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 miR-155 accelerates proliferation of mouse hepatocytes during liver regeneration by directly targeting SOCS1

2018 ◽  
Vol 315 (4) ◽  
pp. G443-G453 ◽  
Author(s):  
Xia Lin ◽  
Li Chen ◽  
Haiyan Li ◽  
Yu Liu ◽  
Yanhong Guan ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Liver Regeneration ◽  
Partial Hepatectomy ◽  
Molecular Mechanisms ◽  
Pharmacological Intervention ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
Proliferation Of Hepatocytes

Liver regeneration after two-thirds partial hepatectomy (PH) is a clinically significant repair process for restoring proper liver architecture. Although microRNA-155 (miR-155) has been found to serve as a crucial microRNA regulator that controls liver cell function and proliferation, little is known about its specific role in the regenerating liver. Using a mouse model with miR-155 overexpression or miR-155 knockout, we investigated the molecular mechanisms of miR-155 in liver regeneration. We found a marked induction of miR-155 in C57BL/6 mice after PH. Furthermore, RL-m155 mice showed enhanced liver regeneration as a result of accelerated progression of hepatocytes into the cell cycle, mainly through an increase in cyclin levels. However, proliferation of hepatocytes was delayed in miR-155-deficient livers. Expression of suppressor of cytokine signaling 1 (SOCS1) was dramatically downregulated in the process of liver regeneration, and enhancement of SOCS1 contributed to impaired proliferation of hepatocytes. Additionally, in vitro and in vivo experiments showed that adenovirus- or adeno-associated virus-mediated overexpression of SOCS1 attenuated improved liver regeneration induced by miR-155 overexpression. Our study shows that miR-155 is a pro-proliferative regulator in liver regeneration by facilitating the cell cycle and directly targeting SOCS1. NEW & NOTEWORTHY Our findings suggest a microRNA-155 (miR-155)-mediated positive regulation pattern in liver regeneration. A series of in vivo and in vitro studies showed that miR-155 upregulation enhanced partial hepatectomy-induced proliferation of hepatocytes by promoting the cell cycle without inducing DNA damage or apoptosis. Suppressor of cytokine signaling 1, a target gene of miR-155, antagonized the proliferation-promoting effect of miR-155. Therefore, pharmacological intervention targeting miR-155 may be therapeutically beneficial in various liver diseases.

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.

Turnover of total proteins and ornithine aminotransferase during liver regeneration in rats

1980 ◽  
Vol 238 (1) ◽  
pp. E46-E52
Author(s):  
S. L. Augustine ◽  
R. W. Swick
Keyword(s):  
Amino Acids ◽  
Liver Regeneration ◽  
Protein Degradation ◽  
Partial Hepatectomy ◽  
Free Amino ◽  
Liver Protein ◽  
Ornithine Aminotransferase ◽  
Fractional Rate

The recovery of approximately 40% of the total liver protein during the first day after partial hepatectomy was shown to be due to the near cessation of protein breakdown rather than to an increase in protein synthesis. The decrease in degradation of total protein was less if rats were adrenalectomized or protein-depleted prior to partial hepatectomy. The effect of these treatments originally suggested that changes in free amino acid levels in liver might be related to the rate of protein degradation. However, no correlation was found between levels of total free amino acids and rates of breakdown. Measurements of individual amino acids during liver regeneration suggested that levels of free methionine and phenylalanine, amino acids that have been found to lower rates of protein degradation in vitro, are not correlated with rates of breakdown in vivo. The difference between the fractional rate of ornithine aminotransferase degradation (0.68/day and 0.28/day in sham-hepatectomized and partially hepatectomized rats, respectively) was sufficient to account for the higher level of this protein 3 days after surgery in the latter group.

Azole-resistant and -susceptible Aspergillus fumigatus isolates show comparable fitness and azole treatment outcome in immunocompetent mice

2017 ◽  
Vol 56 (6) ◽  
pp. 703-710
Author(s):  
Michaela Lackner ◽  
Günter Rambach ◽  
Emina Jukic ◽  
Bettina Sartori ◽  
Josef Fritz ◽  
...  
Keyword(s):  
Body Weight ◽  
Aspergillus Fumigatus ◽  
Severe Disease ◽  
Weight Ratio ◽  
Clinical Parameters ◽  
Fitness Advantage ◽  
Significant Difference ◽  
Immunocompetent Mice

Abstract No data are available on the in vivo impact of infections with in vitro azole-resistant Aspergillus fumigatus in immunocompetent hosts. Here, the aim was to investigate fungal fitness and treatment response in immunocompetent mice infected with A. fumigatus (parental strain [ps]) and isogenic mutants carrying either the mutation M220K or G54W (cyp51A). The efficacy of itraconazole (ITC) and posaconazole (PSC) was investigated in mice, intravenously challenged either with a single or a combination of ps and mutants (6 × 105 conidia/mouse). Organ fungal burden and clinical parameters were measured. In coinfection models, no fitness advantage was observed for the ps strain when compared to the mutants (M220K and G54W) independent of the presence or absence of azole-treatment. For G54W, M220K, and the ps, no statistically significant difference in ITC and PSC treatment was observed in respect to fungal kidney burden. However, clinical parameters suggest that in particular the azole-resistant strain carrying the mutation G54W caused a more severe disease than the ps strain. Mice infected with G54W showed a significant decline in body weight and lymphocyte counts, while spleen/body weight ratio and granulocyte counts were increased. In immunocompetent mice, in vitro azole-resistance did not translate into therapeutic failure by either ITC or PSC; the immune system appears to play the key role in clearing the infection.

scholarly journals Platelet Interactions with Liver Sinusoidal Endothelial Cells and Hepatic Stellate Cells Lead to Hepatocyte Proliferation

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1243 ◽  
Author(s):  
Jeremy Meyer ◽  
Alexandre Balaphas ◽  
Pierre Fontana ◽  
Philippe Morel ◽  
Simon C. Robson ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Liver Regeneration ◽  
Partial Hepatectomy ◽  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
Hepatocyte Proliferation ◽  
Liver Sinusoidal Endothelial Cells ◽  
Hepatocyte Growth

(1) Background: Platelets were postulated to constitute the trigger of liver regeneration. The aim of this study was to dissect the cellular interactions between the various liver cells involved in liver regeneration and to clarify the role of platelets. (2) Methods: Primary mouse liver sinusoidal endothelial cells (LSECs) were co-incubated with increasing numbers of resting platelets, activated platelets, or platelet releasates. Alterations in the secretion of growth factors were measured. The active fractions of platelet releasates were characterized and their effects on hepatocyte proliferation assessed. Finally, conditioned media of LSECs exposed to platelets were added to primary hepatic stellate cells (HSCs). Secretion of hepatocyte growth factor (HGF) and hepatocyte proliferation were measured. After partial hepatectomy in mice, platelet and liver sinusoidal endothelial cell (LSEC) interactions were analyzed in vivo by confocal microscopy, and interleukin-6 (IL-6) and HGF levels were determined. (3) Results: Co-incubation of increasing numbers of platelets with LSECs resulted in enhanced IL-6 secretion by LSECs. The effect was mediated by the platelet releasate, notably a thermolabile soluble factor with a molecular weight over 100 kDa. The conditioned medium of LSECs exposed to platelets did not increase proliferation of primary hepatocytes when compared to LSECs alone but stimulated hepatocyte growth factor (HGF) secretion by HSCs, which led to hepatocyte proliferation. Following partial hepatectomy, in vivo adhesion of platelets to LSECs was significantly increased when compared to sham-operated mice. Clopidogrel inhibited HGF secretion after partial hepatectomy. (4) Conclusion: Our findings indicate that platelets interact with LSECs after partial hepatectomy and activate them to release a large molecule of protein nature, which constitutes the initial trigger for liver regeneration.

Argon Delays Initiation of Liver Regeneration after Partial Hepatectomy in Rats

2017 ◽  
Vol 58 (5-6) ◽  
pp. 204-215 ◽  
Author(s):  
Tom Florian Ulmer ◽  
Athanassious Fragoulis ◽  
Henriette Dohmeier ◽  
Andreas Kroh ◽  
Anne Andert ◽  
...  
Keyword(s):  
Liver Regeneration ◽  
Partial Hepatectomy ◽  
Noble Gas ◽  
Ischemia Reperfusion ◽  
Weight Ratio ◽  
Hepatocyte Proliferation ◽  
Protective Effects ◽  
Test Results ◽  
Ki 67 ◽  
Tissue Samples

Background: The liver can heal up to restitutio ad integrum following damage resulting from various causes. Different studies have demonstrated the protective effect of argon on various cells and organs. To the best of our knowledge, the organ-protective effects of the noble gas argon on the liver have not yet been investigated, although argon appears to influence signal paths that are well-known mediators of liver regeneration. We hypothesized that argon inhalation prior to partial hepatectomy (70%) has a positive effect on the initiation of liver regeneration in rats. Methods: Partial hepatectomy (70%) with or without inhaled argon (50 vol%) was performed for 1 h. Liver tissue was harvested after 3, 36, and 96 h to analyze the mRNA and protein expression of hepatocyte growth factor (HGF), interleukin-6 (IL-6), tumor necrosis factor-α, and extracellular signal-regulated kinase 1/2. Histological tissue samples were prepared for immunohistochemistry (bromodeoxyuridine [BrdU], Ki-67, and TUNEL) and blood was analyzed regarding the effects of argon on liver function. Statistical analyses were performed using 1-way ANOVA followed by the post hoc Tukey-Kramer test. Results: After 3 h, the primary outcome parameter of hepatocyte proliferation was significantly reduced with argon 50 vol% inhalation in comparison to nitrogen inhalation (BrdU: 15.7 ± 9.7 vs. 7.7 ± 3.1 positive cells/1,000 hepatocytes, p = 0.013; Ki-67: 17.6 ± 13.3 vs. 4.7 ± 5.4 positive cells/1,000 hepatocytes, p = 0.006). This was most likely mediated by significant downregulation of HGF (after 3 h: 5.2 ± 3.2 vs. 2.3 ± 1.0 fold, p = 0.032; after 96 h: 2.1 ± 0.5 vs. 1.3 ± 0.3 fold, p = 0.029) and IL-6 (after 3 h: 43.7 ± 39.6 vs. 8.5 ± 9.2 fold, p = 0.032). Nevertheless, we could detect no significant effect on the weight of the residual liver, liver-body weight ratio, or liver blood test results after argon inhalation. Conclusion: Impairment of liver regeneration was apparent after argon 50 vol% inhalation that was most probably mediated by downregulation of HGF and IL-6 in the initial phase. However, the present study was not adequately powered to prove that argon has detrimental effects on the liver. Further studies are needed to evaluate the effects of argon on livers with preexisting conditions as well as on ischemia-reperfusion models.

scholarly journals Hepatic NF-kB-inducing kinase (NIK) suppresses mouse liver regeneration in acute and chronic liver diseases

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Yi Xiong ◽  
Adriana Souza Torsoni ◽  
Feihua Wu ◽  
Hong Shen ◽  
Yan Liu ◽  
...  
Keyword(s):  
Liver Disease ◽  
Liver Regeneration ◽  
Chronic Liver Disease ◽  
Disease Progression ◽  
Partial Hepatectomy ◽  
Cell Cycle Progression ◽  
Underlying Mechanism ◽  
Chronic Liver ◽  
Hepatocyte Proliferation ◽  
Liver Disease Progression

Reparative hepatocyte replication is impaired in chronic liver disease, contributing to disease progression; however, the underlying mechanism remains elusive. Here, we identify Map3k14 (also known as NIK) and its substrate Chuk (also called IKKα) as unrecognized suppressors of hepatocyte replication. Chronic liver disease is associated with aberrant activation of hepatic NIK pathways. We found that hepatocyte-specific deletion of Map3k14 or Chuk substantially accelerated mouse hepatocyte proliferation and liver regeneration following partial-hepatectomy. Hepatotoxin treatment or high fat diet feeding inhibited the ability of partial-hepatectomy to stimulate hepatocyte replication; remarkably, inactivation of hepatic NIK markedly increased reparative hepatocyte proliferation under these liver disease conditions. Mechanistically, NIK and IKKα suppressed the mitogenic JAK2/STAT3 pathway, thereby inhibiting cell cycle progression. Our data suggest that hepatic NIK and IKKα act as rheostats for liver regeneration by restraining overgrowth. Pathological activation of hepatic NIK or IKKα likely blocks hepatocyte replication, contributing to liver disease progression.

scholarly journals Platelet-induced cell signaling during liver regeneration

2021 ◽  
Vol 108 (Supplement_4) ◽  
Author(s):  
A Balaphas ◽  
J Meyer ◽  
R Perozzo ◽  
M Zeisser Labouebe ◽  
S Berndt ◽  
...  
Keyword(s):  
Growth Factor ◽  
Liver Regeneration ◽  
Partial Hepatectomy ◽  
Transforming Growth Factor ◽  
Fold Increase ◽  
Transforming Growth Factor Β1 ◽  
Remnant Liver ◽  
Liver Sinusoidal Endothelial Cells

Abstract Objective To investigate the mechanisms driving the interaction of platelets with liver sinusoidal endothelial cells (LSEC) during liver regeneration. Methods Platelets were tracked in vivo in mice by intravital confocal microscopy after partial hepatectomy. In vitro, we isolated highly pure mouse LSEC and analyzed their interactions with platelets, hepatic stellate cells (HSC), Kupffer cells and hepatocytes. Results Recruited platelets adhered to LSEC in vivo within the remnant liver segments following partial hepatectomy and were necessary for the interleukin 6 (IL-6) burst that occurred afterwards. In vitro, platelets were activated after incubation with LSEC and released transforming growth factor β1 (TGF-β1), which stimulated LSEC to secrete IL-6 (fold increase of 9.8±0.73 relative to baseline). Antibody-mediated neutralization of TGF-B1 or its downstream SMAD signalling pathway prevented the effects of activated platelets on LSEC. We also demonstrated that IL-6 released by LSEC stimulates HSC to produce hepatocyte growth factor (HGF) a main mitogen for hepatocytes. Conclusion Our results suggest that after hepatectomy, platelets initiate liver regeneration by interacting with LSEC and stimulate IL-6 release, which in turn stimulates HSC to produce HGF.

scholarly journals Exosome-Mimetic Nanovesicles from Hepatocytes promote hepatocyte proliferation in vitro and liver regeneration in vivo

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Jun-Yi Wu ◽  
An-Lai Ji ◽  
Zhong-xia Wang ◽  
Guang-Hui Qiang ◽  
Zhen Qu ◽  
...  
Keyword(s):  
Liver Regeneration ◽  
Hepatocyte Proliferation ◽  
Proliferation In Vitro

Effect of Portal Vein Ligation Plus Venous Congestion on Liver Regeneration in Rats

2018 ◽  
Vol 17 (5) ◽  
pp. 0-10
Author(s):  
Daisuke Kawaguchi ◽  
Yukihiko Hiroshima ◽  
Takafumi Kumamoto ◽  
Ryutaro Mori ◽  
Ryusei Matsuyama ◽  
...  
Keyword(s):  
Body Weight ◽  
Portal Vein ◽  
Beneficial Effect ◽  
Liver Regeneration ◽  
Rat Model ◽  
Weight Ratio ◽  
Venous Congestion ◽  
Portal Vein Ligation ◽  
Body Weight Ratio ◽  
Ki 67

Introduction and aim. We developed a rat model of portal vein ligation (PVL) with venous congestion (PVL+C) to investigate beneficial effect PVL plus congestion for regeneration of intact liver segments. Materials and methods. In the PVL group, portal vein branches were ligated except the caudate lobe (CL). In the PVL + C group, the left lateral hepatic vein was ligated in addition to PVL. Chronological changes in the following variables were compared among the groups: CL weight to body weight ratio (CL/BW), embolized liver weight to body weight ratio (EL/BW), histological findings of the embolized/non-embolized liver, and expression of several mediators that affect liver regeneration in the non-embolized liver. Results. Weight regeneration of CL continued up to postoperative day (POD)7 in PVL + C, but terminated at POD2 in PVL. CL/BW at POD7 was significantly higher in PVL + C than in PVL (2.41 ± 0.33% vs. 1.22 ± 0.18%, P < 0.01). In contrast, EL/BW continued to decrease up to POD7 in PVL + C but reached nadir at POD2 in PVL. Furthermore, EL/BW at POD7 was significantly smaller in PVL + C than in PVL (0.35 ± 0.03% vs. 0.67 ± 0.08%, P < 0.01). Histologically-proven injury in the embolized liver was more severe in PVL + C than in PVL. Expression of Ki-67, IL-6, TNF-α, and HGF were greater and/or more prolonged in PVL + C than in PVL. Conclusions. Our rat model of PVL + C was considered useful for investigating the beneficial effect of congestion in addition to PVC. PVL + C caused increased devastation of the embolized liver, and higher and more prolonged expression of factors promoting liver regeneration in the non-embolized liver tan in PVL.

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