Therapeutic effects of hepatocyte growth factor‐overexpressing human umbilical cord blood‐derived mesenchymal stem cells on liver fibrosis in rats

Seo, Kyoung Won; Sohn, Suh Young; Bhang, Dong Ha; Nam, Myeong Jin; Lee, Hee Woo; Youn, Hwa Young

doi:10.1002/cbin.10186

Cited by 43 publications

(38 citation statements)

References 75 publications

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“…HGF-MSCs exhibit anti-fibrotic properties in experimental models of lung, kidney, heart, skin, and liver fibrosis [40][41][42][43]. In our study, treatment with HGF-UCMSCs significantly reduced collagen deposition in the lamina propria based on M&T staining compared with other groups.…”

Section: Discussionsupporting

confidence: 52%

Hepatocyte Growth Factor Gene-Modified Mesenchymal Stem Cells Augment Sinonasal Wound Healing

Zheng

et al. 2015

Stem Cells and Development

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This study was designed to investigate the effects of hepatocyte growth factor (HGF) transgenic mesenchymal stem cells (HGF-MSCs) on wound healing in the sinonasal mucosa and nasal epithelial cells (NECs). We also sought to determine whether HGF-MSCs and MSCs can migrate into the injured mucosa and differentiate into ciliated cells. Human HGF-overexpressing umbilical cord MSCs (hHGF-UCMSCs) were established, and upregulation of hHGF expression was confirmed by real-time PCR (RT-PCR) and enzyme-linked immunosorbant assay (ELISA). To investigate the paracrine effect of human MSCs (hMSCs) on nasal epithelial repair, hMSC-and HGF-MSC-conditioned media (CM) were used in NEC proliferation assays and in an in vitro scratch-wound repair model. The in vivo sinonasal wound-healing model was established, and all enrolled rabbits were randomly assigned to four groups: the GFP-MSC group, the HGF-MSC group, the Ad-HGF group, and the surgery control group. The average decreased diameter was recorded, and the medial wall of the maxillary sinus was removed for histological analysis and scanning electron microscopy. Collagen deposition in the wound tissue was detected via Masson trichrome (M&T) staining. The distribution of MSCs and HGFMSCs was observed by immunofluorescence. MSCs improved nasal wound healing both in vivo and in vitro. HGF overexpression in MSCs augmented the curative effects. Reduced collagen deposition and transforming growth factor beta1 (TGF-b1) expression were detected in the HGF-MSC group compared with the MSC-, Ad-HGF-, and phosphate-buffered saline-treated groups based on M&T staining and ELISA. The enhanced therapeutic effects of HGF-MSCs were accompanied by decreased level of the fibrogenic cytokine TGF-b1. In addition, both HGF-MSCs and MSCs can migrate to the injured mucosa and epithelial layer.

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Section: Discussionsupporting

confidence: 52%

Hepatocyte Growth Factor Gene-Modified Mesenchymal Stem Cells Augment Sinonasal Wound Healing

Zheng

et al. 2015

Stem Cells and Development

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“…Human umbilical cord-derived MSC (UC-MSC) transplanted to CCl4-treated rats indicated that liver fibrosis, TGF-β, and EMT were reduced and improved liver function (Jung et al 2009;Li et al 2013;Seo et al 2014). A pilot study investigated the safety and efficacy of UC-MSC transfusion in primary biliary cirrhosis (PBC) patients and indicated that UC-MSC transfusion is feasible and well tolerated in patients .…”

Section: Management Of Other Immune Cells: Previous Reportsmentioning

confidence: 97%

“…However, due to small numbers of heterogene- to CCl4-treated rats (Jung et al 2009;Li et al 2013;Seo et al 2014) Reduced fibrosis, TGF-β, EMT, and improved liver function UC-MSC transfusion in PBC patients with an incomplete response to UDCA No obvious side effects Bone marrow-derived mesenchymal stem cells (BMMSCs) in CCl4-treated rats (Motawi et al 2014) Reduced fibrosis markers and inflammatory cytokines BM-MSCs in patients with alcoholic cirrhosis (Jang et al 2014) No significant side effects. Histological improvement, reduced TGF-β, collagen I, α-SMA (c) Antagonizing TGF-β and CTGF EW-7197 in CCl4-treated mouse, BDL rat, bleomycin mouse, and unilateral ureteral obstruction mouse models (Park et al 2014) Attenuated myofibroblast activation and ECM accumulation, blockade TGF-β1/Smad2/3 and ROS signaling Not applied for liver fibrosis Human bone morphogenic protein-7 (rhBMP-7) in porcine serum-treated rats (Zhong et al 2013 ous patients tested, the potential effects of this therapy remain unclear (Pellicoro et al 2014).…”

Section: Anti-fibrotic Strategies That Reduce Inflammation and The Immentioning

confidence: 98%

“…The "hepato-protectants" such as HGF (hepatocyte growth factor) and insulin growth factor (IGF) also have potent anti-apoptotic and mitogenic effects on hepatocytes during liver injury and essential roles in liver regeneration. The transplantation of HGFoverexpressing human umbilical cord blood-derived mesenchymal stem cells (hHGF-HUCB-MSCs) in CCl4-induced fibrotic rats improved liver function and induced liver regeneration (Seo et al 2014). HGF and its receptor, c-mesenchymal-epithelial transition factor (c-Met), are essential for liver cell growth and proliferation.…”

Section: Improvement Of Liver Function and Enhanced Liver Regenerationmentioning

confidence: 99%

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Strategies to prevent and reverse liver fibrosis in humans and laboratory animals

Chen

Wang

2015

Arch Toxicol

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Liver fibrosis results from chronic damage to the liver in conjunction with various pathways and is mediated by a complex microenvironment. Based on clinical observations, it is now evident that fibrosis is a dynamic, bidirectional process with an inherent capacity for recovery and remodeling. The major mechanisms involved in liver fibrosis include the repetitive injury of hepatocytes, the activation of the inflammatory response after injury stimulation, and the activation and proliferation of hepatic stellate cells (HSCs), which represents the major extracellular matrix (ECM)-producing cells, stimulated by hepatocyte injury and inflammation. The microenvironment in the liver is synergistically regulated abnormal ECM deposition, scar formation, angiogenesis, and fibrogenesis. Moreover, recent studies have clarified novel mechanism in fibrosis such as epigenetic regulation of HSCs, the leptin and PPARγ pathways, the coagulation system, and even autophagy. Uncovering the mechanisms of liver fibrogenesis provides a basis to develop potential therapies to reverse and treat the fibrotic response, thereby improving the outcomes of patients with chronic liver disease. Although both scientific and clinical challenges remain, emerging studies attempt to reveal the ideal anti-fibrotic drug that could be easily delivered to the liver with high specificity and low toxicity. This review highlights the mechanisms, including novel pathways underlying fibrogenesis that may be translated into preventive and treatment strategies, reviews both current and novel agents that target specific pathways or multiple targets, and discusses novel drug delivery systems such as nanotechnology that can be applied in the treatment of liver fibrosis. In addition, we also discuss some current treatment strategies that are being applied in animal models and in clinical trials.

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“…Cirrhosis and hepatocellular carcinomas are of great concern worldwide due to the high morbidity and mortality rates associated with them (4). There are currently no effective therapies to treat liver cirrhosis; however, it has been suggested that the damage may be reversible if treated appropriately during the early, fibrotic stage of cirrhosis (5). Therefore, identifying an effective treatment for hepatic fibrosis is critical in order to decrease the chances of patients with hepatic fibrosis developing chronic liver disease.…”

Section: Introductionmentioning

confidence: 99%

Detecting serum and urine metabolic profile changes of CCl4-liver fibrosis in rats at 12 weeks based on gas chromatography-mass spectrometry

Gao

Qin

Jiang

et al. 2017

Experimental and Therapeutic Medicine

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Liver fibrosis is caused by liver injury induced by a number of chronic liver diseases, including schistosome infection, hepatitis infection, metabolic disease, alcoholism and cholestasis. The tissue damage occurring after injury or inflammation of the liver is a reversible lesion; however, liver fibrosis has become a worldwide problem and poses a threat to human health. The development of an effective drug for the prevention and treatment of liver fibrosis is ongoing and uses information from different occurrences of liver fibrosis. In the present study, carbon tetrachloride (CCl4)-induced metabonomic changes in serum and urine at 12 weeks were analyzed using gas chromatography-mass spectrometry (GC/MS) to investigate potential biomarkers. Liver fibrosis was induced in rats by subcutaneous injections of CCl4 twice a week for 12 consecutive weeks. Histopathological changes were used to assess the successful production of a CCl4-induced liver fibrosis model. Serum and urine samples from the two groups were collected at 12 weeks. The metabolic profile changes were analyzed by GC/MS alongside principal component analysis and orthogonal projections to latent structures. Metabolic profile studies indicated that the clustering of the two groups could be separated and seven metabolites in serum and five metabolites in urine were identified. In serum, the metabolites identified included isoleucine, L-malic acid, α-copper, carnitine, hippuric acid, glutaric acid and glucose. In urine 2-hydroxy butyric acid, isoleucine, N-acetyl-β-alanine, cytidine and corticoid were identified. The present study demonstrated that the pathogenesis of liver fibrosis may be associated with the dysfunction of a number of metabolic pathways, including glucose, amino acid, P450, fatty acid, nucleic acid, water-electrolyte and glutathione biosynthesis. Assessing potential biomarkers may therefore provide novel targets and theories for the innovation of novel drugs to prevent and cure liver fibrosis.

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Therapeutic effects of hepatocyte growth factor‐overexpressing human umbilical cord blood‐derived mesenchymal stem cells on liver fibrosis in rats

Cited by 43 publications

References 75 publications

Hepatocyte Growth Factor Gene-Modified Mesenchymal Stem Cells Augment Sinonasal Wound Healing

Hepatocyte Growth Factor Gene-Modified Mesenchymal Stem Cells Augment Sinonasal Wound Healing

Strategies to prevent and reverse liver fibrosis in humans and laboratory animals

Detecting serum and urine metabolic profile changes of CCl4-liver fibrosis in rats at 12 weeks based on gas chromatography-mass spectrometry

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