Hepatic parenchymal cells are a type of liver cells that performs important functions such as metabolism and detoxification. The contribution of hepatic parenchymal cells, bile duct cells, and hepatic stem/progenitor cells to new hepatic parenchymal cells in the process of liver injury repair has become a controversial issue due to their strong proliferation ability. Lineage tracing technology, which has emerged in the past decade as a new method for exploring the origin of cells, can trace specific type of cells and their daughter cells by labeling cells that express the specific gene and their progeny. The article reviews the current literature on the origin and contribution of hepatic parenchymal cells by this technique. About 98% of new hepatic parenchymal cells originate from the existing hepatic parenchymal cells during liver homeostasis and after acute injury. However, under conditions of severe liver injury, such as inhibition of hepatic parenchymal cell proliferation, bile duct cells (mainly liver stem/progenitor cells) become the predominant source of hepatic parenchymal cells, contributing a steady increased hepatocyte regeneration with the extension of time.
Hepatocytes/metabolism* ; Liver/metabolism* ; Bile Ducts ; Stem Cells ; Liver Regeneration/physiology* ; Cell Differentiation

BACKGROUND: The clinical trials emerged centromere protein E inhibitor GSK923295 as a promising anticancer drug, but its function in hepatocellular carcinoma (HCC) remain needs to be fully elucidated, especially as chemotherapy after hepatectomy for liver tumors. We aimed to describe anti-HCC activities of GSK923295 and compare its antiproliferative effects on liver regeneration after partial hepatectomy (PH). METHODS: All subjects were randomized to treatment with either vehicle or GSK923295. Antitumor activity of GSK923295 was assessed by xenograft growth assays. The C57BL/6 mice were subjected to 70% PH and the proliferation was calculated by liver coefficient, further confirmed by immunohistochemistry. The proliferation and cell cycle analysis of liver cell AML12 and HCC cells LM3, HUH7, and HepG2 were investigated using the cell counting kit-8 assay and Flow Cytometry. The chromosome misalignment and segregation in AML12 cells were visualized by immunofluorescence. RESULTS: Treatment with GSK923295 induced antiproliferation in HCC cell lines. It also caused delay on HCC tumor growth instead of regression both in a HCC cell line xenograft model and patient-derived tumor xenograft model. With microarray analysis, CENtromere Protein E was gradually increased in mouse liver after PH. Exposure of liver cells to GSK923295 resulted in delay on a cell cycle in mitosis with a phenotype of misaligned chromosomes and chromosomes clustered. In 70% PH mouse model, GSK923295 treatment also remarkably reduced liver regeneration in later stage, in parallel with the mitotic marker phospho-histone H3 elevation. CONCLUSION The anticancer drug GSK923295 causes a significant delay on HCC tumor growth and liver regeneration after PH in later stage.
Animals ; Antineoplastic Agents ; therapeutic use ; Blotting, Western ; Bridged Bicyclo Compounds, Heterocyclic ; therapeutic use ; Carcinoma, Hepatocellular ; drug therapy ; surgery ; Cell Cycle ; drug effects ; Cell Proliferation ; drug effects ; Chromosomal Proteins, Non-Histone ; antagonists & inhibitors ; Electrophoresis, Polyacrylamide Gel ; Female ; Fluorescent Antibody Technique ; Humans ; Immunohistochemistry ; Liver Neoplasms ; drug therapy ; surgery ; Liver Regeneration ; physiology ; Mice ; Mice, Inbred C57BL ; Real-Time Polymerase Chain Reaction ; Sarcosine ; analogs & derivatives ; therapeutic use ; Xenograft Model Antitumor Assays

Mesothelial cells (MCs) cover the surface of visceral organs and the parietal walls of cavities, and they synthesize lubricating fluids to create a slippery surface that facilitates movement between organs without friction. Recent studies have indicated that MCs play active roles in liver development, fibrosis, and regeneration. During liver development, the mesoderm produces MCs that form a single epithelial layer of the mesothelium. MCs exhibit an intermediate phenotype between epithelial cells and mesenchymal cells. Lineage tracing studies have indicated that during liver development, MCs act as mesenchymal progenitor cells that produce hepatic stellate cells, fibroblasts around blood vessels, and smooth muscle cells. Upon liver injury, MCs migrate inward from the liver surface and produce hepatic stellate cells or myofibroblast depending on the etiology, suggesting that MCs are the source of myofibroblasts in capsular fibrosis. Similar to the activation of hepatic stellate cells, transforming growth factor β induces the conversion of MCs into myofibroblasts. Further elucidation of the biological and molecular changes involved in MC activation and fibrogenesis will contribute to the development of novel approaches for the prevention and therapy of liver fibrosis.
Epithelial Cells/*physiology ; Epithelium/metabolism ; Hepatic Stellate Cells/*physiology ; Humans ; Liver/*cytology/injuries/*physiology ; Liver Cirrhosis/etiology/prevention & control ; Liver Regeneration/*physiology ; Mesenchymal Stromal Cells/physiology ; Myofibroblasts/physiology

OBJECTIVEThis study was conducted to determine the histopathological and biochemical effects of Thymus algeriensis essential oil (TEO) on hydrogen peroxide (H2O2)-induced oxidative stress in liver and kidney tissues of rats.

METHODSRats were treated in six groups and were exposed for 2 weeks to low (LD; 100 μmol/L) and high doses (HD; 1 mmol/L) of H2O2 in the presence or absence of TEO (180 mg/kg). Liver and kidney atrophy was measured by using biochemical and histopathological assays.

RESULTSOur study demonstrated that H2O2 induced liver and kidney atrophy, as evidenced by the significant elevation of serum aminotransferase, urea, and creatinine levels compared with those in the control rats. Urea levels were estimated by evaluating the activity of serum urease that hydrolyzes urea into CO2 and ammonia. However, TEO treatment significantly alleviated oxidative stress in the H2O2-induced liver and kidney toxicity model by reducing the levels of malondialdehyde concomitantly with marked elevations in superoxide dismutase, catalase, glutathione peroxidase, and glutathione S-transferase, as well as decrease in glutathione activity.

CONCLUSIONOur data demonstrated that TEO protected against H2O2 toxicity by decreasing oxidant levels and DNA damage, as well as increasing antioxidant levels, indicating that TEO has a spectrum of antioxidant and DNA-protective properties.

Animals ; Antioxidants ; pharmacology ; Hydrogen Peroxide ; metabolism ; toxicity ; Kidney ; drug effects ; physiology ; Lipid Metabolism ; drug effects ; Liver ; drug effects ; physiology ; Male ; Malondialdehyde ; metabolism ; Oils, Volatile ; pharmacology ; Oxidative Stress ; drug effects ; Plant Extracts ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Regeneration ; drug effects ; Thymus Plant ; chemistry

In cirrhotic patients undergoing liver transplantation, reperfusion of a liver graft typically increases portal venous blood flow (PVF) because of a decrease in resistance in the liver graft to the PVF and underlying hyperdynamic splanchnic circulation, which develops due to liver cirrhosis complicated by portal hypertension and persists even after successful liver transplantation. If the liver graft has enough capacity to accommodate the increased PVF, the shear stress inflicted on the sinusoidal endothelial cells of the graft promotes hepatic regeneration; otherwise, small-for-size syndrome (SFSS) develops, leading to poor graft function and graft failure. In particular, a partial graft transplanted to patients undergoing living donor liver transplantation has less capacity to accommodate the enhanced PVF than a whole liver graft. Thus, the clinical conditions that the partial graft encounters determine either hepatic regeneration or development of SFSS. Consistent with this, this review will discuss the two conflicting effects of portal hyperperfusion (hepatic regeneration vs. portal hyperperfusion injury) on the partial grafts in cirrhotic patients suffering from hyperdynamic splanchnic circulation, in addition to normal physiology and pathophysiology of hepatic hemodynamics.
Endothelial Cells ; Hemodynamics ; Humans ; Hypertension, Portal ; Liver Cirrhosis ; Liver Regeneration ; Liver Transplantation ; Liver* ; Living Donors ; Physiology ; Regeneration* ; Reperfusion ; Splanchnic Circulation* ; Transplants*

Amnion ; metabolism ; physiology ; Female ; Hepatectomy ; Humans ; Liver Regeneration ; physiology ; Pregnancy ; Wound Healing ; physiology

Vitamin D3 up-regulated protein 1 (VDUP1) is a potent growth suppressor that inhibits tumor cell proliferation and cell cycle progression when overexpressed. In a previous study, we showed that VDUP1 knockout (KO) mice exhibited accelerated liver regeneration because such animals could effectively control the expression of cell cycle regulators that drive the G1-to-S phase progression. In the present study, we further investigated the role played by VDUP1 in initial priming of liver regeneration. To accomplish this, VDUP1 KO and wild-type (WT) mice were subjected to 70% partial hepatectomy (PH) and sacrificed at different times after surgery. The hepatic levels of TNF-alpha and IL-6 increased after PH, but there were no significant differences between VDUP1 KO and WT mice. Nuclear factor-kappaB (NF-kappaB), c-Jun-N-terminal kinase (JNK), and signal transducer and activator of transcription 3 (STAT-3) were activated much earlier and to a greater extent in VDUP1 KO mice after PH. A single injection of TNF-alpha or IL-6 caused rapid activation of JNK and STAT-3 expression in both mice, but the responses were stronger and more sustained in VDUP1 KO mice. In conclusion, our findings provide evidence that VDUP1 plays a role in initiation of liver regeneration.
Animals ; Blotting, Western ; Carrier Proteins/*genetics/metabolism ; Cell Proliferation ; *Gene Expression Regulation ; Hepatectomy ; Hepatocytes/*cytology/physiology ; JNK Mitogen-Activated Protein Kinases/genetics/metabolism ; Liver/*physiology ; Male ; Mice, Knockout ; NF-kappa B/genetics/metabolism ; Polymerase Chain Reaction ; *Regeneration ; STAT3 Transcription Factor/genetics/metabolism ; Thioredoxins/*genetics/metabolism

OBJECTIVETo observe the effect of D-galactosamine (D-GaIN) and lipopolysaccharide (LPS) on liver tissue regeneration and repair in mice following liver injury induced by partial hepatectomy.

METHODSA total of 40 male BALB/c mice were randomly assigned into 2 equal groups to receive intraperitoneal injections of D-GaIN (500 mg/kg) plus LPS (50 µg/kg, given 1 h later) or two doses of saline 24 h prior to 1/3 hepatectomy. The liver weight/body weight (LW/BW) ratio and liver regeneration rate were observed at different time points after partial hepatectomy. Liver cell injury was assessed using HE staining, hepatocyte proliferation evaluated with BrdU staining, and the oval cell proliferation observed with immunohistochemistry.

RESULTSIn mice receiving saline injection, the liver volume was nearly restored 9 days after partial hepatectomy, while in mice with D-GaIN and LPS injections, the liver failed to recover the normal volume even at 14 days, showing a significant difference in the liver regeneration rate between them [(22.6∓105.93)% vs (9.49∓32.55)%, P<0.001]. Significant degenerative changes of the hepatic cells were found in D-GaIN/LPS-treated group, while only mild inflammatory reaction was observed in saline-treated group after partial hepatectomy. Obvious hepatocyte proliferation was observed at day 7 in saline-treated group but not in D-GaIN/LPS-treated group. Oval cell proliferation in the portal area occurred 3 days after partial hepatectomy in D-GaIN/LPS-treated group.

CONCLUSIOND-GaIN and LPS can obviously inhibit hepatocyte regeneration after liver injury in mice. D-GaIN and LPS combined with partial hepatectomy can induce oval cell proliferation.

Animals ; Cell Proliferation ; drug effects ; Galactosamine ; pharmacology ; Hepatectomy ; methods ; Lipopolysaccharides ; pharmacology ; Liver ; cytology ; injuries ; physiopathology ; Liver Regeneration ; drug effects ; physiology ; Male ; Mice ; Mice, Inbred BALB C ; Stem Cells ; cytology

BACKGROUNDHilar cholangiocarcinoma is a malignant tumor that is difficult to cure. The aim of this study was to observe the effects of flow-controlled partial portal vein arterializations (PPVA) on liver regeneration after hepatectomy in minipigs with chronic obstructive jaundice.

METHODSEight minipigs were made into chronic obstructive jaundice models. United semi-hepatectomy, which imitates extended radical surgery for treatment of hilar cholangiocarcinoma, was then performed. The eight minipigs were randomly divided into groups A and B (n = 4 minipigs each). PPVA was performed in Group A but not in Group B. The effects of flow-controlled PPVA on live regeneration after hepatectomy were observed for 30 days after hepatectomy.

RESULTSThe portal vein PO(2) at the immediate time point and on postoperative day 30 was higher in Group A ((47.33 ± 2.43) and (48.50 ± 4.44) mmHg) than in Group B ((35.38 ± 4.06) and (35.55 ± 2.55) mmHg respectively, all P < 0.01). The mitotic index of liver cells on postoperative days 14 and 21 was higher in Group A (12.55% ± 2.85% and 15.25% ± 1.99% respectively) than in Group B (6.85% ± 2.10% and 11.88% ± 1.15% respectively, all P < 0.05). The regeneration rate of residual liver on postoperative days 14 and 21 was higher in Group A (24.56% ± 6.15% and 70.63% ± 9.83% respectively) than in Group B (11.96% ± 5.43% and 44.92% ± 7.42% respectively, P < 0.05 and P < 0.01 respectively).

CONCLUSIONFlow-controlled PPVA can promote liver regeneration after hepatectomy and prevent liver failure in minipigs with chronic obstructive jaundice.

Acepromazine ; therapeutic use ; Animals ; Arteriovenous Shunt, Surgical ; methods ; Atropine ; therapeutic use ; Female ; Hepatectomy ; methods ; Jaundice, Obstructive ; surgery ; Ketamine ; therapeutic use ; Liver Regeneration ; physiology ; Portal Vein ; surgery ; Swine ; Swine, Miniature

OBJECTIVETo explore the effects of different hepatic inflow occlusion methods on liver regeneration in rats after partial hepatectomy (PH).

METHODSMale Wistar-Furth rats were randomly assigned to three groups: control group, underwent 68% hepatectomy alone; occlusion of portal triad (OPT) group, subjected to occlusion of portal triad under portal blood bypass; and occlusion of portal vein (OPV) group, subjected to occlusion of portal vein under portal blood bypass. Blood flow was occluded for 20, 30, and 40 minutes before 68% hepatectomy. According to the 7-day survival of each group, a same occlusion time T was set. Each group was divided into two subgroups (n = 8), in which animals were killed 3 and 7 days later. Liver regeneration was calculated as a percent of initial liver weight. Immunohistochemistry for proliferating cell nuclear antigen (PCNA) and Ki-67 was performed to quantify proliferating cells. In addition, functional liver volume represented by 99Tc(m)-GSA radioactivity was assessed.

RESULTSThe safe tolerance limit time was 30 minutes for OPT group and 40 minutes for OPV group. At 3 days after PH, no significant difference was observed in the regeneration rate of each group (P > 0.05). However, liver radioactive activity, PCNA labeling index, and Ki-67 index of OPV group was significantly higher than those of OPT group (P < 0.05); the latter were similar to those of control group (P > 0.05). At 7 days after PH, no significant difference was observed in all indexes among three groups (P > 0.05).

CONCLUSIONCompared with Pringle maneuver, preserving the hepatic artery flow during portal triad blood inflow occlusion can promote remnant liver regeneration early after PH.

Animals ; Hepatectomy ; methods ; Liver ; blood supply ; surgery ; Liver Regeneration ; physiology ; Male ; Postoperative Period ; Rats ; Rats, Wistar