expression. Apoptotic activity was also significantly less in the HGF group ( P < .01). Conclusion Hepatocyte growth factor preserved the hepatic ductal system, modulated the hepatic inflammatory response, and reduced the apoptotic index in this chronic cholestatic liver injury model. It may diminish or prevent liver damage in patients with total parenteral nutrition–induced liver injury.

Chronic vocal fold scar restoration with hepatocyte growth factor hydrogel

Therapeutic challenges exist in the management of vocal fold scarring. We have previously demonstrated the therapeutic potential of hepatocyte growth factor (HGF) in the management of acute phase vocal fold scarring using a novel hydrogel-based HGF drug delivery system (DDS). However, the effect of HGF on matured vocal fold scarring remains unclear. The current study aims to investigate the effect of HGF-DDS on chronic vocal fold scarring using a canine model. Animal model. Vocal folds from eight beagles were unilaterally scarred by stripping the entire layer of the lamina propria; contralateral vocal folds were kept intact as normal controls. Six months after the procedures, hydrogels (0.5 mL) containing 1 microg of HGF were injected into the scarred vocal folds of four dogs (HGF-treated group). Hydrogels containing saline solution were injected into the other four dogs (sham group). Histological and vibratory examinations on excised larynges were completed for each group 9 months after the initial surgery. Experiments conducted on excised larynges demonstrated significantly better vibrations in the HGF-treated group in terms of mucosal wave amplitude. Although phonation threshold pressure was significantly lower in the HGF-treated group compared with the sham group, no significant differences were observed in the normalized glottal gap between HGF-treated and sham groups. Histological examinations of the HGF-treated vocal folds showed reduced collagen deposition and less tissue contraction with favorable restoration of hyaluronic acid. Results suggest that administration of HGF may have therapeutic potential in the treatment of chronic vocal fold scarring.

Hepatocyte growth factor protects auditory hair cells from aminoglycosides

To examine the effect of hepatocyte growth factor (HGF) for protection of auditory hair cells against aminoglycosides and its molecular mechanisms. Experimental study. We quantitatively assessed protective effects of HGF on mouse cochlear hair cells against neomycin toxicity using explant culture systems. To understand mechanisms of hair cell protection by HGF, we examined the expression of c-Met, HGF receptor, and 4-hydroxynonenal (a lipid peroxidation marker) in the cochlea by means of immunohistochemistry and Western blotting. The application of HGF to cochlear explant cultures significantly reduced the hair cell loss induced by neomycin. Immunohistochemistry showed c-Met expression in normal auditory hair cells, and its increase in response to neomycin-induced damage. Immunostaining for 4-hydroxynonenal suggested that HGF acted by attenuating the lipid peroxidation of auditory epithelia induced by neomycin. These findings demonstrate that a functional HGF/c-Met coupling is present in the cochlea, and HGF application exerts protective effects on hair cells, indicating the potential of HGF as a therapeutic agent for sensorineural hearing loss.

Effect of Exogenous Hepatocyte Growth Factor on Vocal Fold Fibroblasts

We have previously demonstrated the therapeutic potential of hepatocyte growth factor (HGF) in the treatment of vocal fold scarring, although how exogenous HGF affects gene expression of endogenous HGF or extracellular matrix components in the vocal fold fibroblasts remains unclear. In this in vitro study, we aimed to clarify this aspect in order to better understand the effects of HGF on the vocal folds. Fibroblasts were obtained from the lamina propria of the vocal folds of 5 Sprague-Dawley rats and were cultured with HGF at concentrations of 100, 10, 1, and 0 ng/mL. The cells were collected on days 1, 3, and 7, and the expression of endogenous HGF, its receptor c-Met, transforming growth factor-beta1 (TGF-beta1), procollagen types I and III, and hyaluronic acid synthase (HAS)-1 and HAS-2 messenger RNAs (mRNAs) was examined by real-time reverse transcription-polymerase chain reaction. The expression of endogenous HGF and HAS-1 mRNAs increased significantly when exogenous HGF was administered at a concentration of 1 ng/mL. On day 1, the expression of TGF-beta1 and HAS-2 mRNAs increased significantly in response to 1 ng/mL HGF. Exogenous HGF triggered the up-regulation of endogenous HGF, TGF-beta1, HAS-1, and HAS-2 mRNAs in vocal fold fibroblasts.

Hepatocyte Growth Factor Exerts Promoting Functions on Murine Dental Papilla Cells

Hepatocyte growth factor (HGF) is a potent mitogenic and angiogenic factor involved in the development of many tissues including the teeth. We previously reported that dental pulp cells express the HGF receptor c-met and that HGF can enhance cell proliferation and differentiation. The purpose of this study was to determine whether HGF could stimulate proliferation and/or differentiation of murine dental papilla cells (MDPCs). MDPCs were isolated from neonatal mice, and the mitogenic potential of HGF on MDPCs was measured by 3-(4, 5-dimethyl-thyazol-2-yl)-2, 5-diphenyltetrazolium and flow cytometry. Differentiation of MDPCs in the presence of HGF was characterized by mineralization assay, alkaline phosphatase (ALP) activity and reverse-transcription polymerase chain reaction. We reported that MDPCs expressed both HGF and c-met and that HGF enhanced proliferation of MDPCs by concentrations ranging from 5 ng/mL to 20 ng/mL, with 10 ng/mL as the optimal concentration (p < 0.05). HGF prolonged S phase and shortened G1 phase of MDPCs, increased ALP activity significantly over the control (p < 0.05), and enhanced the formation of mineral nodules. ALP, dentin sialophosphoprotein, and dentin matrix protein-1 expression were significantly increased in the presence of HGF (p < 0.05), as were the expression of Msx1, Runx2, and Pax9. Our data suggest that HGF plays an important role in tooth development, by promoting the proliferation and differentiation of MDPCs.

Hepatocyte Growth Factor Signaling in Mediating Human Muscle Satellite Cell Activation and Proliferation Following Eccentric Exercise

Eight subjects (20.6 ± 2.1 yr; 81.4 ± 9.8 kg) performed 300 isolateral eccentric contractions (knee extensions at 180 °/s) to evaluate the skeletal muscle satellite cell (SC) response and the potential of hepatocyte growth factor (HGF) signaling in mediating SC activation and proliferation following acute damaging exercise. Muscle biopsies were obtained from the vastus lateralis of the non‐exercised leg prior to exercise (PRE) and the exercised leg at 4 (T4), 24 (T24), 72 (T72), and 120 h (T120) post‐exercise. The number of SC (N‐CAM+) increased (p &lt; 0.001) by T4 and remained elevated at T120 (p = 0.002). Serum HGF increased at T4 (p &lt; 0.05) with a trend for increased muscle HGF and HGF activator (HGFA) protein expression at T24 with active HGF detected in all PRE samples. HGFA inhibitors (HAI‐1 and HAI‐2) protein content increased at T72 and remained elevated at T120 (p &lt; 0.05). Myogenic regulatory factors (MyoD and Myf5) mRNA expression increased at T4 and T24 (p &lt; 0.05) respectively, with increased myogenin mRNA expression at T24 (p &lt; 0.05). Furthermore, plasma interleukin‐6 concentration increased ∼200% (p &lt; 0.05) by T4, illustrating a roll of both local and systemic signaling in the activation and proliferation of SC; with HGF signaling playing an important regulatory role in the SC response to exercise‐induced muscle damage.Supported by NSERC

Reorganization of cytoskeletal proteins and prolonged life expectancy caused by hepatocyte growth factor in a hamster model of late-phase dilated cardiomyopathy

It has been postulated recently that changes in cytoskeletal and sarcolemmal proteins initiate a final common pathway for contractile dysfunction in dilated cardiomyopathy. In ischemic cardiomyopathy, hepatocyte growth factor plays an important role in reorganizing the impaired cytoskeletal proteins in several cell types. We have tested the hypothesis that hepatocyte growth factor might improve life expectancy through modification of the molecular process that contributes to impairment in dilated cardiomyopathy. Adult male 27-week-old BIO TO-2 hamsters, which show moderate cardiac remodeling, were divided into treatment groups that received (1) hemagglutinating virus of Japan liposomes containing human hepatocyte growth factor cDNA (H group), (2) culture medium (C group), or (3) sham operation (S group). After the operation, echocardiography demonstrated that the enlarged left ventricular end-systolic dimension and decreased fractional shortening were significantly attenuated in the H group compared with the C group. There was significantly less myocardial fibrosis in the H group compared with the C group. Immunohistochemical analysis showed alpha-dystroglycan and alpha- and beta-sarcoglycan expression in the basement membrane beneath the cardiomyocytes in the H group, whereas no expression of these proteins was seen in the C group. The 40-week survival was significantly better in the H group than in the C and S groups. An improved survival associated with transient reorganization of the cytoskeletal proteins and reduction in myocardial fibrosis was achieved by hepatocyte growth factor treatment in an adult hamster model of dilated cardiomyopathy. The results suggest a therapeutic potential of hepatocyte growth factor in the treatment of dilated cardiomyopathy.

Keratinocyte expression of transgenic hepatocyte growth factor affects melanocyte development, leading to dermal melanocytosis

Using the epidermis-specific cytokeratin 14 promoter to deliver HGF exclusively from epidermal keratinocytes, we have examined the potential of hepatocyte growth factor (HGF) secreted from the normal environment to control morphogenesis. The transgenic mice displayed a significant increase of the number of melanocytes and their precursors in embryos starting not later than 16.5 dpc, and then after birth an explosive increase of dermal melanocytes started within 1 week, and these melanocytes were maintained throughout the entire life of the mice. Thus, HGF acts as a paracrine agent to promote survival, proliferation and differentiation of melanocyte precursors in vivo, and eventually causes melanocytosis. Loss of E-cadherin expression in dermal melanocyte precursors suggests that HGF caused dermal localization of melanocytes and their precursors by down-regulation of E-cadherin molecules.