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 Evidence for and against epithelial-to-mesenchymal transition in the liver

2013 ◽  
Vol 305 (12) ◽  
pp. G881-G890 ◽  
Author(s):  
Guanhua Xie ◽  
Anna Mae Diehl
Keyword(s):  
Liver Injury ◽  
Epithelial Cells ◽  
Hepatic Stellate Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Stellate Cell ◽  
Stellate Cells ◽  
Mesenchymal Cells ◽  
Mesenchymal Transition ◽  
Liver Epithelial Cells ◽  
Liver Repair

The outcome of liver injury is determined by the success of repair. Liver repair involves replacement of damaged liver tissue with healthy liver epithelial cells (including both hepatocytes and cholangiocytes) and reconstruction of normal liver structure and function. Current dogma posits that replication of surviving mature hepatocytes and cholangiocytes drives the regeneration of liver epithelium after injury, whereas failure of liver repair commonly leads to fibrosis, a scarring condition in which hepatic stellate cells, the main liver-resident mesenchymal cells, play the major role. The present review discusses other mechanisms that might be responsible for the regeneration of new liver epithelial cells and outgrowth of matrix-producing mesenchymal cells during hepatic injury. This theory proposes that, during liver injury, some epithelial cells undergo epithelial-to-mesenchymal transition (EMT), acquire myofibroblastic phenotypes/features, and contribute to fibrogenesis, whereas certain mesenchymal cells (namely hepatic stellate cells and stellate cell-derived myofibroblasts) undergo mesenchymal-to-epithelial transition (MET), revert to epithelial cells, and ultimately differentiate into either hepatocytes or cholangiocytes. Although this theory is highly controversial, it suggests that the balance between EMT and MET modulates the outcome of liver injury. This review summarizes recent advances that support or refute the concept that certain types of liver cells are capable of phenotype transition (i.e., EMT and MET) during both culture conditions and chronic liver injury.

scholarly journals Fibrotic liver has prompt recovery after ischemia-reperfusion injury

2020 ◽  
Vol 318 (3) ◽  
pp. G390-G400 ◽  
Author(s):  
Takanori Konishi ◽  
Rebecca M. Schuster ◽  
Holly S. Goetzman ◽  
Charles C. Caldwell ◽  
Alex B. Lentsch
Keyword(s):  
Progenitor Cells ◽  
Hepatic Stellate Cells ◽  
Ischemia Reperfusion ◽  
Normal Liver ◽  
Stellate Cells ◽  
Hepatocyte Proliferation ◽  
Fibrotic Liver ◽  
Diseased Liver ◽  
Liver Repair ◽  
Macrophage Accumulation

Hepatic ischemia-reperfusion (I/R) is a major complication of liver resection, trauma, and liver transplantation; however, liver repair after I/R in diseased liver has not been studied. The present study sought to determine the manner in which the fibrotic liver repairs itself after I/R. Liver fibrosis was established in mice by CCl4 administration for 6 wk, and then liver I/R was performed to investigate liver injury and subsequent liver repair in fibrotic and control livers. After I/R, fibrotic liver had more injury compared with nonfibrotic, control liver; however, fibrotic liver showed rapid resolution of liver necrosis and reconstruction of liver parenchyma. Marked accumulation of hepatic stellate cells and macrophages were observed specifically in the fibrotic septa in early reparative phase. Fibrotic liver had higher numbers of hepatic stellate cells, macrophages, and hepatic progenitor cells during liver recovery after I/R than did control liver, but hepatocyte proliferation was unchanged. Fibrotic liver also had significantly greater number of phagocytic macrophages than control liver. Clodronate liposome injection into fibrotic mice after I/R caused decreased macrophage accumulation and delay of liver recovery. Conversely, CSF1-Fc injection into normal mice after I/R resulted in increased macrophage accumulation and concomitant decrease in necrotic tissue during liver recovery. In conclusion, fibrotic liver clears necrotic areas and restores normal parenchyma faster than normal liver after I/R. This beneficial response appears to be directly related to the increased numbers of nonparenchymal cells, particularly phagocytic macrophages, in the fibrotic liver. NEW & NOTEWORTHY This study is the first to reveal how diseased liver recovers after ischemia-reperfusion (I/R) injury. Although it was not completely unexpected that fibrotic liver had increased hepatic injury after I/R, a novel finding was that fibrotic liver had accelerated recovery and repair compared with normal liver. Enhanced repair after I/R in fibrotic liver was associated with increased expansion of phagocytic macrophages, hepatic stellate cells, and progenitor cells.

scholarly journals CD248/endosialin critically regulates hepatic stellate cell proliferation during chronic liver injury via a PDGF-regulated mechanism

Gut ◽  
2015 ◽  
Vol 65 (7) ◽  
pp. 1175-1185 ◽  
Author(s):  
Annika Wilhelm ◽  
Victoria Aldridge ◽  
Debashis Haldar ◽  
Amy J Naylor ◽  
Christopher J Weston ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Liver Injury ◽  
Hepatic Stellate Cell ◽  
Stellate Cell ◽  
Chronic Liver ◽  
Chronic Liver Injury

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 Hepatic Stellate Cell-Derived Microvesicles Prevent Hepatocytes from Injury Induced by APAP/H2O2

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Renwei Huang ◽  
Qunwen Pan ◽  
Xiaotang Ma ◽  
Yan Wang ◽  
Yaolong Liang ◽  
...  
Keyword(s):  
Liver Injury ◽  
Hepatic Stellate Cells ◽  
Culture Medium ◽  
Caspase 3 ◽  
Cell Function ◽  
Stellate Cell ◽  
Annexin V ◽  
Stellate Cells ◽  
Human Hepatocytes ◽  
Injury Models

Hepatic stellate cells (HSCs), previously described for liver-specific mesenchymal stem cells (MSCs), appear to contribute to liver regeneration. Microvesicles (MVs) are nanoscale membrane fragments, which can regulate target cell function by transferring contents from their parent cells. The aim of this study was to investigate the effect of HSC-derived MVs on xenobiotic-induced liver injury. Rat and human hepatocytes, BRL-3A and HL-7702, were used to build hepatocytes injury models by n-acetyl-p-aminophenol n-(APAP) or H2O2treatment. MVs were prepared from human and rat HSCs, LX-2, and HST-T6 and, respectively, added to injured BRL-3A and HL-7702 hepatocytes. MTT assay was utilized to determine cell proliferation. Cell apoptosis was analyzed by flow cytometry and hoechst33258 staining. Western blot was used for analyzing the expression of activated caspase-3. Liver injury indicators, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) in culture medium were also assessed. Results showed that (1) HSC-MVs derived from LX-2 and HST-T6 were positive to CD90 and annexin V surface markers; (2) HSC-MVs dose-dependently improved the viability of hepatocytes in both injury models; (3) HSC-MVs dose-dependently inhibited the APAP/H2O2induced hepatocytes apoptosis and activated caspase-3 expression and leakage of LDH, ALT, and AST. Our results demonstrate that HSC-derived MVs protect hepatocytes from toxicant-induced injury.

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.

Sign in / Sign up

Export Citation Format

Share Document