Use Of Hepatocyte Growth Factor Research Articles

The effect of hepatocyte growth factor on intestinal adaption in an experimental model of short bowel syndrome

Nowadays, the standard therapy for patients with short bowel syndrome is parenteral nutrition (PN). Various growth factors have been tested to achieve weaning from prolonged PN administration. We evaluated the effectof hepatocyte growth factor (HGF) on structural intestinal adaptation and cell proliferation in a rat model of SBS. Thirty Sprague-Dawley rats were divided into three groups; group A rats (sham) underwent bowel transection, group B rats underwent a 75% bowel resection, and group C rats underwent the same procedure but were treated postoperatively with HGF. Histopathologic parameters of intestinal adaptation were determined, while microarray and rt-PCR analyses of ileal RNA were also performed. Treatment with HGF resulted in significant increase in body weight, while the jejunal and ileal villus height and crypt depth were increased in HGF rats (36%, p < 0.05 and 27%, p < 0.05 respectively).Enterocyte proliferation was also significantly increased in HGF rats (21% p < 0.05). Microarray and quantitative rt-PCR analyses showed that the genes hgfac, rac 1, cdc42, and akt 1 were more than twofold up-regulated after HGF treatment. HGF emerges as a growth factor that enhances intestinal adaptation. The future use of HGF may potentially reduce the requirement for PN in SBS patients.

Human Growth Factor/Immunoglobulin Complexes for Treatment of Myocardial Ischemia-Reperfusion Injury.

Hepatocyte Growth Factor (HGF) and Fibroblast Growth Factor 2 (FGF2) are receptor tyrosine kinase agonists that promote cell survival after tissue injury and angiogenesis, cell proliferation and migration during tissue repair and regeneration. Both ligands have potential as systemic treatments for ischemia-reperfusion injury, however clinical use of HGF and FGF2 has been limited by poor pharmacokinetic profiles, i.e., their susceptibility to serum proteases, rapid clearance and short half-lives. Previously, we reported vaso- and cardioprotective protein complexes formed between HGF and polyclonal, non-specific immunoglobulin (IgG) with therapeutic efficacy in a rat model of myocardial ischemia with reperfusion (MI/R). Here, using a pre-clinical porcine MI/R model, we demonstrate human HGF/IgG complexes provide significant myocardial salvage, reduce infarct size, and are detectable in myocardial tissue 24 h after intracoronary injection. Furthermore, we show that multiple daily infusions of HGF/IgG complexes after MI do not lead to production of HGF-specific auto-antibodies, an important concern for administered biologic drugs. In experiments to identify other growth factors that non-covalently interact with IgG, we found that human FGF2 associates with IgG. Similar to human HGF/IgG complexes, FGF2/IgG complexes protected primary human cardiac endothelial cells under simulated ischemia (1% oxygen and nutrient deprivation) for 48–72 h. Molecular modeling studies suggested that FGF2 and HGF both interact with the Fc domain of IgG. Also, we tested whether an Fc-fusion protein would bind FGF2 to form complexes. By native gel electrophoretic assays and biochemical pulldowns, we found that Jagged1, a Notch1 ligand that controls stem cell self-renewal and tissue regeneration, bound FGF2 when presented as a Jagged1- Fc fusion protein. Our results suggest that human growth factor/IgG and FGF2/Fc- fusion complexes have potential to provide a biologics platform to treat myocardial ischemia-reperfusion and other forms of tissue injury.

Growth factor-eluting hydrogels for management of corneal defects

With 1.5–2.0 million new cases annually worldwide, corneal injury represents a common cause of vision loss, often from irreversible scarring due to surface corneal defects. In this study, we assessed the use of hepatocyte growth factor (HGF) loaded into an in situ photopolymerizable transparent gelatin-based hydrogel for the management of corneal defects. In vitro release kinetics showed that, in regard to the total amount of HGF released over a month, 55 ± 11% was released during the first 24 h, followed by a slow release profile for up to one month. The effect of HGF was assessed using an ex vivo model of pig corneal defect. After three days of organ culture, epithelial defects were found to be completely healed for 89% of the corneas treated with HGF, compared to only 11% of the corneas that had fully re-epithelialized when treated with the hydrogel without HGF. The thickness of the epithelial layer was found to be significantly higher for the HGF-treated group compared to the group treated with hydrogel without HGF (p = 0.0012). Finally, histological and immunostaining assessments demonstrated a better stratification and adhesion of the epithelial layer in the presence of HGF. These results suggest that the HGF-loaded hydrogel system represents a promising solution for the treatment of persistent corneal defects at risk of scarring.

Hepatocyte growth factor mediates a novel form of hepatic stem/progenitor cell-induced tolerance in a rat xenogeneic liver rejection model

We have previously identified novel neural/glial antigen 2-expressing hepatic stem/progenitor cells (NG2+ HSPs) that are beneficial for tissue repair by inhibiting the immune cell response. In this in vivo study, we investigated the use of hepatocyte growth factor (HGF)-secreting NG2+ HSPs as a tolerogen in the well-established Syrian golden hamster (SGH) to Lewis (LEW) xenogeneic rat acute liver rejection (ARJ) model. Liver and blood cells were collected for histology and functional analyses using immunofluorescence staining, western blot, ELISA, and TUNEL assays. All recipient rats were randomly divided into 5 groups (n = 14 rats/group) and treated with: (1) ARJ + PBS: (2) ARJ + NG2: tail vein injection of NG2+ HSPs; (3) ARJ + tacrolimus (FK506, oral administration); (4) ARJ + an anti-cMet functional blocking antibody (a-cMet-Ab, I.V) 24 h before the injection of NG2+ HSPs; (5) ARJ + cHGF (clinically used HGF). LEW to LEW syngeneic rats were considered “normal” (n = 14, namely Syn). Significantly prolonged mean survival times (MSTs) and improved graft functions were observed after NG2+ HSP transplantation. An anti-cMet Ab significantly blocked the effect of NG2+ HSPs, suggesting that the effects were likely associated with HGF secreted from NG2+ HSPs. Notably, when intravenously injected into the xenogeneic rat model, the injected cHGF not only prolonged the MST of recipient rats but also increased the number of TUNEL-expressing xenoreactive cytotoxic T lymphocytes (CD8+ T cells). Based on these results, HGF-secreting NG2+ HSPs may specifically target recipient CD8+ T cells by inducing their apoptosis.

Progress on Mechanism of MET Gene Mutation and Targeted Drugs in Non-small Cell Lung Cancer

间质-上皮细胞转化因子（mesenchymal-epithelial transition factor, MET）基因是非小细胞肺癌（non-small cell lung cancer, NSCLC）的一种重要肿瘤驱动基因，针对MET 14外显子的跳跃突变的靶向治疗药物给患者带来新的希望。目前已经上市或者即将上市的MET抑制剂包括：克唑替尼、卡博替尼、沃利替尼和Tepotinib等。MET抑制剂的客观缓解率较高，并且安全性良好。但是，MET抑制剂的耐药不可避免，因此需要重视对于耐药机制的研究。肝细胞生长因子（hepatocyte growth factor, HGF）/MET信号通路抑制剂与其他药物的联合应用，对于抑制和逆转耐药可能发挥重要作用。

Hepatocyte Growth Factor Regulates Macrophage Transition to the M2 Phenotype and Promotes Murine Skeletal Muscle Regeneration

Hepatocyte growth factor (HGF) is well known for its role in the migration of embryonic muscle progenitors and the activation of adult muscle stem cells, yet its functions during the adult muscle regeneration process remain to be elucidated. In this study, we showed that HGF/c-met signaling was activated during muscle regeneration, and that among various infiltrated cells, the macrophage is the major cell type affected by HGF. Pharmacological inhibition of the c-met receptor by PHA-665752 increased the expression levels of pro-inflammatory (M1) macrophage markers such as IL-1β and iNOS while lowering those of pro-regenerative (M2) macrophage markers like IL-10 and TGF-β, resulting in compromised muscle repair. In Raw 264.7 cells, HGF decreased the RNA level of LPS-induced TNF-α, IL-1β, and iNOS while enhancing that of IL-10. HGF was also shown to increase the phosphorylation of AMPKα through CaMKKβ, thereby overcoming the effects of the LPS-induced deactivation of AMPKα. Transfection with specific siRNA to AMPKα diminished the effects of HGF on the LPS-induced gene expressions of M1 and M2 markers. Exogenous delivery of HGF through intramuscular injection of the HGF-expressing plasmid vector promoted the transition to M2 macrophage and facilitated muscle regeneration. Taken together, our findings suggested that HGF/c-met might play an important role in the transition of the macrophage during muscle repair, indicating the potential use of HGF as a basis for developing therapeutics for muscle degenerative diseases.

The Effect of Hepatocyte Growth Factor on Intestinal Adaption in an Experimental Model of Short Bowel Syndrome

Introduction Short bowel syndrome (SBS) is a relatively uncommon syndrome which is defined as the functional loss of the 75% of normal short bowel length at least. To date, the standard therapy is the administration of total parenteral nutrition (TPN). However, long-term complications in patients with protracted PN are occurred. Intestinal transplantation is a potentially life-saving treatment for patients with severe SBS; its increased morbidity and mortality rates imply a careful preoperative consideration though. Moreover, the lack of compatible donor organs may delay significantly the transplantation. As a result, alternative therapies, like the administration of growth factors, in order to enhance intestinal adaptation acting as a bridge to transplantation have been emerged. The purpose of the present study is to evaluate the effect of hepatocyte growth factor (HGF) on structural intestinal adaptation, cell proliferation and apoptosis in a rat model of short bowel syndrome (SBS). Materials and Methods Thirty Sprague-Dawley female rats were divided into three groups, sham rats underwent bowel transection (group A); SBS rats underwent a 75% bowel resection (group B); and SBS/HGF rats underwent bowel resection and were treated with HGF (75 μg/kg/d) (group C) starting at fourth postoperative day. All rats were sacrificed at 15th postoperative day. Parameters of intestinal adaptation (body weight, villus height and crypt depth in jejunum and ileum), enterocyte proliferation and enterocyte apoptosis were determined. A microarray analysis of RNA extracted from ileal samples was also carried out. Statistical analysis was performed using ANOVA test, with P<0.05 considered statistically significant. Results Treatment with HGF (group C rats) resulted in significant increase in body weight compared to SBS rats (group B). The histopathologic analysis showed that jejunal and ileal villus height and crypt depth were significantly increased in HGF/SBS rats compared to SBS rats (36%, P<0.05 and 27%, P<0.05 respectively), showing that treatment with HGF enhanced the intestinal adaptation making intestinal absorption more efficient. Enterocyte proliferation was also significantly increased in HGF rats (21% P<0.05) compared to SBS rats; however we did not found any significant differences in enterocyte apoptosis rate between HGF/SBS and SBS rats. These findings indicate the augmentation of intestinal hyperplasia through HGF therapy. Microarray analysis of 22 genes showed that 12 genes were significantly up-regulated, and four genes were down-regulated in HGF/SBS rats compared to SBS rats; of note, some of these genes are involved in enterocyte proliferation/apoptosis pathway, indicating also that HGF therapy induces cell proliferation. Conclusion HGF emerges as a growth factor that enhances intestinal adaptation in patients with short bowel syndrome. A future use of HGF may facilitate the prolonged TPN therapy while patients wait for intestinal transplantation.

Hepatocyte Growth Factor Reduces Hypertrophy of Skin Scar

Excessive collagen deposition causes hypertrophic scarring after dermal wound repair. It can be functionally and cosmetically debilitating to many patients. A direct approach to the control of scar tissue formation is pharmacological regulation of collagen synthesis and deposition. Some studies reported that hepatocyte growth factor (HGF) plays an important role in scar formation. Hepatocyte growth factor can improve tissue fibrosis and reverse the imbalance of collagen metabolism. However, an in vivo study has not been reported concerning the use of HGF in controlling hypertrophy of skin scar until now. The authors tested the ability of HGF to reduce hypertrophic scar formation in a rabbit ear model. After the placement of three 5-mm dermal wounds on each ear, New Zealand white rabbits received HGF subcutaneously in the left ear at 4 time points on postwounding days 15, 30, 45, and 90. The left ear of each animal served as a control without HGF treatment. Scars were harvested at postoperative 6 months and scar hypertrophy quantified by measurement of the scar elevation index. The experimental data showed that treatment of scars with HGF decreased scar formation. The HGF treatment resulted in a statistically significant reduction in the scar elevation index (P < .01). The authors' results indicate the potential use of HGF to treat hypertrophic scarring, which shows important significance for antiscarring therapy.

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

BackgroundSegmental bone defect repair remains a clinical and scientific challenge with increasing interest focused on bone tissue engineering. Clinical studies are ongoing to address application of hepatocyte growth factor (HGF) for treatment of some diseases; however, the use of HGF in bone tissue engineering has not been addressed. This study was performed to evaluate the effect of HGF in a complex of β-tricalcium phosphate (β-TCP) and collagen in repairing segmental bone defects. MethodsSegmental bone defects 5mm long were created in the middle of the tibial shafts of rabbits. The defect was stabilized with external fixators and implanted with a complex of β-TCP granules and collagen, with or without 100μg recombinant human HGF. Biweekly, bone regeneration and β-TCP resorption were assessed radiographically and histologically. At 4 and 8weeks, bone regeneration was evaluated by use of micro-computed tomography and mechanical tests. ResultsCompared with the bone tissue treated with β-TCP and collagen, mineralization, angiogenesis, new bone formation, and absorption of β-TCP were promoted 4weeks postoperatively by treatment with HGF in the β-TCP and collagen group. These changes were associated with promoting biomechanical regeneration. By 8weeks, the formation of bone marrow in newly generated bone and absorption of the β-TCP granules were completed in a shorter period by combining HGF with β-TCP and collagen, compared with tissues without HGF. ConclusionsThe combined application of HGF in a β-TCP and collagen matrix promoted histological bone healing and augmented mechanical strength of the healing bone, particularly in the early stages. The combined use of HGF and β-TCP for treatment of bone defects made a substantial difference.

Claudin-5 is involved in breast cancer cell motility through the N-WASP and ROCK signalling pathways

BackgroundRecent studies have shown dysregulation in TJ structure of several cancers including breast. Claudin-5 is a protein member of the TJ structure expressed in both endothelial and epithelial cells. This study examined the level of expression and distribution of Claudin-5 in human breast cancer tissues and the effect of knockdown and forced expression of Claudin-5 in the MDA-MB-231 breast cancer cell line.MethodsImmunohistochemistry and quantitative-PCR were used to analyse patient tissue samples. The Claudin-5 gene was cloned and overexpressed or knocked down using ribozyme technology in human breast cancer cells. Changes in function were assessed using in vitro assays for invasion, growth, adhesion, wounding, motility, transepithelial resistance and electric cell-substrate impedance sensing. Changes in cell behaviour were achieved through the use of Hepatocyte Growth factor (HGF) which we have shown to affect TJ function and expression of TJ proteins. In addition, an in vivo model was used for tumour growth assays. Results data was analyzed using a Students two sample t-test and by Two-way Anova test when the data was found to be normalized and have equal variances. In all cases 95% confidence intervals were used.ResultsPatients whose tumours expressed high levels of Claudin-5 had shorter survival than those with low levels (p = 0.004). Investigating in vitro the effect of altering levels of expression of Claudin-5 in MDA-MB-231cells revealed that the insertion of Claudin-5 gene resulted in significantly more motile cells (p < 0.005). Low levels of Claudin-5 resulted in a decrease in adhesion to matrix (p < 0.001). Furthermore, a possible link between Claudin-5 and N-WASP, and Claudin-5 and ROCK was demonstrated when interactions between these proteins were seen in the cells. Moreover, followed by treatment of N-WASP inhibitor (Wiskostatin) and ROCK inhibitor (Y-27632) cell motility was assessed in response to the inhibitors. Results showed that the knockdown of Claudin-5 in MDA-MB-231 masked their response after treatment with N-WASP inhibitor; however treatment with ROCK inhibitor did not reveal any differences in motility in this cell line.ConclusionsThis study portrays a very new and interesting role for Claudin-5 in cell motility involving the N-WASP signalling cascade indicating a possible role for Claudin-5 in the metastasis of human breast cancer.

Novel therapy for myocardial infarction: can HGF/Met be beneficial?

Myocardial infarction (MI) is a leading cause of hospitalization worldwide. A recently developed strategy to improve the management of MI is based on the use of growth factors which are able to enhance the intrinsic capacity of the heart to repair itself or regenerate after damage. Among others, hepatocyte growth factor (HGF) has been proposed as a modulator of cardiac repair of damage due to the pleiotropic effects elicited by Met receptor stimulation. In this review we describe the mechanistic basis for autocrine and paracrine protection of HGF in the injured heart. We also analyse the role of HGF/Met in stem cell maintenance and in stem cell therapies for MI. Finally, we summarize the most significant results on the use of HGF in experimental models of heart injury and discuss the potential of the molecule for treating ischaemic heart disease in humans.

137P In vitro differentiation of human umbilical vein mesenchymal stem cells into hepatocyte-like cells

Human umbilical vein, as a readily available source of stem cells, is one of the good alternative source for mesenchymal stem cells. Human umbilical cord vein mesenchymal stem cells (UVMSCs) have been recently isolated and demonstrated the ability to differentiate into various cell types such as fat, bone, cartilage and neuronal cells. In this study, we have investigated whether human UVMSC are also able to differentiate into hepatocyte-like cells. Hepatic differentiation was done with a 2-step protocol and with the use of hepatocyte growth factor and oncostatin M. The cells were cultured with hepatocyte growth factor (HGF) and oncostatin M (OSM). During 4 weeks of induction most of the cells displayed a cuboidal morphology. Immunological analysis indicated that UVMSCs-derived hepatocyte-like cells expressed liver-specific protein markers such as albumin (ALB) and cytokeratin-18 (CK-18). The hepatocyte-like cells also displayed several characteristics of hepatocytes, including expression of transthyretin, glucose-6-phosphatase (G6P), cytokeratin-8,18 (CK-8,18), alpha-fetoprotein (AFP), hepatocyte nuclear factor-3β (AFP) and ALB. The result of indocyanine green (ICG) cell uptake as a test substance to evaluate hepatocyte-like cells function was positive for differentiated cells. Glycogen storage was examined by periodic acid–Schiff (PAS) staining and accumulation of intracellular glycogen were detected in hepatocyte-like cells. Based on these observations it can be concluded that UVMSCs encompass suitable hepatogenic potential which may provide a source of stem cells for cell therapy in liver diseases.

Effects of extracellular matrixes and growth factors on the hepatic differentiation of human embryonic stem cells

Hepatocytes derived from human embryonic stem cells (hESCs) are a potential cell source for regenerative medicine. However, the definitive factors that are responsible for hepatic differentiation of hESCs remain unclear. We aimed to evaluate the effects of various extracellular matrixes and growth factors on endodermal differentiation and to optimize the culture conditions to induce hepatic differentiation of hESCs. The transgene vector that contained enhanced green fluorescent protein (EGFP) under the control of human alpha-fetoprotein (AFP) enhancer/promoter was transfected into hESC lines. The transgenic hESCs were cultured on extracellular matrixes (collagen type I, laminin, and Matrigel) in the presence or absence of growth factors including hepatocyte growth factor (HGF), bone morphogenetic protein 4, fibroblast growth factor 4, all-trans-retinoic acid, and activin A. The expression of AFP-EGFP was measured by flow cytometry. The culture on Matrigel-coated dishes with 100 ng/ml activin A showed 19.5% of EGFP-positive proportions. Moreover, the sequential addition of 100 ng/ml activin A and 20 ng/ml HGF resulted in 21.7% and produced a higher yield of EGFP-positive cells than the group stimulated by activin A alone. RT-PCR and immunocytochemical staining revealed these EGFP-positive cells to differentiate into mesendoderm-like cells by use of activin A and then into hepatic endoderm cells by use of HGF. Two other hESC lines also differentiated into endoderm on the hepatic lineage by our method. In conclusion, we therefore found this protocol to effectively differentiate multiple hESC lines to early hepatocytes using activin A and HGF on Matrigel.

Branched-chain amino acids, hepatocyte growth factor and protein production in the liver

Although the functions associated with differentiation are thought to be suppressed when cells proliferate, recent studies have shown that several mitogens can stimulate functions such as protein production under certain physiological conditions. Hepatocyte growth factor (HGF) is now considered to be a pluripotent factor and has been shown to stimulate the differentiated functions of hepatocytes, as well as their proliferation. The use of HGF for the treatment of liver disease, especially hepatic failure, has been suggested. Because patients with decompensated liver cirrhosis have decreased plasma concentrations of branched-chain amino acids (BCAAs), many investigations in laboratory animals and patients have been designed to demonstrate the benefits of supplementation of BCAAs on the hepatic metabolism of proteins. However, the mechanisms involved in the specific actions of BCAAs remain to be elucidated. Amino acids are molecules that modulate numerous cellular functions. BCAAs are known to influence gene expression, cellular metabolism, amino acid transport, and protein turnover. In this paper, we show the potential of BCAAs for stimulating HGF synthesis in the liver and discuss the possibility that BCAAs stimulate protein production by hepatocytes through the induction of HGF.

Hepatocyte growth factor attenuates cerebral ischemia-induced learning dysfunction

Hepatocyte growth factor (HGF) acts as an organotropic factor for regeneration and protection in various organs and has the ability to attenuate cerebral ischemia-induced cell death. However, the effect of HGF on learning and memory function after a cerebral ischemic event is unknown. We demonstrate here that administration of human recombinant HGF (hrHGF) into the ventricle reduced the prolongation of the escape latency in the acquisition and retention tests in the water maze task on days 12–28 after microsphere embolism-induced cerebral ischemia. In addition, disruption of the blood–brain barrier at the early stage after microsphere embolism, which was determined by FITC–albumin leakage, was markedly reduced by treatment with hrHGF. We demonstrated that this effect of hrHGF on the blood–brain barrier was associated with protection against the apoptotic death of the cerebral endothelial cells at the early stage after the ischemia. These results suggest that hrHGF can prevent the learning and memory dysfunction soon after sustained cerebral ischemia by protecting against injury to the endothelial cells. The use of HGF may be a potent strategy for the treatment of cerebrovascular diseases, including cerebral infarct and vascular dementia.

In vitro hepatic differentiation of human mesenchymal stem cells

This study examined whether mesenchymal stem cells (MSCs), which are stem cells originated from embryonic mesoderm, are able to differentiate into functional hepatocyte-like cells in vitro. MSCs were isolated from human bone marrow and umbilical cord blood, and the surface phenotype and the mesodermal multilineage differentiation potentials of these cells were characterized and tested. To effectively induce hepatic differentiation, we designed a novel 2-step protocol with the use of hepatocyte growth factor and oncostatin M. After 4 weeks of induction, cuboidal morphology, which is characteristic of hepatocytes, was observed, and cells also expressed marker genes specific of liver cells in a time-dependent manner. Differentiated cells further demonstrated in vitro functions characteristic of liver cells, including albumin production, glycogen storage, urea secretion, uptake of low-density lipoprotein, and phenobarbital-inducible cytochrome P450 activity. In conclusion, human MSCs from different sources are able to differentiate into functional hepatocyte-like cells and, hence, may serve as a cell source for tissue engineering and cell therapy of hepatic tissues. Furthermore, the broad differentiation potential of MSCs indicates that a revision of the definition may be required.

Morphological and functional changes of human vocal fold fibroblasts with hepatocyte growth factor.

Fibroblasts produce extracellular matrix and play an important role in wound healing and scarring. Hepatocyte growth factor (HGF) has strong antifibrotic activity, and has been suggested to have therapeutic potential for treatment of fibrotic diseases. In the present in vitro study, morphological and functional changes of human vocal fold fibroblasts with HGF were examined by transmission electron microscopy and enzyme-linked immunosorbent assay to help clarify the potential use of HGF in the prevention or treatment of vocal fold scarring. The HGF stimulated the production of hyaluronic acid (HA) and decreased the production of collagen type I from the fibroblasts in Reinke's space (FbRS), whereas fibronectin production was not affected. The HGF also changed the shape of the FbRS from an oval shape toward a spindle and stellate shape, and developed Golgi apparatus (GA) and rough endoplasmic reticulum (rER) in the FbRS. The fibroblasts in the macula flava (FbMF) presented with much more production of HA and collagen type I than did FbRS, and were more frequently formed in a stellate shape with well-developed GA and rER. The HGF decreased the production of collagen type I from the FbMF, but barely affected the FbMF in terms of the shape of the cells, the development of GA and rER, or the production of HA. These results were interpreted to suggest that the FbMF are not as susceptible to HGF as are FbRS. On the contrary, HGF appeared to activate the FbRS and modify the function. The increased HA and decreased collagen type I production from the FbRS suggest that HGF may be useful in the prevention or treatment of fibrotic vocal fold scarring.

Gene therapy of ischemic-damaged kidney in the rat using hepatocyte growth factor gene

IMMUNOSUPPRESSIVE reagents are generally the only therapy available to prevent rejection after renal transplantation. No effective drug for chronic rejection has been established. Hepatocyte growth factor (HGF) is a multifunctional cytokine that induces the regeneration of damaged kidneys, and we first used it for the treatment of tacrolimus-induced nephrotoxicity. Recently, we reported the successful use of HGF for the treatment of chronic rejection after renal transplantation. In that study, recombinant HGF was injected intravenously daily for 4 weeks (100 mg/d) into rats with a renal allograft; all of the treated animals survived, whereas 54.2% of the rats in the control group died within 32 weeks. This experiment proved that cytokine can reduce chronic rejection, suggesting ischemic damage is at least the main part of the phenomena. The problem for the clinical use of this therapy is that a tremendous amount of HGF and frequent injections are required because HGF is metabolized very quickly by the liver. To overcome such limitations, gene therapy with the HGF gene was used successfully in the treatment of liver cirrhosis using a hemagglutinating virus of Japan (HVJ) liposome. This study was designed to develop a basic technique of renal gene therapy in which a single injection of the HGF gene makes a low, but continuous intravenous level of HGF, using an ischemic kidney model.

Hepatocyte growth factor: clinical implications in hepatobiliary pancreatic surgery.

Hepatocyte growth factor (HGF), originally identified as the most potent mitogen for hepatocytes, is now known to be a cytokine with numerous functions in a wide variety of cells. HGF transduces its various activities via a receptor encoded by the c-met proto-oncogene and coupled to a number of transducers integrating the HGF signal inside the target cells. Extcnsive investigation has revealed that HGF has various beneficial effects, especially for liver. HGF significantly stimulates regeneration in damaged, as well as in normal liver, ameliorates hepatic fibrosis/cirrhosis; and attenuates various types of liver dysfunction in animals. Moreover, the fascinating data on HGF in experimental liver and islet transplantation suggest that the use of HGF may represent a breakthrough for reducing the shortage of donor livers, and increasing the success rate of insulin independence after islet transplantation. Further understanding of the biological significance of HGF, including that in carcinogenesis, will undoubtedly have important clinical implications in hepatobiliary pancreatic surgery.

先端医療とＤＤＳ 再生因子ＨＧＦの臨床応用

Hepatocyte growth factor (HGF) was discoverd and cloned as a hepatotropic factor in our laboratory. HGF is now recognized to play an essential role in tissue repair and organ protection during progression of parenchymal injuries. In the recent 10 years, we have demonstrated that HGF is useful as a therapeutic agent in several organ failures, using animal models. For example, HGF prevents onset of acute organ failure, such as fulminant hepatitis, acute renal failure and myocardial infarction. Furthermore, HGF accelerates tissue repair and stimulates recovery from the organ dysfunctions as a tissue repair factor. Of importance, HGF could improve pathophysiological conditions in chronic fibrotic clisorders (including liver cirrhosis, chronic renal failure, cardiomyopathy and so on), accompanied with parenchymal regeneration and reduction in interstitial fibrosis. Based on the experimental backgrounds, HGF gene therapy has been initiated in Japan, focusing on ASO patients. We discuss herein a possible clinical use of HGF as a self-repair therapy for several injured organs.