scholarly journals Telocytes in Pregnancy-Induced Physiological Liver Growth

2015 ◽  
Vol 36 (1) ◽  
pp. 250-258 ◽  
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.

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

Biomolecules ◽  
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.

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

2009 ◽  
Vol 39 (1) ◽  
pp. 86-92 ◽  
Author(s):  
Ali-Reza Biglarnia ◽  
Tomas Lorant ◽  
Hyon-Soek Lee ◽  
Gunnar Tufveson ◽  
Martin Tötsch ◽  
...  
Keyword(s):  
Liver Regeneration ◽  
Hepatocyte Proliferation ◽  
Liver Growth

Loss of NF-κB activation in Kupffer cell-depleted mice impairs liver regeneration after partial hepatectomy

2007 ◽  
Vol 292 (6) ◽  
pp. G1570-G1577 ◽  
Author(s):  
Kerstin Abshagen ◽  
Christian Eipel ◽  
Jörg C. Kalff ◽  
Michael D. Menger ◽  
Brigitte Vollmar
Keyword(s):  
Liver Regeneration ◽  
Liver Weight ◽  
Cyclin B1 ◽  
Binding Activity ◽  
Hepatocyte Proliferation ◽  
Cell Nuclei ◽  
Dna Binding Activity ◽  
Liver Sinusoids ◽  
Tnf Α

Kupffer cells (KCs) are located in the liver sinusoids adjacent to hepatocytes and are capable of producing important growth-regulating mediators that exert both stimulatory and inhibitory influences on hepatocyte proliferation by paracrine mechanisms. To elucidate the overall effect of KC depletion on liver regeneration, mice were selectively and long-standing depleted of KCs by liposome-encapsulated dichloromethylene diphosphonate. Using in vivo fluorescence microscopy, immunohistochemistry, Western blot analysis, and NF-κB transcription factor DNA binding activity and cytokine assays, we analyzed livers of KC-depleted and KC-competent mice at days 3, 5, and 8 after partial (i.e., 68%) hepatectomy (PH). Selective KC elimination delayed cell proliferation, as indicated by significantly reduced PCNA and cyclin B1 protein expression in liver tissue at day 3 after PH. This was associated with a lower liver weight at day 8 upon PH. Resection-associated activation of NF-κB with translocation into parenchymal and nonparenchymal cell nuclei was diminished in livers of KC-depleted mice, primarily at day 3 after PH. KC-depleted mice further lacked the resection-induced rise in TNF-α and IL-6 serum concentrations. These findings imply that KCs play a stimulatory role in liver regeneration, mainly by activating NF-κB with influence on the cell cycle and by enhancing expression of the proliferative cytokines TNF-α and IL-6.

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 Role of vasodilation in liver regeneration and health

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Linda Große-Segerath ◽  
Eckhard Lammert
Keyword(s):  
Blood Flow ◽  
Liver Regeneration ◽  
Molecular Mechanisms ◽  
Vascular System ◽  
Liver Perfusion ◽  
Growth Factor Receptor ◽  
Hepatocyte Proliferation ◽  
Liver Sinusoidal Endothelial Cells ◽  
Liver Growth ◽  
Hepatic Vasculature

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.

scholarly journals Increased Phosphatase of Regenerating Liver-1 by Placental Stem Cells Promotes Hepatic Regeneration in a Bile-Duct-Ligated Rat Model

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2530
Author(s):  
Jong Ho Choi ◽  
Sohae Park ◽  
Gi Dae Kim ◽  
Jae Yeon Kim ◽  
Ji Hye Jun ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bile Duct ◽  
Liver Regeneration ◽  
Rat Model ◽  
Hepatocyte Proliferation ◽  
Hepatic Regeneration ◽  
Regenerating Liver ◽  
Duct Ligation ◽  
Phosphatase Of Regenerating Liver ◽  
Proliferation Of Hepatocytes

Phosphatase of regenerating liver-1 (PRL-1) controls various cellular processes and liver regeneration. However, the roles of PRL-1 in liver regeneration induced by chorionic-plate-derived mesenchymal stem cells (CP-MSCs) transplantation remain unknown. Here, we found that increased PRL-1 expression by CP-MSC transplantation enhanced liver regeneration in a bile duct ligation (BDL) rat model by promoting the migration and proliferation of hepatocytes. Engrafted CP-MSCs promoted liver function via enhanced hepatocyte proliferation through increased PRL-1 expression in vivo and in vitro. Moreover, higher increased expression of PRL-1 regulated CP-MSC migration into BDL-injured rat liver through enhancement of migration-related signals by increasing Rho family proteins. The dual effects of PRL-1 on proliferation of hepatocytes and migration of CP-MSCs were substantially reduced when PRL-1 was silenced with siRNA-PRL-1 treatment. These findings suggest that PRL-1 may serve as a multifunctional enhancer for therapeutic applications of CP-MSC transplantation.

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

2013 ◽  
Vol 305 (7) ◽  
pp. R720-R726 ◽  
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.

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.

Intrahepatic Size Regulation in a Surgical Model: Liver Resection-Induced Liver Regeneration Counteracts the Local Atrophy following Simultaneous Portal Vein Ligation

2016 ◽  
Vol 57 (1-2) ◽  
pp. 125-137 ◽  
Author(s):  
Weiwei Wei ◽  
Tianjiao Zhang ◽  
Haoshu Fang ◽  
Olaf Dirsch ◽  
Andrea Schenk ◽  
...  
Keyword(s):  
Liver Regeneration ◽  
Liver Weight ◽  
Caudate Lobe ◽  
Hepatocyte Proliferation ◽  
Portal Vein Ligation ◽  
Portal Flow ◽  
Liver Lobe ◽  
Size Regulation ◽  
Right Lobe ◽  
The Right

Background/Aim: Liver size regulation is based on the balance between hepatic regeneration and atrophy. To achieve a better understanding of intrahepatic size regulation, we explored the size regulation of a portally deprived liver lobe on a liver subjected to concurrent portal vein ligation (PVL) and partial hepatectomy (PHx). Materials and Methods: Using a surgical rat model consisting of right PVL (rPVL) plus 70% PHx, we evaluated the size regulation of liver lobes 1, 2, 3, and 7 days after the operation in terms of liver weight and hepatocyte proliferation. Portal hyperperfusion was confirmed by measuring portal flow. The portal vascular tree was visualized by injection of a contrast agent followed by CT imaging of explanted livers. Control groups consisted of 70% PHx, rPVL, and sham operation. Results: The size of the ligated right lobe increased to 1.4-fold on postoperative day 7 when subjected to rPVL + 70% PHx. The right lobe increased to 3-fold when subjected to 70% PHx alone and decreased to 0.3-fold when subjected to rPVL only. The small but significant increase in liver weight after the combined procedure was accompanied by a low proliferative response. In contrast, hepatocyte proliferation was undetectable in the right lobe undergoing atrophy after PVL only. The caudate lobe in the rPVL + 70% PHx group increased to 4.6-fold, which is significantly more than in the other groups. This increase in liver weight was paralleled by persisting portal hyperperfusion and a prolonged proliferative phase of 3 days. Conclusions: A discontinued portal blood supply does not always result in atrophy of the ligated lobe. The concurrent regenerative stimulus induced by 70% PHx seemed to counteract the local atrophy after a simultaneously performed rPVL, leading to a low but prolonged regenerative response of the portally deprived liver lobe. This observation supports the conclusion that portal flow is not necessary for liver regeneration. The persisting portal hyperperfusion may be crucial for the specific kinetics of prolonged liver regeneration after rPVL + 70% PHx in the portally supplied caudate lobe. Both observations deserve more attention regarding the underlying mechanism in further studies.

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.

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