Liver regeneration is impaired by FK778 in partially hepatectomized rats, while supplemental uridine restores both liver growth and hepatocyte proliferation

Abstract Recently, we have shown that an enhanced blood flow through the liver triggers hepatocyte proliferation and thereby liver growth. In this review, we first explain the literature on hepatic blood flow and its changes after partial hepatectomy (PHx), before we present the different steps of liver regeneration that take place right after the initial hemodynamic changes induced by PHx. Those parts of the molecular mechanisms governing liver regeneration, which are directly associated with the hepatic vascular system, are subsequently reviewed. These include β1 integrin-dependent mechanotransduction in liver sinusoidal endothelial cells (LSECs), triggering mechanically-induced activation of the vascular endothelial growth factor receptor-3 (VEGFR3) and matrix metalloproteinase-9 (MMP9) as well as release of growth-promoting angiocrine signals. Finally, we speculate how advanced age and obesity negatively affect the hepatic vasculature and thus liver regeneration and health, and we conclude our review with some recent technical progress in the clinic that employs liver perfusion. In sum, the mechano-elastic properties and alterations of the hepatic vasculature are key to better understand and influence liver health, regeneration, and disease.

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Unaltered Liver Regeneration in Post-Cholestatic Rats Treated with the FXR Agonist Obeticholic Acid

Biomolecules ◽

10.3390/biom11020260 ◽

2021 ◽

Vol 11 (2) ◽

pp. 260

Author(s):

Lianne R. de Haan ◽

Joanne Verheij ◽

Rowan F. van Golen ◽

Verena Horneffer-van der Sluis ◽

Matthew R. Lewis ◽

...

Keyword(s):

Liver Regeneration ◽

Bile Flow ◽

Liver Weight ◽

Farnesoid X Receptor ◽

Hepatocyte Proliferation ◽

Obeticholic Acid ◽

Liver Growth ◽

Beneficial Effects ◽

Duct Ligation ◽

Human Validation

In a previous study, obeticholic acid (OCA) increased liver growth before partial hepatectomy (PHx) in rats through the bile acid receptor farnesoid X-receptor (FXR). In that model, OCA was administered during obstructive cholestasis. However, patients normally undergo PHx several days after biliary drainage. The effects of OCA on liver regeneration were therefore studied in post-cholestatic Wistar rats. Rats underwent sham surgery or reversible bile duct ligation (rBDL), which was relieved after 7 days. PHx was performed one day after restoration of bile flow. Rats received 10 mg/kg OCA per day or were fed vehicle from restoration of bile flow until sacrifice 5 days after PHx. Liver regeneration was comparable between cholestatic and non-cholestatic livers in PHx-subjected rats, which paralleled liver regeneration a human validation cohort. OCA treatment induced ileal Fgf15 mRNA expression but did not enhance post-PHx hepatocyte proliferation through FXR/SHP signaling. OCA treatment neither increased mitosis rates nor recovery of liver weight after PHx but accelerated liver regrowth in rats that had not been subjected to rBDL. OCA did not increase biliary injury. Conclusively, OCA does not induce liver regeneration in post-cholestatic rats and does not exacerbate biliary damage that results from cholestasis. This study challenges the previously reported beneficial effects of OCA in liver regeneration in cholestatic rats.

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Prolactin promotes normal liver growth, survival, and regeneration in rodents: effects on hepatic IL-6, suppressor of cytokine signaling-3, and angiogenesis

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00282.2013 ◽

2013 ◽

Vol 305 (7) ◽

pp. R720-R726 ◽

Cited By ~ 16

Author(s):

Bibiana Moreno-Carranza ◽

Maite Goya-Arce ◽

Claudia Vega ◽

Norma Adán ◽

Jakob Triebel ◽

...

Keyword(s):

Liver Regeneration ◽

Weight Ratio ◽

Normal Liver ◽

Hepatocyte Proliferation ◽

Cytokine Signaling ◽

Wild Type ◽

Suppressor Of Cytokine Signaling ◽

Liver Growth ◽

Hepatic Expression ◽

Before And After

Prolactin (PRL) is a potent liver mitogen and proangiogenic hormone. Here, we used hyperprolactinemic rats and PRL receptor-null mice (PRLR−/−) to study the effect of PRL on liver growth and angiogenesis before and after partial hepatectomy (PH). Liver-to-body weight ratio (LBW), hepatocyte and sinusoidal endothelial cell (SEC) proliferation, and hepatic expression of VEGF were measured before and after PH in hyperprolactinemic rats, generated by placing two anterior pituitary glands (AP) under the kidney capsule. Also, LBW and hepatic expression of IL-6, as well as suppressor of cytokine signaling-3 (SOCS-3), were evaluated in wild-type and PRLR−/−mice before and after PH. Hyperprolactinemia increased the LBW, the proliferation of hepatocytes and SECs, and VEGF hepatic expression. Also, liver regeneration was increased in AP-grafted rats and was accompanied by elevated hepatocyte and SEC proliferation, and VEGF expression compared with nongrafted controls. Lowering circulating PRL levels with CB-154, an inhibitor of AP PRL secretion, prevented AP-induced stimulation of liver growth. Relative to wild-type animals, PRLR−/−mice had smaller livers, and soon after PH, they displayed an approximately twofold increased mortality and elevated and reduced hepatic IL-6 and SOCS-3 expression, respectively. However, liver regeneration was improved in surviving PRLR−/−mice. PRL stimulates normal liver growth, promotes survival, and regulates liver regeneration by mechanisms that may include hepatic downregulation of IL-6 and upregulation of SOCS-3, increased hepatocyte proliferation, and angiogenesis. PRL contributes to physiological liver growth and has potential clinical utility for ensuring survival and regulating liver mass in diseases, injuries, or surgery of the liver.

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Telocytes in Pregnancy-Induced Physiological Liver Growth

Cellular Physiology and Biochemistry ◽

10.1159/000374068 ◽

2015 ◽

Vol 36 (1) ◽

pp. 250-258 ◽

Cited By ~ 17

Author(s):

Fei Wang ◽

Yihua Bei ◽

Yingying Zhao ◽

Yang Song ◽

Junjie Xiao ◽

...

Keyword(s):

Liver Regeneration ◽

Liver Weight ◽

Hepatocyte Proliferation ◽

Double Immunostaining ◽

Liver Growth ◽

Pregnant Mice ◽

Two Peaks ◽

Proliferation Of Hepatocytes ◽

Double Immunolabeling ◽

In Pregnancy

Background/Aims: We previously documented the presence of Telocytes (TCs) in liver and further indicated the potential roles of TCs in liver regeneration after hepatectomy. Pregnancy-induced liver growth, other than liver regeneration after hepatectomy, is a physiological hepatic adaption to meet the enhanced nutritional and metabolic demands. However, the possible roles of TCs in pregnancy-induced liver growth remain unknown. Methods: Pregnant mice were sacrificed at different time points (pregnancy day 0.5, 4.5, 8.5, 10.5, 12.5, 14.5, 16.5, and 18.5). The liver weight was used to evaluate the liver growth during pregnancy. Hepatocytes proliferation was determined by albumin and 5-ethynyl-2'- deoxyuridine (EdU) double immunostaining while TCs were counted by double immunolabeling for CD34/PDGFR-α. Results: Pregnancy-induced liver growth was preceded by increased proliferation of hepatocytes at pregnancy day 4.5, 8.5, 14.5 and 16.5. Furthermore, the number of TCs in liver detected by double immunolabeling for CD34/PDGFR-α was significantly increased at pregnancy day 4.5 and day 14.5, that was coincident with the occurrence of two peaks of hepatic cell proliferation during pregnancy. Conclusion: Our results suggest a possible relationship between TCs and hepatocyte proliferation in pregnancy-induced liver growth.

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

Molecules ◽

10.3390/molecules26082231 ◽

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.

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

Bioscience Biotechnology and Biochemistry ◽

10.1093/bbb/zbaa049 ◽

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.

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Implication for Bone Marrow Derived Stem Cells in Hepatocyte Regeneration after Orthotopic Liver Transplantation

International Journal of Hepatology ◽

10.1155/2013/310612 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7 ◽

Cited By ~ 3

Author(s):

N. Pilat ◽

L. Unger ◽

G. A. Berlakovich

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Liver Transplantation ◽

Liver Regeneration ◽

Orthotopic Liver Transplantation ◽

Liver Tissue ◽

Hepatic Regeneration ◽

Liver Growth ◽

Cell Source ◽

The Impact

The liver has the outstanding ability to regenerate itself and restore parenchymal tissue after injury. The most common cell source in liver growth/regeneration is replication of preexisting hepatocytes although liver progenitor cells have been postulated to participate in liver regeneration in cases of massive injury. Bone marrow derived hematopoietic stem cells (BM-HSC) have the formal capacity to act as a source for hepatic regeneration under special circumstances; however, the impact of this process in liver tissue maintenance and regeneration remains controversial. Whether BM-HSC are involved in liver regeneration or not would be of particular interest as the cells have been suggested to be an alternative donor source for the treatment of liver failure. Data from murine models of liver disease show that BM-HSC can repopulate liver tissue and restore liver function; however, data obtained from human liver transplantation show only little evidence for liver regeneration by this mechanism. The cell source for liver regeneration seems to depend on the nature of regeneration process and the extent of injury; however, the precise mechanisms still need to be resolved. Current data suggest, that in human orthotopic liver transplantation, liver regeneration by BM-HSC is a rather rare event and therefore not of clinical relevance.

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

Genetics and Molecular Research ◽

10.4238/2015.july.13.9 ◽

2015 ◽

Vol 14 (3) ◽

pp. 7643-7654 ◽

Cited By ~ 1

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

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The impact of steatosis on liver regeneration

Hormone Molecular Biology and Clinical Investigation ◽

10.1515/hmbci-2018-0050 ◽

2018 ◽

Vol 0 (0) ◽

Cited By ~ 3

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.

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