scholarly journals IL-22 is involved in liver regeneration after hepatectomy

2010 ◽  
Vol 298 (1) ◽  
pp. G74-G80 ◽  
Author(s):  
Xiaodan Ren ◽  
Bin Hu ◽  
Lisa M. Colletti
Keyword(s):  
Liver Regeneration ◽  
General Anesthesia ◽  
Partial Hepatectomy ◽  
Potential Role ◽  
Cellular Proliferation ◽  
Cell Types ◽  
In Vitro Studies ◽  
Hepatocyte Proliferation

Hepatocyte proliferation following partial hepatectomy is an important component of liver regeneration, and recent in vitro studies have shown that IL-22 is involved in cellular proliferation in a variety of cell types, including hepatocytes. IL-22 functions through IL-10Rβ and IL-22Rα. The goal of this study was to investigate the potential role of IL-22 in liver regeneration after 70% hepatectomy. Following 70% hepatectomy, done under general anesthesia in mice, serum IL-22 and hepatic IL-22Rα mRNA were significantly increased. Although administration of exogenous IL-22 prior to hepatectomy did not increase hepatocyte proliferation, administration of anti-IL-22 antibody before hepatectomy did significantly decrease hepatocyte proliferation. Furthermore, IL-22 treatment prior to 70% hepatectomy induced stat-3 activation; no significant changes were seen in ERK1/2 activation, stat-1 activation, or stat-5 activation. IL-22 pretreatment also significantly increased hepatic and serum IL-6 levels. In addition, animals treated with anti-IL-22 antibody also expressed less TGF-α. In conclusion, these data suggest that IL-22 is involved in liver regeneration and this may be due to interaction with IL-6 and TGF-α cascades.

Hodgkin's disease masquerading as fibrous thyroiditis: potential role of cytokines in in vivo and in vitro studies

2002 ◽  
Vol 57 (5) ◽  
pp. 691-697 ◽  
Author(s):  
Jean Pierre Bercovici ◽  
Veronique Machelon ◽  
Françoise Gaudin-Nome ◽  
Nathalie Roudaut ◽  
Virginie Conan-Charlet ◽  
...  
Keyword(s):  
Hodgkin's Disease ◽  
Potential Role ◽  
Hodgkin’S Disease ◽  
In Vitro Studies

scholarly journals Exosomal circ-RBM23 sponging miR-139-5p to promote liver regeneration through RRM2/AKT/mTOR pathway

2021 ◽  
Author(s):  
Guolin He ◽  
Yu Fu ◽  
Zeyi Guo ◽  
Honglei Zhu ◽  
Lei Feng ◽  
...  
Keyword(s):  
Stem Cells ◽  
Liver Regeneration ◽  
Partial Hepatectomy ◽  
Membrane Vesicles ◽  
Hepatocyte Proliferation ◽  
Intercellular Interaction ◽  
Proliferative Effect ◽  
Proliferation In Vitro

Abstract BackgroundExosomes are small nano-size membrane vesicles and are involved in intercellular interaction. Here, we examined if exosomes obtained from human placental stem cells promote liver regeneration after partial hepatectomy. MethodsExosomes generated from primary human placental stem cells were isolated and characterized. Cell co-culture model was used to clarify whether exosomes can induce hepatocytes proliferation in vitro . Partial hepatectomy mouse model was used to evaluate whether exosomes can promote hepatocytes proliferation in vivo . ResultsIt is found that human placental-derived stem cells exosomes (hPDSCs-exo) can induce hepatocyte proliferation in vitro and in vivo . Mechanistically, exosomal circ-RBM23 served as a ceRNA for miR-139-5p, regulated RRM2 and accelerated proliferation through AKT/mTOR pathways. Ablation of exosomal circ-RBM23 suppressed the proliferative effect of exosomes. ConclusionsThe hPMSCs exosomal circ-RBM23 stimulated cell proliferation and liver regeneration after 70% partial hepatectomy by regulated RRM2. Our findings highlight a potential novel therapeutic avenue for liver regeneration after hepatectomy.

scholarly journals A disintegrin and metalloproteinase 17 regulates TNF and TNFR1 levels in inflammation and liver regeneration in mice

2013 ◽  
Vol 305 (1) ◽  
pp. G25-G34 ◽  
Author(s):  
Ryan S. McMahan ◽  
Kimberly J. Riehle ◽  
Nelson Fausto ◽  
Jean S. Campbell
Keyword(s):  
Liver Regeneration ◽  
Cell Types ◽  
Hepatocyte Proliferation ◽  
Growth Factor Signaling ◽  
Chemically Induced ◽  
Tnf Α ◽  
Essential Components ◽  
A Disintegrin And Metalloproteinase ◽  
Necrosis Factor

A disintegrin and metalloproteinase 17 (ADAM17), or tumor necrosis factor (TNF)-α-converting enzyme, is a key metalloproteinase and physiological convertase for a number of putative targets that play critical roles in cytokine and growth factor signaling. These interdependent pathways are essential components of the signaling network that links liver function with the compensatory growth that occurs during liver regeneration following 2/3 partial hepatectomy (PH) or chemically induced hepatotoxicity. Despite identification of many soluble factors needed for efficient liver regeneration, very little is known about how such ligands are regulated in the liver. To directly study the role of ADAM17 in the liver, we employed two cell-specific ADAM17 knockout (KO) mouse models. Using lipopolysaccharide (LPS) as a robust stimulus for TNF release, we found attenuated levels of circulating TNF in myeloid-specific ADAM17 KO mice (ADAM17 m-KO) and, unexpectedly, in mice with hepatocyte-specific ADAM17 deletion (ADAM17 h-KO), indicating that ADAM17 expression in both cell types plays a role in TNF shedding. After 2/3 PH, induction of TNF, TNFR1, and amphiregulin (AR) was significantly attenuated in ADAM17 h-KO mice, implicating ADAM17 as the primary sheddase for these factors in the liver. Surprisingly, the extent and timing of hepatocyte proliferation were not affected after PH or carbon tetrachloride injection in ADAM17 h-KO or ADAM17 m-KO mice. We conclude that ADAM17 regulates TNF, TNFR1, and AR in the liver, and its expression in both hepatocytes and myeloid cells is important for TNF regulation after LPS injury or 2/3 PH, but is not required for liver regeneration.

scholarly journals Partial Hepatectomy-Induced Upregulation of miR-1907 Accelerates Liver Regeneration by Activation Autophagy

2018 ◽  
Vol 2018 ◽  
pp. 1-9
Author(s):  
Tianfei Lu ◽  
Jun Hao ◽  
Chuan Shen ◽  
Guangxiang Gu ◽  
Jianjun Zhang ◽  
...  
Keyword(s):  
Body Weight ◽  
Liver Regeneration ◽  
Partial Hepatectomy ◽  
Weight Ratio ◽  
Underlying Mechanism ◽  
Hepatocyte Proliferation ◽  
Pharmacological Intervention ◽  
Body Weight Ratio

Liver regeneration after partial hepatectomy (PH) is a highly orchestrated biological process in which synchronized hepatocyte proliferation is induced after massive liver mass loss. Hepatocyte proliferation could be regulated by multiple signals, such as miRNAs and autophagy, but underlying mechanism remains unclear. Here a functional miRNA during liver regeneration was identified and its underlying mechanism was delineated in vitro and in vivo. We found that miR-1907 was highly upregulated during liver regeneration after 2/3 PH at various timepoints. The level of miR-1907 was also increased in normal liver cell line treated with HGF at different concentrations. Functionally, miR-1907 enhanced hepatocyte proliferation in vitro and in vivo, and the liver/body weight ratio in miR-1907-overexpressed mice was significantly higher in comparison to the control mice after 2/3 PH. Forced expression of miR-1907 promoted autophagy activation of hepatocyte. Importantly, autophagy inhibition significantly attenuated miR-1907-induced hepatocyte proliferation and the liver/body weight ratio. Finally, GSK3β, a suppressor of autophagy signaling, was identified as the direct target gene of miR-1907. Taken together, miR-1907 accelerates hepatocyte proliferation during liver regeneration by activating autophagy; thus pharmacological intervention regulating miR-1907/autophagy axis may be therapeutically beneficial in liver transplantation and liver failure by inducing liver regeneration.

scholarly journals Regulation of liver regeneration and hepatocarcinogenesis by suppressor of cytokine signaling 3

2007 ◽  
Vol 205 (1) ◽  
pp. 91-103 ◽  
Author(s):  
Kimberly J. Riehle ◽  
Jean S. Campbell ◽  
Ryan S. McMahan ◽  
Melissa M. Johnson ◽  
Richard P. Beyer ◽  
...  
Keyword(s):  
Liver Regeneration ◽  
Liver Weight ◽  
Cell Types ◽  
Hepatocyte Proliferation ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
Cytokine Activation ◽  
Stat3 Phosphorylation ◽  
Multiple Cell

Suppressor of cytokine signaling 3 (SOCS3) down-regulates several signaling pathways in multiple cell types, and previous data suggest that SOCS3 may shut off cytokine activation at the early stages of liver regeneration (Campbell, J.S., L. Prichard, F. Schaper, J. Schmitz, A. Stephenson-Famy, M.E. Rosenfeld, G.M. Argast, P.C. Heinrich, and N. Fausto. 2001.J. Clin. Invest. 107:1285–1292). We developed Socs3 hepatocyte-specific knockout (Socs3 h-KO) mice to directly study the role of SOCS3 during liver regeneration after a two-thirds partial hepatectomy (PH). Socs3 h-KO mice demonstrate marked enhancement of DNA replication and liver weight restoration after PH in comparison with littermate controls. Without SOCS3, signal transducer and activator of transcription 3 (STAT3) phosphorylation is prolonged, and activation of the mitogenic extracellular signal-regulated kinase 1/2 (ERK1/2) is enhanced after PH. In vitro, we show that SOCS3 deficiency enhances hepatocyte proliferation in association with enhanced STAT3 and ERK activation after epidermal growth factor or interleukin 6 stimulation. Microarray analyses show that SOCS3 modulates a distinct set of genes, which fall into diverse physiological categories, after PH. Using a model of chemical-induced carcinogenesis, we found that Socs3 h-KO mice develop hepatocellular carcinoma at an accelerated rate. By acting on cytokines and multiple proliferative pathways, SOCS3 modulates both physiological and neoplastic proliferative processes in the liver and may act as a tumor suppressor.

scholarly journals Enhanced Liver Regeneration After Partial Hepatectomy in Sterol Regulatory Element-Binding Protein (SREBP)-1c-Null Mice is Associated with Increased Hepatocellular Cholesterol Availability

2018 ◽  
Vol 47 (2) ◽  
pp. 784-799 ◽  
Author(s):  
Jun Peng ◽  
Jingwei Yu ◽  
Hu Xu ◽  
Chen Kang ◽  
Philip W. Shaul ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Lipid Metabolism ◽  
Liver Regeneration ◽  
Partial Hepatectomy ◽  
Lipid Accumulation ◽  
Cellular Proliferation ◽  
Cholesterol Metabolism ◽  
Regulatory Element ◽  
Hepatocyte Proliferation ◽  
Sterol Regulatory Element

Background/Aims: Transient lipid accumulation within hepatocytes preceding the peak proliferative process is a characteristic feature of liver regeneration. However, molecular mediators responsible for this lipid accumulation and their functions are not well defined. Sterol regulatory element-binding proteins-1c (SREBP-1c) are critical transcriptional factors that regulate lipid homeostasis in the liver. We hypothesized that SREBP-1c deficiency induced alterations of lipid metabolism may influence hepatocyte proliferation and liver regeneration. Methods: 2/3 partial hepatectomy (PH) was performed in wild type C57BL/6J (WT) and Srebp-1c-/- mice. The lipid contents in serum and liver were measured by enzymatic colorimetric methods. Hepatic lipid droplets were detected by Oil Red O staining and immunohistological staining. Hepatic expression of genes involved in lipid metabolism and cellular proliferation was determined by real-time PCR and/or immunoblot. Hepatocyte proliferation and liver regeneration were assessed by BrdU staining and the weight of remanent liver lobes in Srebp-1c-/- mice, respectively. Results: Srebp-1c-/- mice displayed reduced triglyceride and fatty acids but increased cholesterol in the liver before PH. In response to PH, hepatocellular DNA synthesis was elevated and cell cycle progression was prolonged in Srebp-1c-/- mice, which was associated with enhanced liver regeneration. However, Srebp-1c-/- mice had comparable triglyceride and fatty acid contents and expressions of related genes compared with WT mice during the liver regeneration. In contrast, SREBP-1c-deficiency-induced alteration of cholesterol metabolism was retained during the liver regeneration after PH. Srebp-1c-/- mice exhibited higher cholesterol contents and enhanced expression of SREBP-2 and 3-hydroxy-3-methylglutaryl-Coenzyme A reductase (HMGCR) in the liver than WT mice after PH. Moreover, downregulation of genes involved in cholesterol elimination was observed after PH in Srebp-1c-/- mice. Conclusion: SREBP-1c deficiency in mice did not interfere with triglyceride and fatty acid metabolism but was associated with significant changes in cholesterol profiles during liver regeneration after PH. These results suggest that increased hepatocellular cholesterol storage and cholesterol availability with the enhanced liver regeneration are identified in Srebp-1c-/- mice. This study also shows that providing requisite cholesterol levels to proliferating hepatocytes and keeping appropriate cholesterol metabolism are required for normal liver regeneration.

Impaired phosphatidylcholine biosynthesis does not attenuate liver regeneration after 70% partial hepatectomy in hepatic CTP:phosphocholine cytidylyltransferase-α deficient mice

2012 ◽  
Vol 90 (10) ◽  
pp. 1403-1412 ◽  
Author(s):  
Ji Ling ◽  
Lin Fu Zhu ◽  
Dennis E. Vance ◽  
René L. Jacobs
Keyword(s):  
Liver Regeneration ◽  
Partial Hepatectomy ◽  
Hepatocyte Proliferation ◽  
Phosphocholine Cytidylyltransferase ◽  
Ctp:Phosphocholine Cytidylyltransferase ◽  
Phosphatidylcholine Biosynthesis ◽  
Murine Liver ◽  
Proliferation Of Hepatocytes

Phosphatidylcholine (PC) is the major component of mammalian membranes, and the induction of PC biosynthesis has been shown to be an essential step in cell proliferation in various cell lines. Cytidine triphosphate (CTP):phosphocholine cytidylyltransferase α (CTα) regulates the primary pathway of PC biosynthesis in the liver. The targeted disruption of CTα in murine liver (LCTα−/− mice) decreases hepatic PC mass and the number of cells in the liver, suggesting CTα as an important factor for hepatocyte proliferation. To elucidate the role of CTα in hepatic cell division in vivo, we monitored liver regeneration after 70% partial hepatectomy in LCTα−/− and loxP flanked (floxed) LCTα (control) mice. To our surprise, liver re-growth, DNA synthesis, and PC mass after surgery were not impaired in LCTα−/− mice, despite reduced total PC synthesis. Furthermore, PC synthesis in the control mice was not induced after 70% partial hepatectomy. We conclude that CTα is not essential for proliferation of hepatocytes in vivo, and that basal hepatic PC biosynthesis is sufficient to sustain regeneration after 70% partial hepatectomy.

scholarly journals B-Cell Activating Factor Enhances Hepatocyte-Driven Angiogenesis via B-Cell CLL/Lymphoma 10/Nuclear Factor-KappaB Signaling during Liver Regeneration

2019 ◽  
Vol 20 (20) ◽  
pp. 5022 ◽  
Author(s):  
Chou ◽  
Ho ◽  
Lai ◽  
Chen ◽  
Wu ◽  
...  
Keyword(s):  
Liver Regeneration ◽  
B Cell ◽  
Partial Hepatectomy ◽  
Neutralizing Antibodies ◽  
Protective Role ◽  
Hepatocyte Proliferation ◽  
Endothelial Cell Proliferation ◽  
B Cell Activating Factor ◽  
M Phase

B-cell activating factor (BAFF) is found to be associated with the histological severity of nonalcoholic steatohepatitis (NASH). BAFF was also found to have a protective role in hepatic steatosis via down regulating the expression of steatogenesis genes and enhancing steatosis in hepatocytes through BAFF-R. However, the roles of BAFF during liver regeneration are not well defined. In this study, C57/B6 mice with 70% partial hepatectomy were used as a liver regeneration model. BAFF expression was determined by enzyme immunoassay, and anti-BAFF-neutralizing antibodies were administered to confirm the effects of BAFF on liver regeneration. Western blotting, immunohistochemistry, and florescence staining determined the expression of B-cell CCL/lymphoma 10 (BCL10). The angiogenesis promoting capability was evaluated after the transfection of cells with siRNA targeting BCL10 expression, and the role of NF-κB was assessed. The results revealed that the BAFF and BCL10 levels were upregulated after partial hepatectomy. Treatment with anti-BAFF-neutralizing antibodies caused death in mice that were subjected to 70% partial hepatectomy within 72 h. In vitro, recombinant BAFF protein did not enhance hepatocyte proliferation; however, transfection with BCL10 siRNA arrested hepatocytes at the G2/M phase. Interestingly, conditioned medium from BAFF-treated hepatocytes enhanced angiogenesis and endothelial cell proliferation. Moreover, Matrix metalloproteinase-9 (MMP-9), Fibroblast growth factor 4 (FGF4), and Interleukin-8 (IL-8) proteins were upregulated by BAFF through BCL10/NF-κB signaling. In mice that were treated with anti-BAFF-neutralizing antibodies, the microvessel density (MVD) of the remaining liver tissues and liver regeneration were both reduced. Taken together, our study demonstrated that an increased expression of BAFF and activation of BCL10/NF-κB signaling were involved in hepatocyte-driven angiogenesis and survival during liver regeneration.

scholarly journals Intrahepatic fibrin(ogen) deposition drives liver regeneration after partial hepatectomy in mice and humans

Blood ◽  
2019 ◽  
Vol 133 (11) ◽  
pp. 1245-1256 ◽  
Author(s):  
Dafna Groeneveld ◽  
David Pereyra ◽  
Zwanida Veldhuis ◽  
Jelle Adelmeijer ◽  
Petra Ottens ◽  
...  
Keyword(s):  
Liver Resection ◽  
Liver Regeneration ◽  
Partial Hepatectomy ◽  
Hepatocyte Proliferation ◽  
Protective Function ◽  
Factor Deficiency ◽  
Thrombin Activation ◽  
Platelet Accumulation ◽  
Specific Tissue

AbstractPlatelets play a pivotal role in stimulating liver regeneration after partial hepatectomy in rodents and humans. Liver regeneration in rodents is delayed when platelets are inhibited. However, the exact mechanisms whereby platelets accumulate and promote liver regeneration remain uncertain. Thrombin-dependent intrahepatic fibrin(ogen) deposition was recently reported after partial hepatectomy (PHx) in mice, but the role of fibrin(ogen) deposits in liver regeneration has not been investigated. We tested the hypothesis that fibrin(ogen) contributes to liver regeneration by promoting intrahepatic platelet accumulation and identified the trigger of rapid intrahepatic coagulation after PHx. PHx in wild-type mice triggered rapid intrahepatic coagulation, evidenced by intrahepatic fibrin(ogen) deposition. Intrahepatic fibrin(ogen) deposition was abolished in mice with liver-specific tissue factor deficiency, pinpointing the trigger of coagulation after PHx. Direct thrombin activation of platelets through protease-activated receptor-4 did not contribute to hepatocyte proliferation after PHx, indicating that thrombin contributes to liver regeneration primarily by driving intrahepatic fibrin(ogen) deposition. Fibrinogen depletion with ancrod reduced both intrahepatic platelet accumulation and hepatocyte proliferation after PHx, indicating that fibrin(ogen) contributes to liver regeneration after PHx by promoting intrahepatic platelet accumulation. Consistent with the protective function of fibrin(ogen) in mice, low postoperative plasma fibrinogen levels were associated with liver dysfunction and mortality in patients undergoing liver resection. Moreover, increased intrahepatic fibrin(ogen) deposition was evident in livers of patients after liver resection but was remarkably absent in patients displaying hepatic dysfunction postresection. The results suggest a novel mechanism whereby coagulation-dependent intrahepatic fibrin(ogen) deposition drives platelet accumulation and liver regeneration after PHx.

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