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The liver plays an vital role in glucose and lipid metabolism,synthesis of plasma proteins,and detoxification of xenobiotics.Liver chronic disease is one of the leading causes of death in China.Liver mass can be restored by two mechanisms:division of hepatocytes and hepatic oval cells (HOCs) proliferation and differentiation.However,the origin,specific markers and signaling pathways of HOCs have not been fully elucidated.Recent researches in HOCs isolation methods and genetic lineage tracing have enabled investigators to study multiple aspects of HOCs origin and biology.We reviewed the previous researches in detail.
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Objective Epithelial mesenchymal transition (EMT) has a role in the proliferation and metastasis of various types of cells.This study investigates the hepatic oval cell's mechanism of EMT induced by histone deacetylase inhibition and the resulting cell motility increase from EMT.Methods Hepatic oval cell stem cell markers and marker changes were detected by flow cytometry,and after histone deacetylase inhibition induced EMT,the morphological changes were recorded.Western blot and quantitative real-time polymerase chain reaction detected the expression of E-cadherin,vimentin and Snail.Furthermore,confocal microscopy analysis recognized the nuclear translocation of Snail.Results Flow cytometry revealed no changes in the stem cell properties of hepatic oval cells in the cell culture process.Oval cell EMT,induced by HDACi,was observed through morphological changes,a reduction of the epithelial cell marker E cadherin,and an increase of the mesenchymal cell marker Vimentin.HDACi can promote the expression and nuclear translocation of Snail,which is the key hepatic oval cell transcription factor for both EMT and enhanced motility.Therefore,Snail RNA interference can suppress HDACi induced EMT in hepatic oval cells.Conclusions In conclusion,histone deacetylase inhibition induces hepatic oval cell epithelial-mesenchymal transition by Snail.
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End stage liver disease is a serious threat to human health.Existing conventional therapies are far from ideal,and orthotopic liver transplantation is limited by the lack of donor liver.A new therapy,transplantation of hepatic stem cell,is a promising approach.Hepatic oval cells are hepatic stem/progenitor cells(HSC/HPC)during hepatic regeneration,and they are being referred to as hepatic precursor cells.It got its name because of its oval nucleus,high nuclear/cytoplasmic ratio and other morphological features.Research has shown increasingly importance in the knowledge of hepatic oval cells.There are many signaling pathways in hepatic oval cells activation and proliferation.As a branch of the Wnt signaling pathway,Wnt/β-catenin signaling pathway has a significant effect on hepatic oval cells activation and proliferation.However,the exact mechanisms of this process have not been completely elucidated.This review describes the role of Wnt/β-catenin signaling pathway in hepatic oval cell activation and proliferation.
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Rat hepatic oval cell model was induced by hyperglycemia and streptozotocin in vivo. Expression of insulin and mRNA expression of pancreatic transcription factors(Nkx6.1, PDX-1) were carried out. It showed that under high glucose, liver tissues were positive for insulin staining, the expression of Nkx6.1 and Pdx-1mRNA was significantly enhanced, and insulin-1mRNA was found to be expressed. The result suggests that under high glucose, hepatic oval cells can differentiate into insulin-producing cells.
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Hepatic oval cells (OCs) are the stem cells of the liver. They can differentiate into liver cells, bile duct epithelial cells and other cells, and also are closely related to liver regeneration and liver diseases. In this article, we give a brief summary focused on the source, location, proliferation, differentiation, apoptosis, transplantation of hepatic oval cells, and its role in liver regeneration and liver diseases.
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Objcctive To detect the telomerase activity in rat hepatic oval cells, and to explore the relationship between telomerase expression and the proliferation and differentiation of oval cells. Methods The 2-acetamidofluorene/partial bepatectomy (2-AAF/PH) rat model was used to induce the proliferation of oval cells. Oval cells were isolated by modified collagenase perfusion and gradient centrifugation. Electron microscope exami-nation and immunofluorescence were adopted to identify oval cells. Immunohistochemistry, RT-PCR and fluores-cence quantitative PCR were used to detect the expression of telomerase in oval cells. All the data collected were analyzed by t test. Results The proliferatiun of oval cells was successfully induced by 2-AAF/PH rat model. Freshly isolated oval cells showed a large and ovoid nuclei, a small proportion of cytomplasm and a cobblestone appearance. When viewed by electron microscopy, there were few and immature organelles, and the nucleus/ cytoplasm ratio was high. Immunofluorescence staining showed that oval cells expressed OV-6, alpha-fetoprotein, cytokeratin-19, albumin and c-kit. Telomerase reverse transcriptase (TERT) was located in the nuclei of oval cells which were around the portal areas. As oval cells differentiated into small hepatocytes, the number of TERT-positive cells decreased significantly. The expression level of TERT mRNA in normal rat liver tissue was 2.27 times higher than that in LE-6 oval cells; the expression level of TERT mRNA in the isolated oval cells was 1.26 times higher than that in LE-6 oval cells. The telomerase activity decreased gradually (from △A=1.05, 1.15 to △A=0.25, 0.45) as the increase of oval cells passage (from passage 24 to passage 40) (t=17.74, 12.38, P<0.05). Conclusions Oval cells have telomerase activity. Telomerase may be indispensable for maintaining the proliferative and multi-directional differentiation abilities of oval cells.
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Generally speaking,the hepatocyte stem cell is not a specific cell type.but an overall name of all kinds of cells that possess stem cell characters about embryonic development and regeneration of liver.HSC is a pluripotential stem cells which have self-renewal capacity and could differentiate into mature hepatocytes and bile duct cells.According to the different origin of hepatocyte stem cell,it can be usually divided into two kinds:non liver-derived hepatocyte stem cell and liver-derived hepatocyte stem cell.
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Most liver diseases lead to hepatic dysfunction with organ failure. Liver transplantation is the best curative therapy, but it has some limitations such as donor shortage, possibility of rejection, and maintenance of immunosuppressant. New therapies have been actively searched for over several decades, primarily in the form of artificial liver support devices and hepatocyte transplantation, but both of these modalities remain experimental. Stem cells have recently shown promise in cell therapy because they have the capacity for self-renewal and multilineage differentiation, and are applicable to human diseases. Very recent reports of unexpected plasticity in adult bone marrow have raised hopes of stem cell therapy offering exciting therapeutic possibilities for patients with chronic liver disease. Both rodent and human embryonic stem cells, bone marrow hematopoietic stem cells, mesenchymal stem cells, umbilical cord blood cells, fetal liver progenitor cells, adult liver progenitor cells, and mature hepatocytes have been reported to be capable of self-renewal, giving rise to daughter hepatocytes both in vivo and in vitro. These cells can repopulate livers in animal models of liver injury and appear to be able to improve liver function. However, significant challenges still exist before these cells can be used in humans, such as the lack of consensus about the immunophenotype of liver progenitor cells, uncertainty of the physiological role of reported candidate stem/progenitor cells, practicality of obtaining sufficient quantity of cells for clinical use, and concerns over ethics, long-term efficacy, and safety. There have been reports of phase 1 trials using stem cell transplantation in humans for liver diseases, but more effective trials are needed. We review the use of stem cells (focusing on adult ones) and the reported human clinical trials, and highlight the challenges facing clinicians in their quest to use liver stem cells to save lives.
Subject(s)
Humans , Bone Marrow Cells/cytology , Cell Differentiation , Embryonic Stem Cells/cytology , Hematopoietic Stem Cells/cytology , Immunophenotyping , Liver/cytology , Liver Diseases/therapy , Mesenchymal Stem Cells/cytology , Stem Cell TransplantationABSTRACT
This paper has the objective to analyze the cellular aspects of liver regeneration (LR). Upon damage in this organ, the regenerative capacity of hepatocyte is sufficiently able to reestablish the parenchyma as a whole. Taking into account the regenerative capacity of hepatocyte, the need of a progenitor or a liver trunk cell was not obvious. Nowadays it is well-established that precursor cells take part in the liver regenerative process. The liver trunk cell, oval cell, acts as a bypotential precursor, contributing for the liver restoration, mainly when the hepatocytes are unable to proliferate. Another precursor, trunk cell of hematopoetic origin (HSC), takes part in the regenerative process, originating cells of the hepatocitic lineage and colangiocytes, as well as the oval cell. The way the trans-differentiation takes place is not established yet. A number of studies must be undertaken in order to clarify questions, such as the possible occurrence of cellular fusion process between the HSC and the hepatic cells and the possibility of application as a new therapeutic procedure in the treatment of diseases associated with insufficiency of this noble organ.
Este artigo tem como objetivo analisar aspectos da regeneração hepática (RH) sob a óptica celular. Em vigência de uma lesão neste órgão a capacidade regenerativa do hepatócito é suficientemente capaz de restabelecer o parênquima como um todo. Levando em conta a elevada capacidade regenerativa do hepatócito, a necessidade de um progenitor ou uma célula tronco hepática não era óbvia. Hoje esta bem estabelecido que células precursoras participam do processo regenerativo hepático. A célula tronco hepática, célula oval, atua como um precursor bipotencial, contribuindo para o restauro do fígado principalmente quando os hepatócitos se encontram impossibilitados de proliferar. Um outro precursor, a célula tronco de origem hematopoética (HSC), participa do processo regenerativo, originando células da linhagem hepatocítica e colangiócitos, assim como a células oval. Ainda não está estabelecido o meio como ocorre o fenômeno de transdiferenciação.Muitos estudos devem ser realizados no intuito de esclarecer questões, tais como a possível ocorrência de processo de fusão celular entre a HSC e as células hepáticas e a possibilidade de ser aplicado como uma nova terapêutica no tratamento de doenças associadas à insuficiência deste nobre órgão.
Subject(s)
Humans , Animals , Rats , Cell Differentiation/physiology , Hematopoietic Stem Cells/cytology , Hepatocytes/cytology , Liver Regeneration/physiology , Antigens, Surface/metabolism , Bile Ducts/cytology , Biomarkers/metabolism , Cell ProliferationABSTRACT
Objective To study the expression of proliferating cell nuclear antigen (PCNA) in the occurrence and development of hepatocellular carcinoma. Methods Sixty SD rats were randomly divided into control group and experimental group. 3′-Me-DAB was administrated into rats to establish the experimental model of hepatocarcinoma. The expressions of PCNA of different phases were detected by immunohistochemistry and the liver pathologic changes were observed by optical microscope. Results The process of canceration was divided into three stages: inflammation, proliferative fibrosis and hepatic carcinoma. The expression of PCNA firstly presented in the oval cells that located in the portal area at the stage of inflammation, and a part of PCNA were hyper-expressed in the portal area. The expression rate of PCNA in the middle phase of inflammatory stage was higher than that of any other phases but declined later. Yet, when it came to the stage of hepatic carcinoma, the rate increased again. Conclusion Under the experimental circumstance when liver cancer is caused by the carcinogenic agent, PCNA may be firstly expressed in the oval cells, and the dynamic expression of PCNA may be an indicator for the early diagnosis of hepatocarcinogenesis.
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Objective To investigate the clinical outlook of hepatic stem cells and its relations with liver cancer. Methods The literatures of recent years on the studies of hepatic stem cells were reviewed. Results Liver cancer may consist of cells of various differentiation grades and it may result from the perodifferentiated hepatic stem cells or abnormal differentiated cells. Conclusion The hypothesis of hepatic stem cells has been identified extensively. Further study maybe helpful for revealing the origin, carcinogenesis of hepatic cancer, and may also be useful for the understanding of the mechanism of metastasis.
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Objective To explore the distribution and migration of oval cells in progressive hepatic injury.Methods Sixty SD rats were divided into the control group ( n =20) and experimental group ( n =40). After the establishment of hepatic carcinoma models, C kit was continuously detected by immunohistochemistry and the liver pathologic changes were regularly observed by optical microscopy. Results The hepatic surface was smooth with eumorphism in histology in the control group. The C kit positive cells were occasionally found. In the experimental group, the oval cells with C kit positive were initially discovered in the portal regions in the second week, and these cells proliferated along the bile duct epithelia. With the hepatic injury becoming more serious, the oval cells extended into the hepatic lobular regions from the portal regions. When hepatocellular carcinoma occurred,the majority were mixed carcinomas, and the oval cells were found inside and outside the carcinoma nodes. In this period, the most of C kit positive cells still located in the portal regions. Conclusion ①The oval cells are the most sensitive cells for the hepatic injury. ②The oval cells which migrate unruly participate in the formation of hepatic pseudolobules. ③The oval cells play an important role in hepatocarcinogenesis.
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Objective Hepatic stimulator substance(HSS)is newly defined as a growth mitogen to hepatocytes.This sutdy is aiming to investigate the effect of recombinant human hepatic stimulator substance(rhHSS) on growth of liver oval cells(OVCs). Methods OVCs were prepared from intoxicated rats with 3'-methyl-dimethylaminoazobenzene.After confirmation of OVC morphologically and histochemically,the cell cultures of OVC were exposed to various dosages of rhHSS for 12 and 24?h,respectively.The cellular proliferation was analyzed by MTT and flow cytometry. Results Administration of rhHSS(160-400 mg/L)inhibited the proliferation of OVC,as indicated by MTT and cell cycle analysis,the effect appeared non-dose dependent pattern.The peak of inhibition occurred at 240?mg/L.After incubation with 240?mg/L of HSS for 12 and 24?h,the percentages of S-phase were reduced 47.8% and 35.8% to those of the untreated cells.respectively.Conclusion rhHSS exhibits the inhibitory effect on growth of OVC.
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Objective To observe the morphological characteristics of oval cells in human chronic liver diseases, and determine whether there is a relationship between the number of oval cells and liver fibrotic stage. Methods Oval cells were detected in paraffin bedded liver sections of 3 normal subjects (as controls) and 29 chronic liver diseases, using histoimmunochemistry. Cells were counted if they fulfiled the morphological criteria for oval cells and showed cytoplasmic staining. Results Oval cells were not observed in normal livers. In chronic liver diseases, oval cells were located predominantly in the periportal region and fibrosis septa, characterized by an ovoid nucleus, small size, and scant cytoplasmic. The number of oval cells increased significantly ( F=22.60, P
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This study is aimed to elucidate the biological nature of the precancerous lesions and to evaluate whether the ethanol alters 3'-Methyl-4-dimethylaminoazobenzene (3'-Me-DAB) induced experimental hepatocarcinogenesis. A total of 108 Sprague-Dawley male rats were used for the experiment and divided into 6 groups according to 3'-Me-DAB and ethanol administration. Administration of the drugs were carried out daily by nasogastric tube insertion and the animals were sacrificed at different interval. A part of right lateral lobe was prepared for the histological examination. Cell kinetics of the immunohistochemical method for bromodeoxyuridine (BrdU). The administration of 3'-Me-DAB induced oval cell proliferation, hyperplastic nodule, cholangiofibrosis and carcinoma in the liver. The mean labelling indices, the percentages of BrdU labelled cells, of hepatocytes were increased by administration of 3'-Me-DAB, only to reverse after cessation of the drug (2.58 vs 0.61). The labelling indices of the oval cells were also affected by the administration and cessation of 3'-Me-DAB (11.41 vs 4.48). In contrast, the cholangiofibrosis did not decrease but were still increasing following cessation of 3'-Me-DAB administration (4.37 vs 5.17 and 8.25 vs 11.29). These finding that the hyperplastic nodule and particularly the cholangiofibrosis have an autonomous proliferative potential and are definite precancerous lesions in the experimental hepatocarcinogenesis. Short term administration of ethanol decreased the incidence of development of the precancerous lesions, but did not affect the labelling indices in all the pathologic lesions of hepatocarcinogenesis.