scholarly journals Bromodomain and Extraterminal (BET) Proteins Regulate Hepatocyte Proliferation in Hepatocyte-Driven Liver Regeneration

2018 ◽  
Vol 188 (6) ◽  
pp. 1389-1405 ◽  
Author(s):  
Jacquelyn O. Russell ◽  
Sungjin Ko ◽  
Harvinder S. Saggi ◽  
Sucha Singh ◽  
Minakshi Poddar ◽  
...  
Keyword(s):  
Liver Regeneration ◽  
Hepatocyte Proliferation

scholarly journals F4/80+ Kupffer Cell-Derived Oncostatin M Sustains the Progression Phase of Liver Regeneration through Inhibition of TGF-β2 Pathway

Molecules ◽  
2021 ◽  
Vol 26 (8) ◽  
pp. 2231
Author(s):  
Qingjun Lu ◽  
Hao Shen ◽  
Han Yu ◽  
Jing Fu ◽  
Hui Dong ◽  
...  
Keyword(s):  
Liver Regeneration ◽  
Serum Levels ◽  
Inhibitory Effect ◽  
Regenerative Process ◽  
Oncostatin M ◽  
Hepatocyte Proliferation ◽  
Initiation Phase ◽  
Distinct Role

The role of Kupffer cells (KCs) in liver regeneration is complicated and controversial. To investigate the distinct role of F4/80+ KCs at the different stages of the regeneration process, two-thirds partial hepatectomy (PHx) was performed in mice to induce physiological liver regeneration. In pre- or post-PHx, the clearance of KCs by intraperitoneal injection of the anti-F4/80 antibody (α-F4/80) was performed to study the distinct role of F4/80+ KCs during the regenerative process. In RNA sequencing of isolated F4/80+ KCs, the initiation phase was compared with the progression phase. Immunohistochemistry and immunofluorescence staining of Ki67, HNF-4α, CD-31, and F4/80 and Western blot of the TGF-β2 pathway were performed. Depletion of F4/80+ KCs in pre-PHx delayed the peak of hepatocyte proliferation from 48 h to 120 h, whereas depletion in post-PHx unexpectedly led to persistent inhibition of hepatocyte proliferation, indicating the distinct role of F4/80+ KCs in the initiation and progression phases of liver regeneration. F4/80+ KC depletion in post-PHx could significantly increase TGF-β2 serum levels, while TGF-βRI partially rescued the impaired proliferation of hepatocytes. Additionally, F4/80+ KC depletion in post-PHx significantly lowered the expression of oncostatin M (OSM), a key downstream mediator of interleukin-6, which is required for hepatocyte proliferation during liver regeneration. In vivo, recombinant OSM (r-OSM) treatment alleviated the inhibitory effect of α-F4/80 on the regenerative progression. Collectively, F4/80+ KCs release OSM to inhibit TGF-β2 activation, sustaining hepatocyte proliferation by releasing a proliferative brake.

LINC00265 maintains hepatocyte proliferation during liver regeneration by targeting miRNA-28-5p

2021 ◽  
Vol 85 (3) ◽  
pp. 528-536
Author(s):  
Sheng Yu ◽  
Zhonglin Cui ◽  
Jie Zhou ◽  
Kai Wang ◽  
Qingping Li ◽  
...  
Keyword(s):  
Liver Resection ◽  
Liver Regeneration ◽  
Therapeutic Option ◽  
Weight Ratio ◽  
Hepatocyte Proliferation ◽  
Phase Cell ◽  
Luciferase Reporter ◽  
Hepatocyte Regeneration ◽  
M Phase ◽  
Reporter Assays

ABSTRACT Long noncoding RNAs have been implicated in many biological processes, but their roles in liver regeneration still need to be illustrated. Therefore, we aimed to investigate the role of LINC00265 as a pivotal regulator of hepatocyte proliferation during liver regeneration. It was found that LINC00265 is significantly upregulated in rat liver tissues at various time points after 2/3 liver resection. LINC00265 knockdown inhibited hepatocyte proliferation, induced cell apoptosis and led to G2/M phase cell cycle arrestment. In rats subjected to surgery, LINC00265 knockdown decreased liver/body weight ratio, attenuated improvement from liver damage and reduced Ki67 and PCNA expression. Luciferase reporter assays confirmed that miR-28-5p was a direct target of LINC00265, and inhibition of miR-28-5p abolished the effect of LINC00265 knockdown. In summary, LINC00265 might maintain hepatocyte proliferation by targeting miR-28-5p during liver regeneration and should be considered as a promising therapeutic option for hepatocyte regeneration after liver resection.

scholarly journals Branches of NF-κb signaling pathway regulate hepatocyte proliferation in rat liver regeneration

2015 ◽  
Vol 14 (3) ◽  
pp. 7643-7654 ◽  
Author(s):  
C.F. Chang ◽  
W.M. Zhao ◽  
J.X. Mei ◽  
Y. Zhou ◽  
C.Y. Pan ◽  
...  
Keyword(s):  
Liver Regeneration ◽  
Signaling Pathway ◽  
Rat Liver ◽  
Hepatocyte Proliferation ◽  
Rat Liver Regeneration

The impact of steatosis on liver regeneration

2018 ◽  
Vol 0 (0) ◽  
Author(s):  
Manon Allaire ◽  
Hélène Gilgenkrantz
Keyword(s):  
Growth Factor ◽  
Fatty Liver ◽  
Liver Regeneration ◽  
Liver Diseases ◽  
Growth Factor Receptor ◽  
Receptor Activation ◽  
Liver Graft ◽  
Hepatocyte Proliferation ◽  
Alcoholic Fatty Liver ◽  
The Impact

Abstract Alcoholic and non-alcoholic fatty liver diseases are the leading causes of cirrhosis in Western countries. These chronic liver diseases share common pathological features ranging from steatosis to steatohepatitis. Fatty liver is associated with primary liver graft dysfunction, a higher incidence of complications/mortality after surgery, in correlation with impaired liver regeneration. Liver regeneration is a multistep process including a priming phase under the control of cytokines followed by a growth factor receptor activation phase leading to hepatocyte proliferation. This process ends when the initial liver mass is restored. Deficiency in epidermal growth factor receptor (EGFR) liver expression, reduced expression of Wee1 and Myt1 kinases, oxidative stress and alteration in hepatocyte macroautophagy have been identified as mechanisms involved in the defective regeneration of fatty livers. Besides the mechanisms, we will also discuss in this review various treatments that have been investigated in the reversal of the regeneration defect, for example, omega-3 fatty acids, pioglitazone, fibroblast growth factor (FGF)19-based chimeric molecule or growth hormone (GH). Since dysbiosis impedes liver regeneration, targeting microbiota could also be an interesting therapeutic approach.

scholarly journals Down-Regulation of MiR-127 Facilitates Hepatocyte Proliferation during Rat Liver Regeneration

PLoS ONE ◽  
2012 ◽  
Vol 7 (6) ◽  
pp. e39151 ◽  
Author(s):  
Chuanyong Pan ◽  
Huan Chen ◽  
Lianghua Wang ◽  
Shengsheng Yang ◽  
Hailong Fu ◽  
...  
Keyword(s):  
Liver Regeneration ◽  
Rat Liver ◽  
Hepatocyte Proliferation ◽  
Down Regulation ◽  
Rat Liver Regeneration

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.

scholarly journals Notch Inhibition Promotes Differentiation of Liver Progenitor Cells into Hepatocytes via sox9b Repression in Zebrafish

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Jacquelyn O. Russell ◽  
Sungjin Ko ◽  
Satdarshan P. Monga ◽  
Donghun Shin
Keyword(s):  
Liver Disease ◽  
Liver Regeneration ◽  
Notch Signaling ◽  
Chronic Liver Disease ◽  
Progenitor Cells ◽  
Molecular Mechanisms ◽  
Therapeutic Option ◽  
Chronic Liver ◽  
Hepatocyte Proliferation ◽  
Hepatocyte Differentiation

Liver regeneration after most forms of injury is mediated through the proliferation of hepatocytes. However, when hepatocyte proliferation is impaired, such as during chronic liver disease, liver progenitor cells (LPCs) arising from the biliary epithelial cell (BEC) compartment can give rise to hepatocytes to mediate hepatic repair. Promotion of LPC-to-hepatocyte differentiation in patients with chronic liver disease could serve as a potentially new therapeutic option, but first requires the identification of the molecular mechanisms driving this process. Notch signaling has been identified as an important signaling pathway promoting the BEC fate during development and has also been implicated in regulating LPC differentiation during regeneration. SRY-related HMG box transcription factor 9 (Sox9) is a direct target of Notch signaling in the liver, and Sox9 has also been shown to promote the BEC fate during development. We have recently shown in a zebrafish model of LPC-driven liver regeneration that inhibition of Hdac1 activity through MS-275 treatment enhances sox9b expression in LPCs and impairs LPC-to-hepatocyte differentiation. Therefore, we hypothesized that inhibition of Notch signaling would promote LPC-to-hepatocyte differentiation by repressing sox9b expression in zebrafish. We ablated the hepatocytes of Tg(fabp10a:CFP-NTR) larvae and blocked Notch activation during liver regeneration through treatment with γ-secretase inhibitor LY411575 and demonstrated enhanced induction of Hnf4a in LPCs. Alternatively, enhancing Notch signaling via Notch3 intracellular domain (N3ICD) overexpression impaired Hnf4a induction. Hepatocyte ablation in sox9b heterozygous mutant embryos enhanced Hnf4a induction, while BEC-specific Sox9b overexpression impaired LPC-to-hepatocyte differentiation. Our results establish the Notch-Sox9b signaling axis as inhibitory to LPC-to-hepatocyte differentiation in a well-established in vivo LPC-driven liver regeneration model.

scholarly journals MicroRNA‐125b‐5p Regulates Hepatocyte Proliferation During the Termination Phase of Liver Regeneration

2020 ◽  
Vol 4 (12) ◽  
pp. 1851-1863
Author(s):  
Dakai Yang ◽  
Zhen Dai ◽  
Taihua Yang ◽  
Asha Balakrishnan ◽  
Qinggong Yuan ◽  
...  
Keyword(s):  
Liver Regeneration ◽  
Hepatocyte Proliferation ◽  
Termination Phase

Poly(ADP-ribose) Polymerase-1 is required for hepatocyte proliferation and liver regeneration in mice

2019 ◽  
Vol 511 (3) ◽  
pp. 531-535
Author(s):  
Chenhui Ju ◽  
Chang Liu ◽  
Shu Yan ◽  
Yilong Wang ◽  
Xiaoxiang Mao ◽  
...  
Keyword(s):  
Liver Regeneration ◽  
Hepatocyte Proliferation

scholarly journals MicroRNAs control hepatocyte proliferation during liver regeneration

Hepatology ◽  
2010 ◽  
Vol 51 (5) ◽  
pp. 1735-1743 ◽  
Author(s):  
Guisheng Song ◽  
Amar Deep Sharma ◽  
Garrett R. Roll ◽  
Raymond Ng ◽  
Andrew Y. Lee ◽  
...  
Keyword(s):  
Liver Regeneration ◽  
Hepatocyte Proliferation
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