Markers of liver regeneration—the role of growth factors and cytokines: a systematic review

Hoffmann, Katrin; Nagel, A.; Tanabe, Kazukata; Fuchs, Juri; Dehlke, Karolin; Ghamarnejad, Omid; Lemekhova, Anastasia; Mehrabi, Arianeb

doi:10.1186/s12893-019-0664-8

Cited by 64 publications

(68 citation statements)

References 182 publications

(192 reference statements)

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“…TGF-α is an important growth factor in liver regeneration that directly stimulates DNA synthesis in hepatocytes [ 28 ], and HGF is produced in the liver by nonparenchymal cells and acts as a complete mitogen for efficient liver regeneration and repair [ 27 , 40 ]. The important roles of these growth factors in liver regeneration have been extensively reported [ 37 , 40 ]. These findings indicate that the TLR5 pathway also regulates the proliferation phase of liver regeneration through inducing hepatocyte proliferation-associated growth factors.…”

Section: Discussionmentioning

confidence: 99%

Toll-like receptor 5-mediated signaling enhances liver regeneration in mice

et al. 2021

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Background Toll-like receptor 5 (TLR5)-mediated pathways play critical roles in regulating the hepatic immune response and show hepatoprotective effects in mouse models of hepatic diseases. However, the role of TLR5 in experimental models of liver regeneration has not been reported. This study aimed to investigate the role of TLR5 in partial hepatectomy (PHx)-induced liver regeneration. Methods We performed 2/3 PHx in wild-type (WT) mice, TLR5 knockout mice, or TLR5 agonist CBLB502 treated mice, as a model of liver regeneration. Bacterial flagellin content was measured with ELISA, and hepatic TLR5 expression was determined with quantitative PCR analyses and flow cytometry. To study the effects of TLR5 on hepatocyte proliferation, we analyzed bromodeoxyuridine (BrdU) incorporation and proliferating cell nuclear antigen (PCNA) expression with immunohistochemistry (IHC) staining. The effects of TLR5 during the priming phase of liver regeneration were examined with quantitative PCR analyses of immediate early gene mRNA levels, and with Western blotting analysis of hepatic NF-κB and STAT3 activation. Cytokine and growth factor production after PHx were detected with real-time PCR and cytometric bead array (CBA) assays. Oil Red O staining and hepatic lipid concentrations were analyzed to examine the effect of TLR5 on hepatic lipid accumulation after PHx. Results The bacterial flagellin content in the serum and liver increased, and the hepatic TLR5 expression was significantly up-regulated in WT mice after PHx. TLR5-deficient mice exhibited diminished numbers of BrdU- and PCNA-positive cells, suppressed immediate early gene expression, and decreased cytokine and growth factor production. Moreover, PHx-induced hepatic NF-κB and STAT3 activation was inhibited in Tlr5−/− mice, as compared with WT mice. Consistently, the administration of CBLB502 significantly promoted PHx-mediated hepatocyte proliferation, which was correlated with enhanced production of proinflammatory cytokines and the recruitment of macrophages and neutrophils in the liver. Furthermore, Tlr5−/− mice displayed significantly lower hepatic lipid concentrations and smaller Oil Red O positive areas than those in control mice after PHx. Conclusion We reveal that TLR5 activation contributes to the initial events of liver regeneration after PHx. Our findings demonstrate that TLR5 signaling positively regulates liver regeneration and suggest the potential of TLR5 agonist to promote liver regeneration.

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Section: Discussionmentioning

confidence: 99%

Toll-like receptor 5-mediated signaling enhances liver regeneration in mice

et al. 2021

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“…The fact that the optimum serum concentration for the stimulation of tumour cell proliferation is lower when using serum from hepatectomized animals suggests that there is something in it which make it more a powerful stimulus for cell growth. It is well known that following any kind of surgery there is an increase in GF levels in serum, both in humans 48 , 49 and in rats 49 , 50 . HGF increases following lung surgery 51 , but the increment is quite greater following liver resection (from 50 to 250 ng/ml) 42 .…”

Section: Discussionmentioning

confidence: 99%

Partial hepatectomy enhances the growth of CC531 rat colorectal cancer cells both in vitro and in vivo

Parte

González-Arribas

Diaz-Sanz

et al. 2021

Sci Rep

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Partial hepatectomy (PHx) is the gold standard for the treatment of colorectal cancer liver metastases. However, after removing a substantial amount of hepatic tissue, growth factors are released to induce liver regeneration, which may promote the proliferation of liver micrometastases or circulating tumour cells still present in the patient. The aim of this study is to assess the effect of PHx on the growth of liver metastases induced by intrasplenic cell inoculation as well as on in vitro proliferation of the same cancer cell line. Liver tumours were induced in 18 WAG/RijHsd male rats, by seeding 250,000 syngeneic colorectal cancer cells (CC531) into the spleen. The left lateral lobe of the liver was mobilized and in half of the animals it was removed to achieve a 40% hepatectomy. Twenty-eight days after tumour induction, the animals were sacrificed and the liver was removed and sliced to assess the relative tumour surface area (RTSA%). CC531 cells were cultured in presence of foetal calf serum, non-hepatectomised (NRS) or hepatectomized rat serum (HRS), and their proliferation rate at 24, 48, and 72 h was measured. RTSA% was significantly higher in animals which had undergone PHx than in the controls (non-hepatectomised) (46.98 ± 8.76% vs. 18.73 ± 5.65%; p < 0.05). Analysing each lobe separately, this difference in favour of hepatectomized animals was relevant and statistically significant in the paramedian and caudate lobes. But in the right lobe the difference was scarce and not significant. In vitro, 2.5% HRS achieved stronger proliferative rates than the control cultures (10% FCS) or their equivalent of NRS. In this experimental model, a parallelism has been shown between the effect of PHx on the growth of colorectal cancer cells in the liver and the effect of the serum on those cells in vitro.

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“…It is thought that the appearance of these mitogenic factors and signaling molecules (endothelial growth factor, transforming growth factor, tumor necrosis factor, NO, etc .) is associated with both mechanical damage of the liver tissue during PH and/or the realization by the blood vessels of residual liver[ 16 , 33 , 37 , 38 ]. The acute portal hypertension acts as a triggering mechanism in post-resection liver regeneration.…”

Section: Discussionmentioning

confidence: 99%

“…From the obtained suspensions smears were prepared. The Feulgen method (Schiff reaction) was used to determine the concentration of DNA in the nuclei of dissociated cells[ 32 , 33 ]. The capture of the specimen stained with the Schiff's reagent was performed by using a light microscope (ZEN 2.3 SP1; 100 × 10).…”

Section: Methodsmentioning

confidence: 99%

Liver structural transformation after partial hepatectomy and repeated partial hepatectomy in rats: A renewed view on liver regeneration

Tsomaia

Patarashvili

Karumidze

et al. 2020

WJG

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BACKGROUND The phenomenon of liver regeneration after partial hepatectomy (PH) is still a subject of considerable interest due to the increasing frequency of half liver transplantation on the one hand, and on the other hand, new surgical approaches which allow removal of massive space-occupying hepatic tumors, which earlier was considered as inoperable. Interestingly, the mechanisms of liver regeneration are extensively studied after PH but less attention is paid to the architectonics of the regenerated organ. Because of this, the question “How does the structure of regenerated liver differ from normal, regular liver?” has not been fully answered yet. Furthermore, almost without any attention is left the liver's structural transformation after repeated hepatectomy (of the re-regenereted liver). AIM To compare the architectonics of the lobules and circulatory bed of normal, re-generated and re-regenerated livers. METHODS The livers of 40 adult, male, albino Wistar rats were studied. 14 rats were subjected to PH - the 1 st study group (SG1); 10 rats underwent repeated PH – the 2 nd study group (SG2); 16 rats were subjected to sham operation - control group (CG); The livers were studied after 9 months from PH, and after 6 months from repeated PH. Cytological (Schiff reaction for the determination of DNA concen-tration), histological (H&E, Masson trichrome, CK8 Immunohistochemical marker, transparent slides after Indian Ink injection, ), morphometrical (hepatocytes areas, perimeters and ploidy) and Electron Microscopical (Scanning Electron Microscopy of corrosion casts) methods were used. RESULTS In the SG1 and SG2, the area of hepatocytes and their perimeter are increased compared to the CG ( P < 0.05). However, the areas and perimeters of the hepatocytes of the SG 1 and SG 2 groups reveal a lesser difference. In regenerated (SG 1 ) and re-regenerated (SG 2 ) livers, the hepatocytes form the remodeled lobules, which size (300-1200 µm) exceeds the sizes of the lobules from CG (300-600 µm). The remodeled lobules (especially the “mega-lobules” with the sizes 1000-1200 µm) contain the transformed meshworks of the sinusoids, the part of which is dilated asymmetrically. This meshwork might have originated from the several portal venules (interlobular and/or inlet). The boundaries between the adjacent lobules (including mega-lobules) are widened and filled by connective tissue fibers, which gives the liver parenchyma a nodular look. In SG 2 the unevenness of sinusoid diameters, as well as the boundaries between the lobules (including the mega-lobules) are more vividly expressed in comparison with SG 1 . The liver tissue of both SG 1 and SG 2...

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Markers of liver regeneration—the role of growth factors and cytokines: a systematic review

Cited by 64 publications

References 182 publications

Toll-like receptor 5-mediated signaling enhances liver regeneration in mice

Toll-like receptor 5-mediated signaling enhances liver regeneration in mice

Partial hepatectomy enhances the growth of CC531 rat colorectal cancer cells both in vitro and in vivo

Liver structural transformation after partial hepatectomy and repeated partial hepatectomy in rats: A renewed view on liver regeneration

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