Identification and localization of xylose-binding proteins as potential biomarkers for liver fibrosis/cirrhosis

2016 ◽  
Vol 12 (2) ◽  
pp. 598-605 ◽  
Author(s):  
Yaogang Zhong ◽  
Xiu-Xuan Sun ◽  
Peixin Zhang ◽  
Xinmin Qin ◽  
Wentian Chen ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Hepatic Stellate Cells ◽  
Binding Proteins ◽  
Stellate Cells ◽  
Expression Levels ◽  
Activated Hepatic Stellate Cells ◽  
And Function ◽  
Potential Biomarkers

In our recent study, we found that the expression levels of total xylose-binding proteins (XBPs) were up-regulated significantly in activated hepatic stellate cells (HSCs); however, the denomination, distribution, and function of the XBPs were uncharted.

scholarly journals Activated Hepatic Stellate Cells Induce Infiltration and Formation of CD163+ Macrophages via CCL2/CCR2 Pathway

2020 ◽  
Author(s):  
Sujuan Xi ◽  
Xiaoyan Zheng ◽  
Yuming Jiang ◽  
Yuankai Wu ◽  
Jiao Gong ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
Immunofluorescence Assay ◽  
M2 Macrophage ◽  
Staining Score ◽  
Activated Hepatic Stellate Cells ◽  
High Level ◽  
And Function

Abstract Background: Growing evidence indicates that activated hepatic stellate cells (aHSCs) play unexpected roles in regulating immune cells’ function during liver fibrosis. Macrophages feature with inducible plasticity according to the circumstances while patrol for potential pathogens. However, studies seldom investigate whether and how the aHSCs regulate the phenotype and function of macrophages during liver fibrosis. Methods: 96 patients with different stages of liver fibrosis were involved in our study. Metavir score system was used to evaluate the degree of fibrosis. The expression of hepatic CCL2 and CD163 were detected by immunohistochemistry, and the relationship among CD163, CCL2, and fibrosis scores were explored. We co-cultured the aHSCs and THP-1-derived M0-type macrophages (M0MФ) to observe whether aHSCs modulate the expression of CD163 on macrophages in vitro. Furthermore, we treated the M0MФ with aHSCs’ supernatant and investigated the production of CCL2 in aHSCs by ELISA and immunofluorescence assay. To explore whether CCL2/CCR2 axis plays a crucial role in macrophage phenotypic changes during liver fibrosis, we used recombinant CCL2 and its specific receptor antagonist. Moreover, we employed LX2 system to confirm our results. Results: We found that hepatic M2 macrophages (CD163+) infiltration increased in different stages of liver fibrosis (F0-1: 34.95±18.12; F2-3: 77.57±32.48; F4: 99.62±40.84, F0-1 vs. F2-3, P<0.001; F2-3 vs. F4, P=0.074). After in vitro co-cultured with aHSCs, the macrophages expressed higher levels of CD163 (29.5±6.1% vs. 2.7±1.1%) as well as CD206 (28.0±4.2% vs. 2.4±1.2%) compared with the control. Then we found aHSC supernatant up-regulated the expression of CD163 (26.1±2.8%) and CD206 (25.8±3.8%) on macrophages independently. We noted aHSCs’ supernatant contained a high level of CCL2, which increased dramatically while TGF-β stimulation. Meanwhile, CCL2 staining score increased with the progress of fibrosis ( N: 23.26±13.85; F1: 4 8.56±19.18; F2: 58.25±16.24; F3: 81.32±18.48; F4: 110.93±24.75). Intriguingly, CCL2 significantly up-regulated the expression of CD163 (27.6±7.0%) and CD206 (26.5±5.1%) on macrophages besides inducing their aggregation. Results were confirmed with LX2 co-culture system. Conclusions: (1) The expression of M2 macrophage marker CD163 increased significantly during the progress of liver fibrosis and associated with fibrosis severity. (2) AHSCs can recruit macrophages and induce their M2 phenotypic transformation through CCL2/CCR2 pathway.

scholarly journals Activated Hepatic Stellate Cells Induce Infiltration and Formation of CD163+ Macrophages via CCL2/CCR2 Pathway

2021 ◽  
Vol 8 ◽  
Author(s):  
Sujuan Xi ◽  
Xiaoyan Zheng ◽  
Xiangyong Li ◽  
Yuming Jiang ◽  
Yuankai Wu ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
M2 Macrophage ◽  
Macrophage Phenotype ◽  
Macrophage Marker ◽  
Activated Hepatic Stellate Cells ◽  
And Function ◽  
M2 Phenotype

Background: Activated hepatic stellate cells (aHSCs) regulate the function of immune cells during liver fibrosis. As major innate cells in the liver, macrophages have inducible plasticity. Nevertheless, the mechanisms through which aHSCs regulate macrophages' phenotype and function during liver fibrosis and cirrhosis remain unclear. In this study, we examined the immunoregulatory function of aHSCs during liver fibrosis and explored their role in regulating macrophage phenotype and function.Methods: A total of 96 patients with different stages of chronic hepatitis B-related liver fibrosis were recruited in the study. Metavir score system was used to evaluate the degree of fibrosis. The expression of hepatic CCL2 and M2 phenotype macrophage marker CD163 were detected by immunohistochemistry, and the relationship among hepatic CD163, CCL2, and fibrosis scores were also explored. In the in vitro model, the aHSCs isolated from human liver tissues and THP-1-derived M0-type macrophages (M0MΦ) were co-cultured to observe whether and how aHSCs regulate the phenotype and function of macrophages. To explore whether CCL2/CCR2 axis has a crucial role in macrophage phenotypic changes during liver fibrosis, we treated the M0MΦ with recombinant human CCL2 or its specific receptor antagonist INCB-3284. Furthermore, we used LX2 and TGF-β-activated LX2 to mimic the different activation statuses of aHSCs to further confirm our results.Results: In patients, the infiltration of M2 macrophages increased during the progression of liver fibrosis. Intriguingly, as a key molecule for aHSC chemotactic macrophage aggregation, CCL2 markedly up-regulated the expression of CD163 and CD206 on the macrophages, which was further confirmed by adding the CCR2 antagonist (INCB 3284) into the cell culture system. In addition, the TGF-β stimulated LX2 further confirmed that aHSCs up-regulate the expression of CD163 and CD206 on macrophages. LX2 stimulated with TGF-β could produce more CCL2 and up-regulate other M2 phenotype macrophage-specific markers, including IL-10, ARG-1, and CCR2 besides CD163 and CD206 at the gene level, indicating that the different activation status of aHSCs might affect the final phenotype and function of macrophages.Conclusions: The expression of the M2 macrophage marker increases during liver fibrosis progression and is associated with fibrosis severity. AHSCs can recruit macrophages through the CCL2/CCR2 pathway and induce M2 phenotypic transformation.

Gli2-regulated activation of hepatic stellate cells and liver fibrosis by TGF-β signaling

2021 ◽  
Author(s):  
Junyan Yan ◽  
Baowei Hu ◽  
Wenjie Shi ◽  
Xiaoyi Wang ◽  
Jiayuan Shen ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
Conditional Knockout ◽  
Rna Seq ◽  
Expression Levels ◽  
Liver Fibrogenesis ◽  
Hh Signaling ◽  
Signaling Activity

The Hedgehog (Hh) signaling pathway is correlated with hepatic stellate cells (HSCs) activation and liver fibrosis. Gli2 is a key transcription effector of Hh signaling. However, the role of Gli2 in HSC-mediated liver fibrosis progression is largely unknown. In the present study, we investigated the effect of Gli2 on liver fibrogenesis and its possible mechanism using conditional knockout (cKO) Gli2 mice and HSC models. Wild-type (WT) and GFAP-CreERT;Gli2flox/flox male mice were exposed to CCl4 for one month to induce liver fibrosis. Primary HSCs were isolated from mice and the transition of HSCs into a myofibroblastic phenotype was evaluated. Livers from mice underwent histological, immunohistochemical, and immunofluorescence analyses. The expression levels of proteins and genes were evaluated by Western blot (WB) analysis and quantitative real-time polymerase chain reaction (qRT-PCR), respectively. RNA-seq was used to screen differentially expressed genes. Results showed that CCl4 treatment induced liver fibrosis, promoted HSCs activation and proliferation, and up-regulated Hh signaling activity. The cKO of Gli2 in GFAP-CreERT;Gli2flox/flox mice decreased liver fibrosis as well as HSC activation and proliferation. In vitro studies showed that KO of Gli2 in HSCs blocked cell proliferation and activation by decrease of cyclin D1/D2 expression. The RNA-seq results revealed that the expression levels TGF-β1 ligands were down-regulated in Gli2 KO HSCs. Furthermore, overexpression of Gli2 rescued proliferation and activation of HSCs by up-regulation of TGF-β signaling activity. Our data demonstrated that Gli2 regulated HSC activation and liver fibrosis by TGF-β signaling, thus providing support for future Gli2-based investigations of liver fibrosis therapy.

scholarly journals Astaxanthin Attenuates the Changes in the Expression of miRNAs Involved in the Activation of Hepatic Stellate Cells (P02-011-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Minkyung Bae ◽  
Ji-Young Lee
Keyword(s):  
Liver Fibrosis ◽  
Mirna Expression ◽  
Hepatic Stellate Cells ◽  
Expression Profiles ◽  
Stellate Cells ◽  
Expression Levels ◽  
Candidate Mirnas ◽  
Primary Mouse ◽  
Mirna Expression Profiles ◽  
Human Hscs

Abstract Objectives MicroRNAs (miRNAs) are known to be associated with human diseases, including liver fibrosis. We previously demonstrated that astaxanthin (ASTX), a xanthophyll carotenoid, has anti-fibrogenic effects in hepatic stellate cells (HSCs). HSCs are the major cell type responsible for the accumulation of extracellular matrix during the development of liver fibrosis once they are activated. The objective of this study was to compare miRNA expression profiles in activated HSCs (aHSCs) with those of quiescent HSCs (qHSCs) to identify miRNAs that may play crucial roles in the activation of HSCs. We also determined the effect of ASTX on the changes in miRNAs during HSC activation. Methods Primary mouse HSCs were cultured on uncoated plastic dishes for activation. The cells cultured for 1 day and 7 days after isolation served as qHSCs and aHSCs, respectively. qHSCs were treated with/without 25 µM ASTX during the activation for 7 days. miRNA expression profiles were determined using a miScript miRNA PCR array for mouse fibrosis. miRNAs whose expression were altered by more than 2-folds during HSC activation and by ASTX were selected. Their expression levels were further confirmed by quantitative real-time PCR in primary mouse and human HSCs and LX-2 cells, a human HSC cell line. Results Compared with qHSCs, the expression levels of 14 miRNAs and 23 miRNAs were increased and decreased by more than 2-folds, respectively, in aHSCs. Among 14 miRNAs increased in aHSCs, the expression of miR-192–5p, miR-382–5p, and miR-874–3p was reduced by ASTX. In addition, ASTX increased the expression of miR-19a-3p, miR-19b-3p, and miR-101a-3p which were among the 23 miRNAs that were decreased in aHSCs. Of the selected 6 miRNAs, miR-382–5p was chosen for further analysis based on its high expression in HSCs and the magnitude of differences between groups. Unlike in primary mouse HSCs, the expression of miR-382–5p was not altered by transforming growth factor β1, a fibrogenic cytokine, or by ASTX in primary human HSCs and LX-2 cells, which are cells somewhat activated. Conclusions We identified candidate miRNAs that may be important for the activation of HSCs from qHSCs, which were also sensitive to ASTX. Of the candidate miRNAs, miR-382–5p is likely involved in the early stage of HSC activation, i.e., transdifferentiation of qHSCs to aHSCs. Funding Sources NIH.

PDGFRβ-targeted TRAIL specifically induces apoptosis of activated hepatic stellate cells and ameliorates liver fibrosis

APOPTOSIS ◽  
2020 ◽  
Vol 25 (1-2) ◽  
pp. 105-119
Author(s):  
Rui Li ◽  
Zhao Li ◽  
Yanru Feng ◽  
Hao Yang ◽  
Qiuxiao Shi ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
Activated Hepatic Stellate Cells

scholarly journals Targeting activated hepatic stellate cells (aHSCs) for liver fibrosis imaging

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Dan Li ◽  
Li He ◽  
Huizhuang Guo ◽  
Hanwei Chen ◽  
Hong Shan
Keyword(s):  
Liver Fibrosis ◽  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
Activated Hepatic Stellate Cells

scholarly journals Serine Protease HtrA2/Omi Deficiency Impairs Mitochondrial Homeostasis and Promotes Hepatic Fibrogenesis via Activation of Hepatic Stellate Cells

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1119 ◽  
Author(s):  
Hur ◽  
Kang ◽  
Kim ◽  
Lee ◽  
Kim ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Serine Protease ◽  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
Mitochondrial Morphology ◽  
Mice Model ◽  
Hepatic Fibrogenesis ◽  
Mitochondrial Homeostasis ◽  
And Function ◽  
Intracellular Energy

The loss of mitochondrial function impairs intracellular energy production and potentially results in chronic liver disease. Increasing evidence suggests that mitochondrial dysfunction in hepatocytes contributes to the activation of hepatic stellate cells (HSCs), thereby resulting in hepatic fibrogenesis. High-temperature requirement protein A2 (HtrA2/Omi), a mitochondrial serine protease with various functions, is responsible for quality control in mitochondrial homeostasis. However, little information is available regarding its role in mitochondrial damage during the development of liver fibrosis. This study examined whether HtrA2/Omi regulates mitochondrial homeostasis in hepatocyte during the development of hepatic fibrogenesis. In this study, we demonstrated that HtrA2/Omi expression considerably decreased in liver tissues from the CCl4-induced liver fibrotic mice model and from patients with liver cirrhosis. Knockdown of HtrA2/Omi in hepatocytes induced the accumulation of damaged mitochondria and provoked mitochondrial reactive oxygen species (mtROS) stress. We further show that the damaged mtDNA isolated from HtrA2/Omi-deficient hepatocytes as a form of damage-associated molecular patterns can induce HSCs activation. Moreover, we found that motor neuron degeneration 2-mutant mice harboring the missense mutation Ser276Cys in the protease domain of HtrA2/Omi displayed altered mitochondrial morphology and function, which increased oxidative stress and promoted liver fibrosis. Conversely, the overexpression of HtrA2/Omi via hydrodynamics-based gene transfer led to the antifibrotic effects in CCl4-induced liver fibrosis mice model through decreasing collagen accumulation and enhancing anti-oxidative activity by modulating mitochondrial homeostasis in the liver. These results suggest that suppressing HtrA2/Omi expression promotes hepatic fibrogenesis via modulating mtROS generation, and these novel mechanistic insights involving the regulation of mitochondrial homeostasis by HtrA2/Omi may be of importance for developing new therapeutic strategies for hepatic fibrosis.

Activated hepatic stellate cells participate in liver fibrosis in a patient with transfusional iron overload

1998 ◽  
Vol 33 (5) ◽  
pp. 751-754 ◽  
Author(s):  
Yoshinori Harada ◽  
Masaki Iwai ◽  
Masamichi Kakusui ◽  
Takahiro Mori ◽  
Kazunobu Tada ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Iron Overload ◽  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
Activated Hepatic Stellate Cells
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