Actin-binding proteins as molecular targets to modulate hepatic stellate cell proliferation. Focus on “MARCKS actin-binding capacity mediates actin filament assembly during mitosis in human hepatic stellate cells”

2012 ◽  
Vol 303 (4) ◽  
pp. C355-C356 ◽  
Author(s):  
Gemma Odena ◽  
Ramon Bataller
Keyword(s):  
Cell Proliferation ◽  
Actin Filament ◽  
Hepatic Stellate Cell ◽  
Hepatic Stellate Cells ◽  
Stellate Cell ◽  
Binding Capacity ◽  
Molecular Targets ◽  
Stellate Cells ◽  
Actin Binding ◽  
Filament Assembly

MARCKS actin-binding capacity mediates actin filament assembly during mitosis in human hepatic stellate cells

2012 ◽  
Vol 303 (4) ◽  
pp. C357-C367 ◽  
Author(s):  
Krista Rombouts ◽  
Tommaso Mello ◽  
Francesco Liotta ◽  
Andrea Galli ◽  
Alessandra Caligiuri ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Actin Filament ◽  
Hepatic Stellate Cells ◽  
Binding Proteins ◽  
Binding Capacity ◽  
Stellate Cells ◽  
Mitotic Cell ◽  
Significant Loss ◽  
Actin Binding ◽  
Cell Cycle Time

Cross-linking between the actin cytoskeleton and plasma membrane actin-binding proteins is a key interaction responsible for the mechanical properties of the mitotic cell. Little is known about the identity, the localization, and the function of actin filament-binding proteins during mitosis in human hepatic stellate cells (hHSC). The aim of the present study was to identify and analyze the cross talk between actin and myristoylated alanine-rich kinase C substrate (MARCKS), an important PKC substrate and actin filament-binding protein, during mitosis in primary hHSC. Confocal analysis and chromosomal fraction analysis of mitotic hHSC demonstrated that phosphorylated (P)-MARCKS displays distinct phase-dependent localizations, accumulates at the perichromosomal layer, and is a centrosomal protein belonging to the chromosomal cytosolic fraction. Aurora B kinase (AUBK), an important mitotic regulator, β-actin, and P-MARCKS concentrate at the cytokinetic midbody during cleavage furrow formation. This localization is critical since MARCKS-depletion in hHSC is characterized by a significant loss in cytosolic actin filaments and cortical β-actin that induces cell cycle inhibition and dislocation of AUBK. A depletion of AUBK in hHSC affects cell cycle, resulting in multinucleation. Quantitative live cell imaging demonstrates that the actin filament-binding capacity of MARCKS is key to regulate mitosis since the cell cycle inhibitory effect in MARCKS-depleted cells caused abnormal cell morphology and an aberrant cytokinesis, resulting in a significant increase in cell cycle time. These findings implicate that MARCKS, an important PKC substrate, is essential for proper cytokinesis and that MARCKS and its partner actin are key mitotic regulators during cell cycle in hHSC.

scholarly journals Proliferation of hepatic stellate cells, mediated by YAP and TAZ, contributes to liver repair and regeneration after liver ischemia-reperfusion injury

2018 ◽  
Vol 314 (4) ◽  
pp. G471-G482 ◽  
Author(s):  
Takanori Konishi ◽  
Rebecca M. Schuster ◽  
Alex B. Lentsch
Keyword(s):  
Cell Proliferation ◽  
Liver Injury ◽  
Hepatic Stellate Cell ◽  
Hepatic Stellate Cells ◽  
Stellate Cell ◽  
Ischemia Reperfusion ◽  
Stellate Cells ◽  
Hepatocyte Proliferation ◽  
Binding Motif ◽  
Liver Repair

Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are key regulators of cell proliferation and organ size; however, their physiological contribution after liver injury has not been fully understood. In this study, we sought to determine the role of YAP and TAZ during liver recovery after ischemia-reperfusion (I/R). A murine model of partial (70%) I/R was used to induce liver injury and study the reparative and regenerative response. After liver injury, there was marked activation and proliferation of hepatic stellate cells. The Hippo pathway components, large tumor suppressor 1 (LATS1) and its adapter protein, Mps one binder 1 (MOB1), were inactivated during liver repair, and YAP and TAZ were activated selectively in hepatic stellate cells. Concurrently, the expression of connective tissue growth factor and survivin, both of which are YAP and TAZ target genes, were upregulated. Hepatic stellate cell expansion and concomitant activation of YAP and TAZ occurred only in the injured liver and were not observed in the nonischemic liver. Treatment of mice with verteporfin, an inhibitor of YAP and TAZ, decreased hepatic stellate cell proliferation, survivin, and cardiac ankyrin repeat protein expression. These changes were associated with a significant decrease in hepatocyte proliferation. The data suggest that liver repair and regeneration after I/R injury are dependent on hepatic stellate cell proliferation, which is mediated by YAP and TAZ. NEW & NOTEWORTHY This study is the first to assess the proliferation of hepatic stellate cells (HSCs) after ischemia-reperfusion (I/R) injury and their role in the reparative and regenerative process. Here we show that the Hippo pathway is inactivated after I/R and that Yes-associated protein/transcriptional coactivator with PDZ-binding motif (YAP/TAZ) activation is detected in HSC. HSC proliferation and expansion are prominent during liver recovery after I/R injury. Inhibition of YAP/TAZ activation with verteporfin reduces HSC proliferation and target gene expression and attenuates hepatocyte proliferation.

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.

Exploitation of the hepatic stellate cell Raman signature for their detection in native tissue samples

2014 ◽  
Vol 6 (10) ◽  
pp. 946-956 ◽  
Author(s):  
Kerstin Galler ◽  
Franziska Schleser ◽  
Esther Fröhlich ◽  
Robert Pascal Requardt ◽  
Andreas Kortgen ◽  
...  
Keyword(s):  
Raman Spectra ◽  
Hepatic Stellate Cell ◽  
Hepatic Stellate Cells ◽  
Stellate Cell ◽  
Stellate Cells ◽  
Living Tissue ◽  
Tissue Samples ◽  
Native Tissue ◽  
Unique Information

The unique information concentrated in Raman spectra serves to differentiate hepatic stellate cells from hepatocytes, detect them in living tissue and provide insight in their activation state.

scholarly journals Dysregulation of miR-21-associated miRNA regulatory networks by chronic ethanol consumption impairs liver regeneration

2021 ◽  
Author(s):  
Austin Parrish ◽  
Ankita Srivastava ◽  
Egle Juskeviciute ◽  
Jan B. Hoek ◽  
Rajanikanth Vadigepalli
Keyword(s):  
Liver Regeneration ◽  
Hepatic Stellate Cell ◽  
Mirna Expression ◽  
Hepatic Stellate Cells ◽  
Regulatory Networks ◽  
Stellate Cell ◽  
Stellate Cells ◽  
Chronic Ethanol ◽  
Regenerative Capacity

Impaired liver regeneration has been considered as a hallmark of progression of alcohol-associated liver disease. Our previous studies demonstrated that in vivo inhibition of the microRNA (miRNA) miR21 can restore regenerative capacity of the liver in chronic ethanol-fed animals. The present study focuses on the role of microRNA regulatory networks that are likely to mediate the miR-21 action. Rats were chronically fed an ethanol-enriched diet along with pair-fed control animals and treated with AM21 (anti-miR-21), a locked nucleic acid antisense to miR-21. Partial hepatectomy (PHx) was performed and miRNA expression profiling over the course of liver regeneration was assessed. Our results showed dynamic expression changes in several miRNAs post PHx, notably with altered miRNA expression profiles between ethanol versus control groups. We found that in vivo inhibition of miR-21 led to correlated differential expression of miR-340-5p, and anti-correlated expression of miR-365, let-7a, miR-1224 and miR-146a across all sample groups post PHx. Gene set enrichment analysis identified a miRNA signature significantly associated with hepatic stellate cell activation within whole-liver tissue data. We hypothesized that at least part of the PHx-induced miRNA network changes responsive to miR-21 inhibition is localized to hepatic stellate cells. We validated this hypothesis using AM21 and TGF-β treatments in LX-2 human hepatic stellate cells in culture, and measured expression levels of select miRNAs by quantitative RT-PCR. Based on the in vivo and in vitro results, we propose a hepatic stellate cell miRNA regulatory network as contributing to the restoration of liver regenerative capacity by miR-21 inhibition.

Sign in / Sign up

Export Citation Format

Share Document