Showing papers on "Liver cell published in 2007"
TL;DR: The self-renewal capacity of hHpSCs is indicated by phenotypic stability after expansion for >150 population doublings in a serum-free, defined medium and with a doubling time of ∼36 h, and they are candidates for liver cell therapies.
Abstract: Human hepatic stem cells (hHpSCs), which are pluripotent precursors of hepatoblasts and thence of hepatocytic and biliary epithelia, are located in ductal plates in fetal livers and in Canals of Hering in adult livers. They can be isolated by immunoselection for epithelial cell adhesion molecule–positive (EpCAM+) cells, and they constitute ∼0.5–2.5% of liver parenchyma of all donor ages. The self-renewal capacity of hHpSCs is indicated by phenotypic stability after expansion for >150 population doublings in a serum-free, defined medium and with a doubling time of ∼36 h. Survival and proliferation of hHpSCs require paracrine signaling by hepatic stellate cells and/or angioblasts that coisolate with them. The hHpSCs are ∼9 μm in diameter, express cytokeratins 8, 18, and 19, CD133/1, telomerase, CD44H, claudin 3, and albumin (weakly). They are negative for α-fetoprotein (AFP), intercellular adhesion molecule (ICAM) 1, and for markers of adult liver cells (cytochrome P450s), hemopoietic cells (CD45), and mesenchymal cells (vascular endothelial growth factor receptor and desmin). If transferred to STO feeders, hHpSCs give rise to hepatoblasts, which are recognizable by cordlike colony morphology and up-regulation of AFP, P4503A7, and ICAM1. Transplantation of freshly isolated EpCAM+ cells or of hHpSCs expanded in culture into NOD/SCID mice results in mature liver tissue expressing human-specific proteins. The hHpSCs are candidates for liver cell therapies.
573 citations
TL;DR: It is shown that Cu2+ triggers hepatocyte apoptosis through activation of acid sphingomyelinase (Asm) and release of ceramide, which suggests a previously unidentified mechanism for liver cirrhosis and anemia in Wilson disease.
Abstract: Wilson disease is caused by accumulation of Cu(2+) in cells, which results in liver cirrhosis and, occasionally, anemia. Here, we show that Cu(2+) triggers hepatocyte apoptosis through activation of acid sphingomyelinase (Asm) and release of ceramide. Genetic deficiency or pharmacological inhibition of Asm prevented Cu(2+)-induced hepatocyte apoptosis and protected rats, genetically prone to develop Wilson disease, from acute hepatocyte death, liver failure and early death. Cu(2+) induced the secretion of activated Asm from leukocytes, leading to ceramide release in and phosphatidylserine exposure on erythrocytes, events also prevented by inhibition of Asm. Phosphatidylserine exposure resulted in immediate clearance of affected erythrocytes from the blood in mice. Accordingly, individuals with Wilson disease showed elevated plasma levels of Asm, and displayed a constitutive increase of ceramide- and phosphatidylserine-positive erythrocytes. Our data suggest a previously unidentified mechanism for liver cirrhosis and anemia in Wilson disease.
421 citations
TL;DR: A number of authors have suggested that apoptosis and necrosis are no separate processes but the opposing ends in only one cell mechanism designated necrapoptosis.
Abstract: Cell death is a process accompanying many physiological and pathological situations in organisms. The first cell death pattern that was identified was cell necrosis, described by Virchow in 1871. It was subsequently seen that cell death was an integral part of normal cell and tissue differentiation mechanisms in superior organisms. In this respect early embryological studies revealed that cell death processes were required to model organisms in their final configuration. Morphogenesis systematically entails the removal and generation of new cell and tissue structures. A similar phenomenon is encountered during metamorphosis in invertebrates and inferior vertebrates, where massive tissue involution and cell clearance are coordinately developed physiological processes. This cell death process, designated apoptosis, was characterized by Kerr in 1965. Cell apoptosis and necrosis can be differentiated by a number of both morphological and biochemical parameters. Apoptosis is a controlled removal of the involved cell with no relevant changes in cell metabolism. This process is characterized by the sequential activation of a number of proteases known as caspases, which affect cysteine-aspartate bonds in the substrate. Caspase activation entails DNA fragmentation and cell architecture changes, associated with morphological changes such as nuclear DNA condensation, decreased cell volume, and the generation of apoptotic bodies with no intracellular contents release. Necrosis results from an extreme disruption of cell balance dramatically affecting cell metabolism with a drastic decrease in cell energy contents in the form of adenosine triphosphate (ATP), ion contents changes, increased mitochondrial and cell volume, and intracellular protease activation. This process ultimately leads to a disruption of cell membranes, and release of cell contents, which promotes a secondary inflammatory response. In the liver cell apoptosis usually has a focal distribution, whereas necrosis shows a regional distribution. Despite a clear-cut differentiation between apoptosis and necrosis, both types of cell death usually coexist in the liver, because one stimulus may induce apoptosis or necrosis depending on cell type involved, exposure extent, cell metabolic status, and the integrity of the machinery involved in cell death. In this sense a number of authors have suggested that apoptosis and necrosis are no separate processes but the opposing ends in only one cell mechanism designated necrapoptosis (1). Mitochondriagenerated ATP contents are a key factor in the regulation of apoptosis or necrosis induction during the process of cell death. In this respect a lesion involving a few mitochondria may be solved by autophagia of altered organelles. If more mitochondria are involved, and an adequate amount of proapoptotic factors is released while intracellular ATP levels remain, the cell undergoes apoptosis. If the cell undergoes a severe lesion, the dramatic reduction of ATP contents will not allow for many enerMechanisms of liver cell injury
366 citations
TL;DR: The impact of virus-host interactions for the pathogenesis of HBV infection and liver disease are discussed, including the relevance of naturally occurring viral variants for clinical disease, the role of viruses-induced apoptosis for HBV-induced liver cell injury and the impact of antiviral immune responses for outcome of infection.
Abstract: Infection with hepatitis B virus (HBV) leads to a wide spectrum of clinical presentations ranging from an asymptomatic carrier state to self-limited acute or fulminant hepatitis to chronic hepatitis with progression to cirrhosis and hepatocellular carcinoma. Infection with HBV is one of the most common viral diseases affecting man. Both viral factors as well as the host immune response have been implicated in the pathogenesis and clinical outcome of HBV infection. In this review, we will discuss the impact of virus-host interactions for the pathogenesis of HBV infection and liver disease. These interactions include the relevance of naturally occurring viral variants for clinical disease, the role of virus-induced apoptosis for HBV-induced liver cell injury and the impact of antiviral immune responses for outcome of infection.
271 citations
TL;DR: Transplantation experiments reveal that EpCAM+ cells are true progenitors capable of repopulating injured rat liver and show a mixed epithelial/mesenchymal phenotype that has not been recognized previously.
240 citations
TL;DR: Liver biopsy evaluation is often the primary end point in clinical trials of treatment, thus, standardization of diagnosis and methods of grading and staging have become important.
210 citations
TL;DR: They cannot replace needle biopsy but some of them might be complementary in follow-up studies, and innovative methods like proteomics and glycomics to establish fibrosis-specific serum protein and glycosylation patterns might have a high potential for diagnosis and monitoring of fibrogenesis.
203 citations
TL;DR: In the future, chemokines might be used to monitor the natural course and progression of HCV‐associated liver disease, to identify patients with a high likelihood of achieving a therapeutic response, and they may even have potential as therapeutic targets.
Abstract: Hepatitis C virus (HCV) is a leading cause of chronic liver disease that can progress to cirrhosis and/or hepatocellular carcinoma. Intrahepatic inflammation and liver cell injury are defining features of chronic HCV infection. Chemokines, chemotactic cytokines that attract leucocytes to inflammatory sites, may be important in the development of intrahepatic inflammation. As T-helper (Th)1 inflammatory cells, characterized by interferon (IFN)-gamma and interleukin (IL)-2 secretion, predominate in the liver during chronic HCV infection, chemokines that attract these cells might be particularly important in disease progression. In this review, we focus on the role of Th1 chemokines, which are all members of the CXC or CC subfamilies. Among the CXC chemokines, the non-ELR group comprised of IFN-gamma-inducible protein 10 (IP-10), monokine induced by IFN-gamma (Mig) and IFN-inducible T-cell-alpha chemoattractant (I-TAC), attract Th1 cells through the interaction with their receptor, CXCR3. Among the CC subfamily, Th1-associated chemokines include regulated upon activation, normal T-cell expressed and secreted (RANTES) and macrophage inflammatory proteins (MIP)1alpha and beta. These chemokines attract cells through an interaction with their receptor, CCR5. While peripheral blood and intrahepatic levels of all of these chemokines are elevated in chronic hepatitis C patients, only select chemokines have been found to be correlated with hepatic inflammation. Among the six chemokines, IP-10 has uniquely been shown to have prognostic utility as a marker of treatment outcome. In the future, chemokines might be used to monitor the natural course and progression of HCV-associated liver disease, to identify patients with a high likelihood of achieving a therapeutic response, and they may even have potential as therapeutic targets.
193 citations
TL;DR: The ability of isolated adult-derived liver mesenchymal stem-like cells to proliferate and differentiate into hepatocyte- like cells both in vitro and in vivo leads to propose them as an attractive expandable cell source for stem cell therapy in human liver diseases.
186 citations
TL;DR: The usefulness of the prognostic index was tested by a cross‐validation method, and no statistical significant difference was found between the estimated and observed survivorship functions.
170 citations
TL;DR: In conclusion, IDN‐6556 when administered in cold storage and flush solutions during liver transplantation offers local therapeutic protection against CI/WR‐mediated apoptosis and injury, however, larger studies are required to confirm these observations.
TL;DR: Analysis of liver from rats exposed to chemical hepatocarcinogens has led to a model that postulates sequential premalignant changes, culminating in hepatoma formation from neoplastic nodules, however, recent work suggests that chemically induced hepatomas may also arise from nonnodular cell populations.
TL;DR: It is demonstrated that wogonin possesses potent anti-HBV activity both in vitro and in vivo, and is under early development as an anti- HBV drug candidate.
TL;DR: It is established that UbC constitutes an essential source of Ub during cell proliferation and stress that cannot be compensated by other Ub genes, and is regulated by a process that senses Ub pool dynamics.
Abstract: UbC is one of two stress-inducible polyubiquitin genes in mammals and is thought to supplement the constitutive UbA genes in maintaining cellular ubiquitin (Ub) levels during episodes of cellular stress. We have generated mice harboring a targeted disruption of the UbC gene. UbC−/− embryos die between embryonic days 12.5 and 14.5 in utero, most likely owing to a severe defect in liver cell proliferation. Mouse embryonic fibroblasts from UbC−/− embryos exhibit reduced growth rates, premature senescence, increased apoptosis and delayed cell-cycle progression, with slightly, but significantly, decreased steady-state Ub levels. UbC−/− fibroblasts are hypersensitive to proteasome inhibitors and heat shock, and unable to adequately increase Ub levels in response to these cellular stresses. Most, but not all of the UbC−/− phenotypes can be rescued by providing additional Ub from a poly hemagglutinin-tagged Ub minigene expressed from the Hprt locus. We propose that UbC is regulated by a process that senses Ub pool dynamics. These data establish that UbC constitutes an essential source of Ub during cell proliferation and stress that cannot be compensated by other Ub genes.
TL;DR: Oxidative stress in mitochondria and inappropriate MPT are important in the pathogenesis of arsenic induced apoptotic liver cell injury, which is GSH dependent and supplementation of NAC might have beneficial effects.
TL;DR: Evidence is concentrated on the evidence from animal models and human studies that BMSCs may aid in the regeneration of liver cell populations and may also contribute to the pathogenesis of liver damage.
Abstract: Stem cells are present in a variety of organs including the bone marrow (BM). Their role is to replenish multiple mature differentiated cell types and thereby achieve long-term tissue reconstitution. Stem cells retain the capacity to generate progeny and renew themselves throughout life. Haematopoietic stem cells (HSCs) are the main stem cell population within the BM and give rise to all mature blood lineages via erythroid, myelomonocytic and lymphoid precursors. A second type of bone marrow stem cell (BMSC), the mesenchymal stem cell (MSC), forms stromal tissue and can give rise to cells of mesodermal origin.
A longstanding principle of cell biology has been that cell loss is reconstituted via stem cells resident within and specific to an organ. However, recent work suggests that this paradigm may not hold for all organs or all types of injury, and tissue damage may attract migratory stem cell populations, particularly those from the BM. This observation has caused considerable interest in the field of liver disease, where new strategies to restore hepatocyte number, augment liver function and counteract progressive organ fibrosis are required. This article will focus on the various relationships between BMSCs and liver disease. It will concentrate on the evidence from animal models and human studies that BMSCs may aid in the regeneration of liver cell populations and may also contribute to the pathogenesis of liver damage. It will discuss the potential to use BMSCs for therapeutic application and review the current status of clinical trials in patients with liver disorders.
### The physiology of liver cell regeneration
The hepatic parenchyma is made up of hepatocytes and cholangiocytes. Unlike other organs such as the gut, liver cell mass is restored primarily through division of the majority of mature hepatocytes and not via a dedicated stem cell population. After a regenerative stimulus, such as a two-thirds partial hepatectomy, most …
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TL;DR: The intake of dietary fructose has increased significantly from 1970 to 2000, and there has been a 25% increase in available “added sugars” during this period, which could aggravate health concerns with fructose.
TL;DR: The results showed that the presented microfluidic devices are low-cost and suitable for clinical use, and capable of highly functional separation with relatively high-speed processing.
Abstract: Liver is composed of various kinds of cells, including hepatic parenchymal cells (hepatocytes) and nonparenchymal cells, and separation of these cells is essential for cellular therapies and pharmacological and metabolic studies. Here, we present microfluidic devices for purely hydrodynamic and size-dependent separation of liver cells, which utilize hydrodynamic filtration. By continuously introducing cell suspension into a microchannel with multiple side-branch channels, cells smaller than a specific size are removed from the mainstream, while large cells are focused onto a sidewall in the microchannel and then separated into two or three groups. Two types of PDMS-glass hybrid microdevices were fabricated, and rat liver cells were successfully separated. Also, cell size, morphology, viability and several cell functions were analyzed, and the separation performances of the microfluidic devices were compared to that of a conventional centrifugal technique. The results showed that the presented microfluidic devices are low-cost and suitable for clinical use, and capable of highly functional separation with relatively high-speed processing.
TL;DR: The role of cytokines and particularly chemokines in instigating and driving the inflammatory infiltrate in steatohepatitis is focused on.
Abstract: Nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) share similar morphological characteristics despite the obvious etiological differences between the two conditions. In both conditions the first manifestation of injury is the accumulation of fat within hepatocytes (steatosis), and in a proportion of patients this is followed by the development of necroinflammatory activity that leads to cirrhosis. Steatosis alone is considered to be relatively innocuous and is usually reversible, and it is the development of liver cell ballooning and inflammation (steatohepatitis) that determines whether a patient progresses to irreversible liver damage and fibrosis. This has led to the two-hit theory in which the first hit is accumulation of fat in the liver and the second hit involves an inflammatory insult or challenge to the liver, for example, through oxidative stress or in response to pathogenic stimuli such as endotoxin. Although the nature of the hits remains poorly understood, it is clear that the critical event in progression is the development of inflammation, and the fact that it is impossible to distinguish alcoholic from nonalcoholic steatohepatitis on histological grounds suggests that common pathogenic mechanisms are involved. We focus on the role of cytokines and particularly chemokines in instigating and driving the inflammatory infiltrate in steatohepatitis. A better understanding of this process might allow therapeutic intervention to switch off the inflammatory response before irreversible damage occurs in both ALD and NAFLD.
TL;DR: To investigate the roles of epigenetic and genetic alterations of the phosphatase and tensin homologue on chromosome 10 gene (PTEN) in carcinogenesis and the development of hepatocellular carcinomas (HCC).
TL;DR: It is concluded that 10‐min IPC protects against I/R injury in deceased donor LT and significantly improved the serum aspartate aminotransferase levels and reduced the need for reoperation in the postoperative period.
TL;DR: The IL-10-like cytokine IL-22 is produced by activated T cells and the role of this cytokine system in hepatic cells is analyzed in this study.
Abstract: The IL-10-like cytokine IL-22 is produced by activated T cells. In this study, we analyzed the role of this cytokine system in hepatic cells. Expression studies were performed by RT-PCR and quantit...
TL;DR: Investigation of the protective effect and possible mechanism of aqueous extract from Phyllanthus amarus Schum and its possible mechanism confirmed the beneficial roles of PA and SL against ethanol-induced liver injury in rats, including their antioxidant activity.
TL;DR: Melatonin remarkably prevents hepatocyte apoptosis in mice induced during malaria as indicated by caspase 3 and TUNEL assays as well as transmission electron microscopy of the liver tissue.
Abstract: We showed earlier that malarial infection significantly induces liver apoptosis mediated by oxidative stress mechanisms. Thus, a nontoxic antioxidant-antiapoptotic molecule may be beneficial for hepatoprotection. Melatonin remarkably prevents hepatocyte apoptosis in mice induced during malaria as indicated by caspase 3 and TUNEL assays as well as transmission electron microscopy (TEM) of the liver tissue. The mitochondrial apoptotic pathway, which plays a critical role in liver cell death during malarial infection, was almost completely suppressed by melatonin as it corrects both the overexpression of Bax and down-regulation of bcl-2 as revealed by semiquantitative RT-PCR. Fluorometric studies using JC-1 documented that melatonin also restores mitochondrial transmembrane potential (DeltaPsim) in malaria-infected mice liver. The antiapoptotic effect of melatonin is associated with its antioxidant role because melatonin protects liver from oxidative stress induced during malaria by scavenging the hydroxyl radicals, preventing the depletion of reduced glutathione, inhibiting lipid peroxidation and protein carbonyl formation. The effective antioxidant dose of melatonin to protect liver from oxidative stress during malaria is 20 times lower than that of known antioxidants, vitamin C and vitamin E. Apoptosis of hepatocytes during malarial infection is well correlated with dysfunction of the liver while melatonin offers hepatoprotective effects as indicated by different liver function tests. Thus, melatonin may well be effective in combating oxidative stress-induced apoptosis and liver damage during malaria infection.
TL;DR: By combining the use of the different cell and tissue culture models, the mechanisms underlying multicellular fibrosis development can be studied in vitro and potential pro- or anti-fibrotic properties of compounds can be identified both on single liver cell types and in human liver tissue.
TL;DR: Bio‐based assays showed that non‐polar and low-polar solvent fractions of SB had dose‐dependent cytotoxicities on six cancer cell lines and the chloroform fraction had the strongest cytotoxicity on cancer cell Lines with a lower cytot toxic effect on a normal liver cell line.
Abstract: Scutellaria barbata (SB) is widely used as an antitumor agent in China, but the antitumor components of SB are still unclear. The antitumor activity of various fractions of an ethanol extract of SB was studied in six human malignant cell lines. Bio-based assays showed that non-polar and low-polar solvent fractions of SB had dose-dependent cytotoxicities on six cancer cell lines. The IC(50) values of these fractions on the cancer cell lines tested ranged from 16 to 70 microg/mL after 48 h of treatment. Among them, the chloroform fraction (CE-SB) had the strongest cytotoxicity on cancer cell lines with a lower cytotoxic effect on a normal liver cell line. Bel-7402 cell apoptosis induced by CE-SB was examined using Hoechst 33258 staining, agarose gel electrophoresis and flow cytometry. CE-SB dose-dependently decreased the S phase content. Treatment with CE-SB caused cytochrome c release and activation of caspase-9. The antitumor activity of CE-SB in vivo was also evaluated. At 60 mg/kg/day, CE-SB significantly inhibited the solid tumor proliferation and increased the life span of ascites tumor bearing mice (p < 0.01). CE-SB was subjected to bioassay-guided isolation of the active compounds by chromatography on silica gel and Sephadex LH-20. Phytol, wogonin, luteolin and hispidulin were obtained as cytotoxic constituents.
TL;DR: Of the ten active compounds, treatment with 1, 3, and 12 led to significant reduction in the extracellular HBV DNA level, suggesting that they could be potent phytochemical agents against hepatitis B virus.
TL;DR: The results suggest that Zn and Cd are efficiently involved with mt expression induced in zebrafish embryos and with MTF‐1 nuclear translocation and that this induction is achieved through the activation of M TF‐1 binding at the MREs.
Abstract: Metallothionein is a small (6-kDa), cysteine-rich protein expressed by a six-zinc finger protein called metal-responsive element-binding transcription factor-1 (MTF-1) in response to Zn and Cd. Our previous reports have shown the basal expression of metallothionein (mt) and MTF-I (mtf-1) genes in embryo and early larval stages of zebrafish (Danio rerio). In the present study, we investigated the mt expression in zebrafish early larvae induced by exposure to Cd and Zn (48, 72, 96, and 120 h postfertilization). Whole-mount in situ hybridization showed that Zn induced mt expression in the olfactory pit, cerebellum, ceratobranchials, liver, chloride cells, and neuromasts of the lateral line. Cadmium also induced mt expression in all the above regions except the cerebellum. Using fluorescence techniques, we have shown that Zn and Cd mediate cytoplasmic and nuclear translocation of MTF- 1-enhanced green fluorescent protein fusion protein in zebrafish liver cell line. The MTF-1 protein was produced recombinantly by inserting zebrafish mtf-1 cDNA (1.8 kb) into pET-20b(+) expression vector and expressing in Escherichia coli BL21 (DE3) pLysS host strain competent cell on induction with isopropyl-beta-D-thiogalactopyranoside. The protein was then purified by affinity chromatography on a nickel-nitrilotriacetic acid column. Electrophoretic mobility shift assay revealed binding of the recombinant MTF-1 in response to Zn and Cd at the putative metal-responsive elements (MREs) in the promoter region of the mt gene. Taken together, these results suggest that Zn and Cd are efficiently involved with mt expression induced in zebrafish embryos and with MTF-1 nuclear translocation and that this induction is achieved through the activation of MTF-1 binding at the MREs.
TL;DR: Results confirm a proposed role for GRP78 as a dengue virus serotype 2 receptor protein and suggest that the recently identified hsp90/70 complex does not play a role in d Dengue virus internalization into liver cells.
Abstract: Recently, several stress-related proteins including GRP78, hsp70, and hsp90 have been implicated as dengue virus receptors in various cell types, with hsp90/70 being implicated as a receptor complex in monocytes and macrophages, while GRP78 has been implicated as a liver cell expressed dengue virus receptor. To assess whether the hsp90/70 complex plays a role in the internalization of the dengue viruses into liver cells, we undertook infection inhibition studies with lipopolysaccharide and antibodies directed against both hsp70 and hsp90, individually and in combination. No inhibition of any dengue serotype was seen in the presence of lipopolysaccharide or antibodies directed against either hsp70 or hsp90 either singly or in combination. A moderate inhibition of dengue virus serotype 2 entry into liver cells was observed in the presence of antibodies directed against GRP78. These results confirm a proposed role for GRP78 as a dengue virus serotype 2 receptor protein and suggest that the recently identified hsp90/70 complex does not play a role in dengue virus internalization into liver cells.