Suppression of lipopolysaccharide-induced corneal opacity by hepatocyte growth factor

Keratitis induced by bacterial toxins, including lipopolysaccharide (LPS), is a major cause of corneal opacity and vision loss. Our previous study demonstrates hepatocyte growth factor (HGF) promotes epithelial wound healing following mechanical corneal injury. Here, we investigated whether HGF has the capacity to suppress infectious inflammatory corneal opacity using a new model of LPS-induced keratitis. Keratitis, induced by two intrastromal injections of LPS on day 1 and 4 in C57BL/6 mice, resulted in significant corneal opacity for up to day 10. Following keratitis induction, corneas were topically treated with 0.1% HGF or PBS thrice daily for 5 days. HGF-treated mice showed a significantly smaller area of corneal opacity compared to PBS-treated mice, thus improving corneal transparency. Moreover, HGF treatment resulted in suppression of α-SMA expression, compared to PBS treatment. HGF-treated corneas showed normalized corneal structure and reduced expression of pro-inflammatory cytokine, demonstrating that HGF restores corneal architecture and immune quiescence in corneas with LPS-induced keratitis. These findings offer novel insight into the potential application of HGF-based therapies for the prevention and treatment of infection-induced corneal opacity.

Prognostic value of hepatocyte growth factor for muscle-invasive bladder cancer

Purpose The HGF/MET pathway is involved in cell motility, angiogenesis, proliferation, and cancer invasion. We assessed the clinical utility of plasma HGF level as a prognostic biomarker in patients with MIBC. Methods We retrospectively analyzed 565 patients with MIBC who underwent radical cystectomy. Logistic regression and Cox regression models were used, and predictive accuracies were estimated using the area under the curve and concordance index. To estimate the clinical utility of HGF, DCA and MCID were applied. Results Plasma HGF level was significantly higher in patients with advanced pathologic stage and LN metastasis (p = 0.01 and p < 0.001, respectively). Higher HGF levels were associated with an increased risk of harboring LN metastasis and non-organ-confined disease (OR1.21, 95%CI 1.12–1.32, p < 0.001, and OR1.35, 95%CI 1.23–1.48, p < 0.001, respectively) on multivariable analyses; the addition of HGF improved the predictive accuracies of a standard preoperative model (+ 7%, p < 0.001 and + 8%, p < 0.001, respectively). According to the DCA and MCID, half of the patients had a net benefit by including HGF, but the absolute magnitude remained limited. In pre- and postoperative predictive models, a higher HGF level was significant prognosticator of worse RFS, OS, and CSS; in the preoperative model, the addition of HGF improved accuracies by 6% and 5% for RFS and CSS, respectively. Conclusion Preoperative HGF identified MIBC patients who harbored features of clinically and biologically aggressive disease. Plasma HGF could serve, as part of a panel, as a biomarker to aid in preoperative treatment planning regarding intensity of treatment in patients with clinical MIBC.

Reprogramming the spleen into a functioning ‘liver’ in vivo

ObjectiveLiver regeneration remains one of the biggest clinical challenges. Here, we aim to transform the spleen into a liver-like organ via directly reprogramming the splenic fibroblasts into hepatocytes in vivo.DesignIn the mouse spleen, the number of fibroblasts was through silica particles (SiO2) stimulation, the expanded fibroblasts were converted to hepatocytes (iHeps) by lentiviral transfection of three key transcriptional factors (Foxa3, Gata4 and Hnf1a), and the iHeps were further expanded with tumour necrosis factor-α (TNF-α) and lentivirus-mediated expression of epidermal growth factor (EGF) and hepatocyte growth factor (HGF).ResultsSiO2 stimulation tripled the number of activated fibroblasts. Foxa3, Gata4 and Hnf1a converted SiO2-remodelled spleen fibroblasts into 2×106 functional iHeps in one spleen. TNF-α protein and lentivirus-mediated expression of EGF and HGF further enabled the total hepatocytes to expand to 8×106 per spleen. iHeps possessed hepatic functions—such as glycogen storage, lipid accumulation and drug metabolism—and performed fundamental liver functions to improve the survival rate of mice with 90% hepatectomy.ConclusionDirect conversion of the spleen into a liver-like organ, without cell or tissue transplantation, establishes fundamental hepatic functions in mice, suggesting its potential value for the treatment of end-stage liver diseases.

Favorable Cardiovascular Health Is Associated With Lower Hepatocyte Growth Factor Levels in the Multi-Ethnic Study of Atherosclerosis

Introduction: Hepatocyte growth factor (HGF) is a cytokine released in response to endothelial injury and a potential biomarker of cardiovascular disease (CVD) risk. We examined the association between cardiovascular health (CVH) and HGF in a multi-ethnic cohort of adults free from CVD at baseline.Methods: This cross-sectional study conducted between 2020 and 2021 used MESA baseline examination data (2000–2002) from 6,490 US adults aged 45–84 years. The independent variable was CVH measured by the CVH score and number of ideal metrics. The score was derived from seven metrics: smoking, body mass index, physical activity, diet, total cholesterol, blood pressure and blood glucose. Each metric was scored 0 points (poor), 1 point (intermediate) and 2 points (ideal). The total CVH score ranged from 0 to 14. An inadequate score was 0–8, average, 9–10 and optimal, 11–14. The dependent variable was logarithmically transformed HGF. We used regression analyses to estimate associations between CVH and HGF adjusting for sociodemographic factors.Results: Participants' mean (SD) age was 62 (10) years. Fifty-three percent were female. A one-unit increment in the CVH score was significantly associated with 3% lower HGF levels. Average and optimal CVH scores were significantly associated with 8% and 12% lower HGF levels, respectively, compared to inadequate scores. Additionally, a greater number of ideal metrics was associated with lower HGF levels.Conclusion: Favorable CVH was significantly associated with lower HGF levels in this ethnically diverse cohort. Interventions aimed at promoting and preserving favorable CVH may reduce the risk of endothelial injury as indicated by lower serum HGF levels.

Analysis of Soluble Mesenchymal-Epithelial Transition Factor and Hepatocyte Growth Factor Serum Levels in Children With Autism Spectrum Disorder

Background: Hepatocyte Growth Factor (HGF) and its receptor, Mesothelial-Epithelial Transition (cMet) factor signaling, play an essential role in controlling synaptogenesis. Objectives: Because of the vital role of HGF and Met signaling in synaptogenesis and spatial learning function of the brain’s hippocampal region, we aimed to study the HGF and soluble cMet (s-cMet) serum levels in children with different stages of Autism Spectrum Disorders (ASD). Materials & Methods: A total of 189 ASD patients (mild; n=69, moderate; n=63 and severe; n=57) and 82 control were enrolled in this project. Blood samples were collected from ASD patients referred to Pediatric Neurology Clinic, 17 Shahrivar Hospital, Rasht City, Iran, and serum concentrations of s-cMet and HGF were measured by ELISA. The control children with no clinical characteristics of ASD attended routine blood tests. Results: HGF Mean±SD serum concentration in ASD patients was 239±52.02 pg/mL compared to controls which was 360.04±71.15 pg/mL (P=0.004). Also, the Mean±SD serum concentrations of HGF in mild, moderate, and severe ASD patients were 297.54±69.82, 232.81±56.41, and 189±33.25 ng/mL, respectively, compared to control, which was 360.18±57.40. Besides, the s-cMet Mean±SD serum concentrations in ASD and controls were 143.54±32.50 and 200.25±31.16 pg/mL, respectively (P=0.005). The Mean±SD serum concentrations of s-cMet in the mild, moderate, and severe ASD patients were 172.81±37.69, 129.81±45.55, and 85.18±22.95 ng/mL, respectively, as compared to the control, which was 214.54±34.17 ng/mL. Conclusion: Serum HGF and s-cMet concentration decreased in ASD patients corresponding to disease severity. Also, detecting serum HGF and s-cMet may help classify ASD.

Hepatocyte Growth Factor-Dependent Antiviral Activity of Activated cdc42-Associated Kinase 1 Against Hepatitis B Virus

Activated cdc42-associated kinase 1 (ACK1) is a well-known non-receptor tyrosine kinase that regulates cell proliferation and growth through activation of cellular signaling pathways, including mitogen-activated protein kinase (MAPK). However, the anti-HBV activity of ACK1 has not been elucidated. This study aimed to investigate the role of ACK1 in the HBV life cycle and the mechanism underlying the anti-HBV activity of ACK1. To examine the antiviral activity of ACK1, we established HepG2-ACK1 cells stably overexpressing ACK1. The HBV life cycle, including HBeAg/HBsAg secretion, HBV DNA/transcription, and enhancer activity, was analyzed in HepG2 and HepG2-ACK1 cells with HBV replication-competent HBV 1.2mer (HBV 1.2). Finally, the anti-HBV activity of ACK1 was examined in an HBV infection system. ACK1 suppressed HBV gene expression and transcription in HepG2 and HepG2-ACK1 cells. Furthermore, ACK1 inhibited HBV replication by decreasing viral enhancer activity. ACK1 exhibited its anti-HBV activity via activation of Erk1/2, which consequently downregulated the expression of HNF4α binding to HBV enhancers. Furthermore, hepatocyte growth factor (HGF) induced ACK1 expression at an early stage. Finally, ACK1 mediated the antiviral effect of HGF in the HBV infection system. These results indicated that ACK1 induced by HGF inhibited HBV replication at the transcriptional level by activating the MAPK-HNF signaling pathway. Our findings suggest that ACK1 is a potentially novel upstream molecule of MAPK-mediated anti-HBV activity.

Improved bladder contractility after transplantation of human mesenchymal stem cells overexpressing hepatocyte growth factor into underactive bladder from bladder outlet obstruction models of rats

Introduction An underactive bladder can lead to difficulty in voiding that causes incomplete emptying of the bladder, suggesting the need for a new strategy to increase bladder contractility in such patients. This study was performed to investigate whether human mesenchymal stem cells (hMSCs) were capable of restoring bladder contractility in rats with underactive bladder due to bladder outlet obstruction (BOO) and enhancing their effects by overexpressing hepatocyte growth factor (HGF) in hMSCs. Materials and methods The hMSCs were transplanted into the bladder wall of rats. Fifty female Sprague-Dawley rats at six weeks of age were divided into five groups: group 1: control; group 2: sham intervention; group 3: eight-week BOO; group 4: BOO rats transplanted with hMSCs; and group 5: BOO rats transplanted with hMSCs overexpressing HGF. Two weeks after the onset of BOO in groups 4 and 5, hMSCs were injected into the bladder wall. Cystometry evaluation was followed by Masson’s trichrome staining of bladder tissues. Realtime PCR and immunohistochemical staining were performed to determine for hypoxia, apoptosis, and angiogenesis. Results Collagen deposition of bladder increased in BOO but decreased after transplantation of hMSCs. The increased inter-contraction interval and residual urine volume after BOO was reversed after hMSCs transplantation. The decreased maximal voiding pressure after BOO was restored by hMSCs treatment. The mRNA expression of bladder collagen1 and TGF-β1 increased in BOO but decreased after hMSCs transplantation. The decrease in vWF-positive cells in the bladder following BOO was increased after hMSCs transplantation. Caspase 3 and TUNEL-positive apoptosis of bladder cells increased in BOO but decreased after transplantation of hMSCs. These effects were enhanced by overexpressing HGF in hMSCs. Conclusion Transplantation of hMSCs into bladder wall increased the number of micro-vessels, decreased collagen deposition and apoptosis of detrusor muscle, and improved bladder underactivity. The effects were enhanced by overexpressing HGF in hMSCs. Our findings suggest that the restoration of underactive bladder using hMSCs may be used to rectify micturition disorders in patients following resolution of BOO. Further studies are needed before hMSCs can be used in clinical applications.