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 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

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.

Evidence of nitric oxide, a flow-dependent factor, being a trigger of liver regeneration in rats

1998 ◽  
Vol 76 (12) ◽  
pp. 1072-1079 ◽  
Author(s):  
H Helen Wang ◽  
W Wayne Lautt
Keyword(s):  
Nitric Oxide ◽  
Shear Stress ◽  
Liver Regeneration ◽  
Partial Hepatectomy ◽  
Cultured Cells ◽  
Portal Blood Flow ◽  
Liver Weight ◽  
Proliferative Effect

The hypothesis tested was that the hemodynamic consequence of partial hepatectomy (PHX) triggers the cascade of events that leads to liver regeneration. After PHX, all the portal flow must go through the remaining vascular bed, thus producing increased shear stress and release of nitric oxide (NO), which then initiates the next stages of the regeneration process. As an index of triggering of the regeneration cascade, we used an in vitro bioassay detecting the appearance of proliferating factors (PFs; various growth factors, cytokines, and hormones) in plasma 4 h after two-thirds PHX in rats. PF levels, assessed using proliferation of cultured hepatocytes, were elevated in two-thirds PHX rats, fully blocked by the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME), and restored by L-arginine. L-NAME inhibited liver weight restoration at 48 h but resulted in high mortality. L-NAME lacked toxic effects in non-PHX rats. NO was directly antiproliferative on cultured cells, suggesting that the proliferative effect of NO in vivo was secondary to the activation of other proliferative stimuli. The data support the hypothesis that vascular shear stress induced release of NO following PHX serves as a primary trigger to initiate the regeneration process.Key words: shear stress, portal blood flow, hyperplasia, hepatic partial 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.

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.

PXR stimulates growth factor-mediated hepatocyte proliferation by cross-talk with the FOXO transcription factor

2016 ◽  
Vol 473 (3) ◽  
pp. 257-266 ◽  
Author(s):  
Ryota Shizu ◽  
Taiki Abe ◽  
Satoshi Benoki ◽  
Miki Takahashi ◽  
Susumu Kodama ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transcription Factor ◽  
Growth Factor ◽  
Liver Injury ◽  
Hepatocyte Proliferation ◽  
Suppressor Genes ◽  
Proliferation In Vitro ◽  
Murine Hepatocyte

Activation of PXR enhanced growth factor- and liver injury-mediated murine hepatocyte proliferation in vitro and in vivo. Mechanistic analyses suggest that activated PXR down-regulates the expression of cell-cycle suppressor genes by inhibiting their FOXO3-dependent transcription.

scholarly journals Proliferative effect of aqueous extract of Hyptis fructicosa on liver regeneration after partial hepatectomy in rats

2012 ◽  
Vol 27 (1) ◽  
pp. 71-75 ◽  
Author(s):  
Sônia Oliveira Lima ◽  
Luciano da Costa Viana ◽  
Fábio Rafael Teixeira de Santana ◽  
Ségio Zucoloto ◽  
Ricardo Luiz de Albuquerque Junior ◽  
...  
Keyword(s):  
Liver Regeneration ◽  
Partial Hepatectomy ◽  
Aqueous Extract ◽  
Hepatocyte Proliferation ◽  
Hepatic Regeneration ◽  
Control Group ◽  
Immunohistochemical Technique ◽  
Proliferative Effect

PURPOSE: To evaluate the effect of aqueous extract of Hyptis fructicosa on hepatic regeneration after partial hepatectomy in rats. METHODS: Sixteen rats were divided in two groups: C (Control Group) and HF (Whose rats received aqueous extract of Hyptis fructicosa during 4 days using the dose of 100 mg/kg/day). On the consecutive day of this treatment, the animals of both groups underwent hepatectomy of about 67% of liver. Twenty four hours later, they were sacrificed, and the remaining mass of liver was removed and prepared to be studied through the PCNA immunohistochemical technique. RESULTS: The liver regeneration index of HF group was 53.56 ± 18.91%, while in C group was 21.12 ± 8.29% (p=0.0003). CONCLUSION: These results show that the administration of aqueous extract of Hyptis fructicosa using the dose of 100mg/kg/day increased the hepatocyte proliferation in the group HF.

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 Genes Inducing iPS Phenotype Play a Role in Hepatocyte Survival and Proliferation In Vitro and Liver Regeneration In Vivo

2011 ◽  
Vol 25 (S1) ◽  
Author(s):  
Vishakha Bhave ◽  
Shirish Paranjpe ◽  
William C Bowen ◽  
Shashikiran Donthamsetty ◽  
Aaron Bell ◽  
...  
Keyword(s):  
Liver Regeneration ◽  
Proliferation In Vitro
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