Studies on the hyperplasia ('regeneration') of the rat liver following partial hepatectomy. Changes in lipid peroxidation and general biochemical aspects.
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ABSTRACT:
SUBMITTER: Slater TF
PROVIDER: S-EPMC1136613 | biostudies-other | 1990 Jan
REPOSITORIES: biostudies-other
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Project description:Aberrant transcriptional regulation contributes to the pathogenesis of both congenital and adult forms of liver disease. Although the transcription factor RBPJ is essential for liver morphogenesis and biliary development, its specific function in the differentiation of hepatic progenitor cells (HPC) has not been investigated, and little is known about its role in adult liver regeneration. HPCs are bipotent liver stem cells that can self-replicate and differentiate into hepatocytes or cholangiocytes in vitro. HPCs are thought to play an important role in liver regeneration and repair responses. While the coordinated repopulation of both hepatocyte and cholangiocyte compartment is pivotal to the structure and function of the liver after regeneration, the mechanisms coordinating biliary regeneration remain vastly understudied. Here, we utilized complex genetic manipulations to drive liver-specific deletion of the Rbpj gene in conjunction with lineage tracing techniques to delineate the precise functions of RBPJ during biliary development and HPC-associated biliary regeneration after hepatectomy. Furthermore, we demonstrate that RBPJ promotes HPC differentiation toward cholangiocytes in vitro and blocks hepatocyte differentiation through mechanisms involving Hippo-Notch crosstalk. Overall, this study demonstrates that the Notch-RBPJ signaling axis critically regulates biliary regeneration by coordinating the fate decision of HPC and clarifies the molecular mechanisms involved.
| S-EPMC4782135 | biostudies-literature
Project description:The resectable liver volume is strictly limited and this reduces the number of patients who may be treated. Recently, "tissue/organ decellularization", a new approach in bioengineering, has been investigated for its ability to produce a native organ scaffold by removing all the viable cells. Such a scaffold may support the repair of damaged or injured tissue. The purpose of this study was to evaluate the potential contribution of liver scaffolds to hepatic regeneration after hepatectomy. We sutured the partial liver scaffolds onto the surfaces of partially hepatectomized porcine livers and assessed their therapeutic potential by immune histological analysis at various time points. Animals were sacrificed after surgery and the implanted scaffolds were evaluated for the infiltration of various types of cells. Immune histochemical study showed that blood vessel-like structures, covered with CD31 positive endothelial cells and ALB positive cells, were present in all parts of the scaffolds at days 10 and 28. Blood inflow was observed in some of these ductal structures. More interestingly, CK19 and EpCAM positive cells appeared at day 10. These results suggest that the implantation of a decellularized organ scaffold could promote structural reorganization after liver resection.
| S-EPMC6715632 | biostudies-literature
Project description:BackgroundWhile evaluation of liver function in preclinical animal studies is commonly performed at selected time-points by invasive determination of the liver/body weight ratio and histological analyses, the validation of longitudinal measurement tools for monitoring liver function are of major interest.AimsTo longitudinally evaluate serum cholinesterase (CHE) and total serum bilirubin (TSB) levels as non-invasive markers to determine injury- and partial hepatectomy (PHx)-induced alterations of liver function in rats.MethodsMale and female Lewis rats were subjected to either methionine/choline deficient (MCD) diet or treatment with FOLFOX chemotherapy prior to PHx. Body weight and CHE/TSB levels are determined weekly. Following PHx and at the study end, histological analyses of liver tissue are performed.ResultsFollowing MCD diet, but not after FOLFOX chemotherapy treatment, results indicate gender-specific alterations in serum CHE levels and gender-independent alterations in TSB levels. Likewise, histological analyses of resected liver parts indicate significant liver injury following MCD-diet, but not following FOLFOX treatment. While TSB levels rapidly recover following MCD diet/FOLFOX treatment combined with a PHx, serum CHE levels are subject to significant model- and gender-specific differences, despite full histopathological recovery of liver tissue.ConclusionsLongitudinal measurements of serum CHE levels and TSB levels in rats are highly complementary as non-invasive parameters for evaluation of liver injury and/or recovery.
| S-EPMC3688924 | biostudies-literature
Project description:Understanding the molecular mechanisms of liver regeneration is essential to improve the survival rate of patients after surgical resection of large amounts of liver tissue. Focal adhesion kinase (FAK) regulates different cellular functions, including cell survival, proliferation and cell migration. The role of FAK in liver regeneration remains unknown. In this study, we found that Fak is activated and induced during liver regeneration after two-thirds partial hepatectomy (PHx). We used mice with liver-specific deletion of Fak and investigated the role of Fak in liver regeneration in 2/3 PHx model (removal of 2/3 of the liver). We found that specific deletion of Fak accelerates liver regeneration. Fak deletion enhances hepatocyte proliferation prior to day 3 post-PHx but attenuates hepatocyte proliferation 3 days after PHx. Moreover, we demonstrated that the deletion of Fak in liver transiently increases EGFR activation by regulating the TNF?/HB-EGF axis during liver regeneration. Furthermore, we found more apoptosis in Fak-deficient mouse livers compared to WT mouse livers after PHx.ConclusionOur data suggest that Fak is involved in the process of liver regeneration, and inhibition of FAK may be a promising strategy to accelerate liver regeneration in recipients after liver transplantation.
| S-EPMC5039626 | biostudies-literature
Project description:Our aim was to study the impact of bleeding and red blood cell (RBC) resuscitation on liver regeneration. We assessed the impact of RBC storage time on liver regeneration following 50% partial hepatectomy (PHx) in rats, and explored possible contributing molecular mechanisms using immunohistochemistry, RNA-Seq, and macrophage depletion.
2022-11-14 | GSE216924 | GEO
Project description:Nearly 50 % of colorectal cancer (CRC) patients develop liver metastases with liver resection being the only option to cure patients. Residual micrometastases or circulating tumor cells are considered a cause of tumor relapse. This work investigates the influence of partial hepatectomy (PH) on the growth and molecular composition of CRC liver metastasis in a syngeneic rat model. One million CC531 colorectal tumor cells were implanted via the portal vein in WAG/Rij rats followed by a 30 % PH a day later. Control groups either received tumor cells followed by a sham-operation or were injected with a buffer solution followed by PH. Animals were examined with magnetic resonance imaging (MRI) and liver tissues were processed for immunolabeling and PCR analysis. One-third PH was associated with an almost threefold increase in relative tumor mass (MRI volumetry: 2.8-fold and transcript levels of CD44: 2.3-fold). Expression of molecular markers for invasiveness and aggressiveness (CD49f, CXCR4, Axin2 and c-met) was increased following PH, however with no significant differences when referring to the relative expression levels (relating to tumor mass). Liver metastases demonstrated a significantly higher proliferation rate (Ki67) 2 weeks following PH and cell divisions also increased in the surrounding liver tissue. Following PH, the stimulated growth of metastases clearly exceeded the compensation in liver volume with long-lasting proliferative effects. However, the distinct tumor composition was not influenced by liver regeneration. Future investigations should focus on the inhibition of cell cycle (i.e. systemic therapy strategies, irradiation) to hinder liver regeneration and therefore restrain tumor growth.
| S-EPMC3663204 | biostudies-literature
Project description:Paracrine interactions are critical to liver physiology, particularly during regeneration, although physiological involvement of extracellular ATP, a crucial intercellular messenger, remains unclear. The physiological release of ATP into extracellular milieu and its impact on regeneration after partial hepatectomy were investigated in this study.Hepatic ATP release after hepatectomy was examined in the rat and in human living donors for liver transplantation. Quinacrine was used for in vivo staining of ATP-enriched compartments in rat liver sections and isolated hepatocytes. Rats were treated with an antagonist for purinergic receptors (Phosphate-6-azo(benzene-2,4-disulfonic acid), PPADS), and liver regeneration after hepatectomy was analyzed.A robust and transient ATP release due to acute portal hyperpressure was observed immediately after hepatectomy in rats and humans. Clodronate liposomal pre-treatment partly inhibited ATP release in rats. Quinacrine-stained vesicles, co-labeled with a lysosomal marker in liver sections and isolated hepatocytes, were predominantly detected in periportal areas. These vesicles significantly disappeared after hepatectomy, in parallel with a decrease in liver ATP content. PPADS treatment inhibited hepatocyte cell cycle progression after hepatectomy, as revealed by a reduction in bromodeoxyuridine incorporation, phosphorylated histone 3 immunostaining, cyclin D1 and A expression and immediate early gene induction.Extracellular ATP is released immediately after hepatectomy from hepatocytes and Kupffer cells under mechanical stress and promotes liver regeneration in the rat. We suggest that in hepatocytes, ATP is released from a lysosomal compartment. Finally, observations made in living donors suggest that purinergic signalling could be critical for human liver regeneration.
| S-EPMC3625734 | biostudies-literature
Project description:All serious liver injuries alter metabolism and initiate hepatic regeneration. Recent studies using partial hepatectomy (PH) and other experimental models of liver regeneration implicate the metabolic response to hepatic insufficiency as an important source of signals that promote regeneration. Based on these considerations, the analyses reported here were undertaken to assess the impact of interrupting the hypoglycemic response to PH on liver regeneration in mice. A regimen of parenteral dextrose infusion that delays PH-induced hypoglycemia for 14 hours after surgery was identified, and the hepatic regenerative response to PH was compared between dextrose-treated and control mice. The results showed that regenerative recovery of the liver was postponed in dextrose-infused mice (versus vehicle control) by an interval of time comparable to the delay in onset of PH-induced hypoglycemia. The regulation of specific liver regeneration-promoting signals, including hepatic induction of cyclin D1 and S-phase kinase-associated protein 2 expression and suppression of peroxisome proliferator-activated receptor ? and p27 expression, was also disrupted by dextrose infusion. These data support the hypothesis that alterations in metabolism that occur in response to hepatic insufficiency promote liver regeneration, and they define specific pro- and antiregenerative molecular targets whose regenerative regulation is postponed when PH-induced hypoglycemia is delayed.
| S-EPMC4816713 | biostudies-literature
Project description:Alveolar echinococcosis (AE) is caused by the larval stage of echinococcus multilocularis (E. multilocularis), and hepatectomy is the main modality in hepatic AE patients. Liver regeneration after partial hepatectomy (PHx) in such patients is challenging, and further investigation is needed. Thus far, knowledge regarding the possible impact of E. multilocularis on liver regeneration after PHx is limited. Herein, a subcutaneous infection model of E. multilocularis was developed in C57 BL/6 mice, and after 3 months, PHx was performed. Plasma and liver samples were harvested under inhalational isofluorane (2%) anaesthesia at designated post-PHx time points (0, 24, 48, 96 and 168 h). The parameters included the future remnant liver/body weight ratio (FLR/BW), liver function tests (AST and ALT) and related cytokines (TNF-α, IL-6, Factor V, HMGB1, TGF-β, TSP-1, and TLR4) and proteins (MyD88 and STAT3). To assess the proliferation intensity of hepatocytes, BrdU, Ki67 and PAS staining were carried out in regenerated liver tissue. The FLR/BW in the infected group from 48 h after surgery was lower than that in the control group. The BrdU positive hepatocyte proportions reached their peak at 48 h in the control group and 96 h in the infected group and then gradually decreased. During the first 48 h after surgery, both the AST and ALT levels in the infected group were lower; however, these levels were altered from 96 h after surgery. In the infected group, the concentrations and mRNA expression levels of the pre-inflammatory cytokines TNF-α and IL-6 demonstrated a delayed peak. Moreover, post-operatively, the TGF-β and TSP-1 levels showed high levels in the infected group at each different time-point compared to those in the control group; however, high levels of TGF-β were observed at 96 h in the control group. The MyD88 and STAT3 protein expression levels in the infected group were markedly higher than those in the control group 96 h after surgery. Delayed liver regeneration after PHx was observed in the C57 BL/6 mice with the subcutaneous infection of E. multilocularis in the current study. This phenomenon could be partially explained by the alteration in the pro-inflammatory cytokines in the immunotolerant milieu induced by chronic E. multilocularis infection.
| S-EPMC6345980 | biostudies-literature
Project description:The goal of this study is to obtain an expression profile of regenerating mouse livers. We used microarray analysis to study the gene groups coordinately expressed temporally during mouse a liver regeneration. One of the syn-expression groups that showed a sharp rise in gene expression immediately after hepatectomy contains a set pancreatic exocrine genes. The syn-expression profile of pancreatic genes and the pancreatic-specific transcription factors Ptf1a and Ipf1 was confirmed using real-time PCR. Electron microscopic examination showed the presence of morphological features reminiscent of pancreatic acinar cells with the presence of characteristic zymogen granules and ER organization. These results indicate that there is a transient liver-to-pancreas transdifferentiation event at the beginning of liver regeneration. A strong coordinated up-regulation of pancreatic genes was found to accompany the injury response in the pancreas, suggesting a compensatory mechanism for pancreatic functions. There seems to be a relationship between the induction of pancreatic genes and acute phase response at the beginning of liver regeneration. Experiment Overall Design: Total RNA was extracted from livers of mice recovered at Experiment Overall Design: various hours after partial hepatectomy (PHx 4h, 8h, 12h, 36h, Experiment Overall Design: 48h, 72h). We grouped livers of four to six mice together for Experiment Overall Design: RNA extraction. Genes showed differentially up- or downregulated Experiment Overall Design: by two-fold with respect to the normal mouse livers Experiment Overall Design: were identified using GeneSpring software version 7.2 (Silicon Experiment Overall Design: Genetics, Agilent Technologies).
2008-06-13 | E-GEOD-4528 | biostudies-arrayexpress