scholarly journals Extracellular Vesicles From Steatotic Hepatocytes Provoke Pro-Fibrotic Responses in Stellate Cells.

2020 ◽  
Author(s):  
M. Teresa Koenen ◽  
Tim Caspers ◽  
Alexandra C.A. Heinzmann ◽  
Petra Fischer ◽  
Daniel Heinrichs ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Cell Line ◽  
Extracellular Vesicles ◽  
Hepatic Stellate Cells ◽  
Hepg2 Cells ◽  
High Speed ◽  
Stellate Cell ◽  
Stellate Cells ◽  
Proliferation Markers ◽  
Prolonged Incubation

Abstract Background and aimsHigh caloric dietary intake is associated with hepatic steatosis and chronic hepatocyte damage leading ultimately to liver fibrosis and cirrhosis with organ failure. Although the pathophysiologic process orchestrating liver fibrosis is not completely clarified, pivotal steps are the activation and transdifferentiation of hepatic stellate cells. In this study, we aim to assess the direct interplay between hepatocytes and hepatic stellate cells under normal and steatotic conditions and hypothesize that extracellular vesicles (EV) isolated from hepatocytes can directly manipulate the phenotype of stellate cells.MethodsBy high speed centrifugation, EV were isolated from conditioned media of the hepatocellular carcinoma cell line HepG2, under baseline conditions (C-EV) or after induction of steatosis by linoleic and oleic acid for 24 hours (FA-EV). Migration of the stellate cell line TWNT4 towards respective EV as well as sera of NASH patients was investigated using Boyden chambers. TWNT4 phenotype alterations after incubation with EV was determined by qPCR, western blotting and immunofluorescence staining. ResultsHepG2 cells released more EV after treatment with fatty acids. Chemotactic migration of TWNT4 cells was increased specifically towards FA-EV. Prolonged incubation of TWNT4 cells with FA-EV induce expression of proliferation markers and a myofibroblast-like phenotype. Whereas the expression of the collagen type 1 1 gene did not change after FA-EV-treatment, expression of the myofibroblast markers e.g. -smooth muscle cell actin and TIMP1 were significantly increased. ConclusionWe concluded that EV from steatotic HepG2 cells can influence the behavior and phenotype of TWNT4 cells as well as the expression of remodeling markers and guides directed migration. These findings imply EV as operational, intercellular communicators in the pathophysiology of steatosis associated liver fibrosis.

Possible Therapeutic Uses of Extracellular Vesicles for Reversion of Activated Hepatic Stellate Cells: Context and Future Perspectives

2021 ◽  
Vol 21 ◽  
Author(s):  
Fahim Rejanur Tasin ◽  
Debasish Halder ◽  
Chanchal Mandal
Keyword(s):  
Liver Fibrosis ◽  
Extracellular Vesicles ◽  
Hepatic Stellate Cells ◽  
Cell Activation ◽  
Stellate Cell ◽  
Stellate Cells ◽  
Target Cells ◽  
Fibrotic Liver ◽  
Paracrine Effects ◽  
Cell Therapies

: Liver fibrosis is one of the leading causes for cirrhotic liver disease and the lack of therapies to treat fibrotic liver is a major concern. Liver fibrosis is mainly occurred by activation of hepatic stellate cells and some stem cell therapies had previously reported for treatment. However, due to some problems with cell-based treatment, a safe therapeutic agent is vehemently sought by the researchers. Extracellular vesicles are cell-derived nanoparticles that are employed in several therapeutic approaches, including fibrosis, for their ability to transfer specific molecules in the target cells. In this review the possibilities of extracellular vesicles to inactivate stellate cells are summarized and discussed. According to several studies, extracellular vesicles from different sources can either put beneficial or detrimental effects by regulating the activation of stellate cells. Therefore, targeting extracellular vesicles for maximizing or inhibiting their production is a potential approach for fibrotic liver treatment. Extracellular vesicles from different cells can also inactivate stellate cells by carrying out the paracrine effects of those cells, working as the agents. They are also implicated as smart carrier of anti-fibrotic molecules when their respective parent cells are engineered to produce specific stellate cell-regulating substances. A number of studies showed stellate cell activation can be regulated by up/downregulation of specific proteins, and extracellular vesicle-based therapies can be an effective move to exploit these mechanisms. In conclusion, EVs are advantageous nano-carriers with the potential to treat fibrotic liver by inactivating activated stellate cells by various mechanisms.

Activation of corticotropin releasing factor receptors up regulates collagen production by hepatic stellate cells via promoting p300 expression

2016 ◽  
Vol 397 (5) ◽  
pp. 437-444 ◽  
Author(s):  
Changzhen Wang ◽  
Shan Yang ◽  
Jingjing Huang ◽  
Songlin Chen ◽  
Yuan Li ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Rna Polymerase Ii ◽  
Cell Line ◽  
Hepatic Stellate Cell ◽  
Hepatic Stellate Cells ◽  
Stellate Cell ◽  
Stellate Cells ◽  
Corticotropin Releasing Factor ◽  
Human Hepatic Stellate Cell ◽  
Collagen Promoter

Abstract Liver fibrosis is characterized with the over expression and excessive accumulation of extracellular matrix proteins, including collagens. The causative factors in the over production of collagens are not fully understood. This study aims to test a hypothesis that activation of corticotropin releasing factor receptors up regulates the expression of collagen in hepatic stellate cells. In this study, human hepatic stellate cell line, LX-2 cells were cultured. Expression of collagens by LX-2 cells was assessed by real time RT-PCR, Western blotting. The results showed that, upon exposure to urocortin in the culture, LX-2 cells (a human hepatic stellate cell line) increased the expression of collagen IV (Col4) markedly. The exposure to urocortin also enhanced the levels of pTip60, H3K9, RNA polymerase II and forkhead box protein 3 at the collagen promoter locus as well as increase in the expression of Col4 mRNA and protein in the cells. Blocking p300 efficiently suppressed the urocortin-induced Col4 expression in LX-2 cells and unveiled an apoptosis-inducing effect of urocortin. In conclusion, activation of CRF receptors is capable of enforcing the production of Col4 by LX-2 cells via up regulating the p300 pathway, which may contribute to the development of liver fibrosis.

scholarly journals Identification of GDF15 as A Pro-Fibrotic Factor in Mouse Liver Fibrosis Progression

2021 ◽  
Author(s):  
Peng Qi ◽  
Ming-Ze Ma ◽  
Jing-Hua Kuai
Keyword(s):  
Carbon Tetrachloride ◽  
Liver Fibrosis ◽  
Hepatic Stellate Cell ◽  
Hepatic Stellate Cells ◽  
Liver Tissue ◽  
Cell Activation ◽  
Stellate Cell ◽  
Neutralizing Antibody ◽  
Stellate Cells ◽  
Fibrosis Progression

Abstract Aim:To elucidate the inhibitory role of growth differentiation factor 15 (GDF15) in liver fibrosis and its possible activation mechanism in hepatic stellate cells of mice.Methods:We generated a GDF15-neutralizing antibody that can inhibit TGF-β1-induced activation of the TGF-β/Smad2/3 pathway in LX-2 cells. All the mice in this study were induced by carbon tetrachloride and thioacetamide. In addition, primary hepatic stellate cells from mice were isolated from fresh livers using Nycodenz density gradient separation. The severity and extent of liver fibrosis in mice were evaluated by Sirius Red and Masson staining. The effect of GDF15 on the activation of the TGF-β pathway was detected using dual-luciferase reporter assays and Western blotting assays.Results:The expression of GDF15 in cirrhotic liver tissue was higher than that in normal liver tissue. Blocking GDF15 with a neutralizing antibody resulted in a delay in primary hepatic stellate cell activation and remission of liver fibrosis induced by carbon tetrachloride or thioacetamide. Meanwhile, TGF-β pathway activation was partly inhibited by a GDF15-neutralizing antibody in primary hepatic stellate cells. These results indicated that GDF15 plays an important role in regulating HSC activation and liver fibrosis progression.Conclusions:The inhibition of GDF15 attenuates chemical-inducible liver fibrosis and delays hepatic stellate cell activation, and this effect is probably mainly attributed to its regulatory role in TGF-β signalling.

Lycopene inhibits hepatic stellate cell activation and modulates cellular lipid storage and signaling

2019 ◽  
Vol 10 (4) ◽  
pp. 1974-1984 ◽  
Author(s):  
Monique de Barros Elias ◽  
Felipe Leite Oliveira ◽  
Fatima Costa Rodrigues Guma ◽  
Renata Brum Martucci ◽  
Radovan Borojevic ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Hepatic Stellate Cell ◽  
Hepatic Stellate Cells ◽  
Cell Activation ◽  
Stellate Cell ◽  
Stellate Cells ◽  
Lipid Storage ◽  
Cellular Lipid ◽  
Perivascular Cells ◽  
Hepatic Stellate Cell Activation

Hepatic stellate cells are liver-specific perivascular cells, identified as the major source of collagen in liver fibrosis, following their activation and conversion to myofibroblast-like cells.

scholarly journals Serum-Derived miR-574-5p-Containing Exosomes Contribute to Liver Fibrosis by Activating Hepatic Stellate Cells

2021 ◽  
Author(s):  
Xia Zhou ◽  
Ziyu Liang ◽  
Shanyu Qin ◽  
Xianxian Ruan ◽  
Haixing Jiang
Keyword(s):  
Liver Fibrosis ◽  
Human Serum ◽  
Hepatic Stellate Cells ◽  
High Speed ◽  
Stellate Cells ◽  
Collagen Deposition ◽  
Serum Samples ◽  
Serum Exosomes ◽  
Masson Staining ◽  
Liver Tissues

Abstract Aim: To investigate the association of serum exosomes miR-574-5p with liver fibrosis, and explore the effect and mechanism of serum exosomes on HSC activation.Materials and methods: Using serum samples collected from healthy adults and patients with liver cirrhosis, we extracted human serum exosomes via ultra-high-speed centrifugation, and co-cultured them with hepatic stellate cells (HSCs) line LX2.LX-2-mediated intake of human serum exosomes was examined by confocal microscopy. To induce liver fibrosis, we administered 20% CCl4 to mice intraperitoneally and adopted an exoEasy MIDI kit to extract serum exosomes.Liver fibrosis-related molecules were determined via qRT-PCR, Western blot, Masson staining, and Immunohistochemical staining.Results: Significantly high miR-574-5p levels were expressed in serum exosomes and were positively correlated with the expression of miR-574-5p, collagen deposition, and α-SMA expression in liver tissues of mice during liver fibrosis. Compared to healthy subjects, serum exosomes from cirrhosis patients were associated with higher expression of miR-574-5p, α-SMA, and COL1A1 in LX-2. miR-574-5p mimic promoted the expression of α-SMA and COL1A1 mRNA and protein in LX-2, whereas miR-574-5p inhibitor exerted no effect.Conclusion: This article demonstrates that miR-574-5p expression in serum exosomes is positively correlated with collagen deposition and HSC activation in liver tissues during liver fibrosis.Serum exosomes potentially activate HSC through the transfer of miR-574-5p to HSC during liver fibrosis.

scholarly journals Suberoylanilide hydroxamic acid suppresses hepatic stellate cells activation by HMGB1 dependent reduction of NF-κB1

PeerJ ◽  
2015 ◽  
Vol 3 ◽  
pp. e1362 ◽  
Author(s):  
Wenwen Wang ◽  
Min Yan ◽  
Qiuhong Ji ◽  
Jinbiao Lu ◽  
Yuhua Ji ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Hepatic Stellate Cells ◽  
Hydroxamic Acid ◽  
Molecular Mechanisms ◽  
Stellate Cell ◽  
Smooth Muscle Actin ◽  
Cdna Array ◽  
Stellate Cells ◽  
Type I ◽  
Suberoylanilide Hydroxamic Acid

Hepatic stellate cells (HSCs) activation is essential to the pathogenesis of liver fibrosis. Exploring drugs targeting HSC activation is a promising anti-fibrotic strategy. In the present study, we found suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, prominently suppressed the activation phenotype of a human hepatic stellate cell line—LX2. The production of collagen type I andα-smooth muscle actin (α-SMA) as well as the proliferation and migration of LX2 cells were significantly reduced by SAHA treatment. To determine the molecular mechanisms underlying this suppression, genome wild gene regulation by SAHA was determined by Affymetrix 1.0 human cDNA array. Upon SAHA treatment, the abundance of 331 genes was up-regulated and 173 genes was down-regulated in LX2 cells. Bioinformatic analyses of these altered genes highlighted the high mobility group box 1 (HMGB1) pathway was one of the most relevant pathways that contributed to SAHA induced suppression of HSCs activation. Further studies demonstrated the increased acetylation of intracellular HMGB1 in SAHA treated HSCs, and this increasing is most likely to be responsible for SAHA induced down-regulation of nuclear factor kappa B1 (NF-κB1) and is one of the main underlying mechanisms for the therapeutic effect of SAHA for liver fibrosis.

Hepatic Stellate Cell: A Potential Target for Hepatocellular Carcinoma

2020 ◽  
Vol 13 (4) ◽  
pp. 261-272 ◽  
Author(s):  
Mengna Wu ◽  
Huajie Miao ◽  
Rong Fu ◽  
Jie Zhang ◽  
Wenjie Zheng
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Fibrosis ◽  
Hepatic Stellate Cells ◽  
Stellate Cell ◽  
Stellate Cells ◽  
Liver Inflammation ◽  
Cancer Stemness ◽  
Effector Cells ◽  
Promising Therapeutic Target ◽  
Underlying Mechanisms

: Liver cancer is a leading cause of cancer-related death worldwide, in which hepatocellular carcinoma (HCC) accounts for the majority. Despite the progression in treatment, the prognosis remains extremely poor for HCC patients. The mechanisms of hepatocarcinogenesis are complex, of which fibrosis is acknowledged as the pre-cancerous stage of HCC. Approximately, 80-90% of HCC develops in the fibrotic or cirrhotic livers. Hepatic stellate cells (HSCs), the main effector cells of liver fibrosis, could secret various biological contents to maintain the liver inflammation. By decades, HSCs are increasingly correlated with HCC in the tumor microenvironment. : In this review, we summarized the underlying mechanisms that HSCs participated in the genesis and progression of HCC. HSCs secrete various bioactive contents and regulate tumor-related pathways, subsequently contribute to metastasis, angiogenesis, immunosuppression, chemoresistance and cancer stemness. The study indicates that HSC plays vital roles in HCC progression, suggesting it as a promising therapeutic target for HCC treatment.

scholarly journals Fibronectin Type III Domain-Containing 5 Attenuates Liver Fibrosis Via Inhibition of Hepatic Stellate Cell Activation

2018 ◽  
Vol 48 (1) ◽  
pp. 227-236 ◽  
Author(s):  
Bing Zhou ◽  
Li Ling ◽  
Feng Zhang ◽  
Tong-Yan Liu ◽  
Hong Zhou ◽  
...  
Keyword(s):  
Growth Factor ◽  
Liver Fibrosis ◽  
Hepatic Stellate Cells ◽  
Stellate Cell ◽  
Stellate Cells ◽  
Beneficial Effects ◽  
Ampk Phosphorylation ◽  
Fibronectin Type Iii ◽  
Fibronectin Type Iii Domain ◽  
Fibronectin Type

Background/Aims: Fibronectin type III domain-containing 5 (FNDC5) protein is involved in the beneficial effects of exercise on metabolism. FNDC5 attenuates hepatic steatosis induced by high fat diet (HFD). Here, we examined the effects of FNDC5 on liver fibrosis and underline mechanisms. Methods: Experiments were carried out on wild-type and FNDC5-/- mice, primary mouse hepatic stellate cells (HSCs) and human hepatic stellate cell line (LX-2). The mice were fed with HFD for 6 months to induce liver fibrosis. Oxidized low density lipoprotein (oxLDL) were used to induce the activation of hepatic stellate cells and fibrosis in mouse HSCs and human LX-2 cells. H&E, Masson’s trichrome staining and Sirius red staining were used for liver sections. Protein and mRNA expressions were evaluated with Western blot and RT-PCR, respectively. Results: FNDC5 deficiency aggravated the HFD-induced liver fibrosis and HSCs activation in mice. It exacerbated the HFD-induced inhibition of AMPK phosphorylation, upregulation of connective tissue growth factor (CTGF) and transforming growth factor-β (TGF-β), and deposition of extracellular matrix (ECM) in liver of mice. Administration of FNDC5 attenuated oxLDL-induced AMPK deactivation, HSCs activation, CTGF and TGF-β upregulation and ECM deposition in mouse HSCs. The beneficial effects of FNDC5 on oxLDL-induced AMPK dephosphorylation, HSCs activation and ECM deposition were prevented by the inhibition of AMPK with compound C in human LX-2 cells. However, the effects of FNDC5 on hepatic fibrosis in vivo in this study cannot be distinguished from its effects on adiposity and hepatic steatosis. Conclusions: FNDC5 deficiency aggravates HFD-induced liver fibrosis in mice. FNDC5 plays beneficial roles in attenuating liver fibrosis via AMPK phosphorylation-mediated inhibition of HSCs activation.

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