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Hepatic Progenitor Cells (hepatic + progenitor_cell)
Selected AbstractsIsolation and characterization of epithelial progenitor cells from human fetal liverHEPATOLOGY RESEARCH, Issue 1 2008Yi-Nan Liu Aim:, Hepatic progenitor cells can serve as an alternative source of hepatocytes for the treatment of liver diseases. Methods:, We isolated and expanded the epithelial progenitor cells (EPC) from the human fetal liver and investigated the differentiation of EPC into hepatic cells by fluorescence-activated cell sorter (FACS), real-time polymerase chain reaction (PCR), immunofluorescence assay, western blotting, and periodic acid,Schiff staining. Results:, Isolated EPC possessed highly proliferative ability and subpassaged for more than 25 passages. Real-time PCR showed that EPC expressed liver epithelial markers (cytokeratin [CK]8 and CK18) and biliary-specific markers (CK7 and CK19). FACS analysis indicated that these cells were positive for CD117, CD147, CD90, CD44, human leucocyte antigen class I and CD71, but negative for CD34 and CD45. The EPCpossessed multipotential indicated by differentiating into osteoblasts and adipocytes; when subjected to the hepatic differentiation condition, EPC could be induced to hepatocyte-like cells, which expressed albumin, alpha-fetoprotein, and CK18 proteins. Two months after EPC transplantation, we observed that the grafted cells differentiated into hepatocyte-like cells and there was no observable tumor mass. Conclusion:, We have isolated and characterized the human fetal liver-derived EPC and these cells may serve as an ideal cell source for cell-replacement therapy of diseased livers. [source] Hepatic progenitor cells, stem cells, and AFP expression in models of liver injuryINTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY, Issue 5 2006Wolf D. Kuhlmann Abstract Adult hepatocytes and liver-cell progenitors play a role in restoring liver tissue after injury. For the study of progenitor cells in liver repair, experimental models included (a) surgical removal of liver tissue by partial hepatectomy; (b) acute injury by carbontetrachloride; (c) acute injury by d -galactosamine (GalN) and N -nitrosomorpholine (NNM); and (d) chemical hepatocarcinogenesis by feeding NNM in low and high doses. Serological and immunohistological detection of alpha-fetoprotein gene expression served to follow pathways of cellular differentiation. Stem cells were not required in models of surgical removal of parenchyma and in carbon tetrachloride intoxication of adult hepatocytes. In contrast, regeneration of liver occurred through biliary epithelial cells in injuries induced by GalN and NNM. These biliary epithelial cells, collectively called oval cells, are most probably derived from the canals of Hering. Proliferating bile duct cells reached a level of differentiation with reactivation of foetal genes and significant alpha-1-fetoprotein (AFP) synthesis signalling a certain degree of retrodifferentiation with potential stemness. Due to the same embryonic origin of bile ducts and hepatocytes, biliary epithelium and its proliferating progeny (oval cells) have a defined role in liver regeneration as a transit and amplification compartment. In their early proliferation stage, oval cells were heavily engaged in DNA synthesis ([3H]thymidine labelling). Pulse-chase experiments during experimental hepatocarcinogenesis exhibited their development into hepatocytes with high risk for transformation and leading to foci of altered hepatocytes. Hepatocellular carcinomas may arise either from proliferating/differentiating oval cells or from adult hepatocytes; both cell types have stem-like properties. AFP-positive and AFP-negative carcinomas occurred in the same liver. They may represent random clonal origin. The heterogeneity of phenotypic marker (AFP) correlated with a process of retrodifferentiation. [source] Expression of contactin associated protein-like 2 in a subset of hepatic progenitor cell compartment identified by gene expression profiling in hepatitis B virus-positive cirrhosisLIVER INTERNATIONAL, Issue 1 2010Huafeng Wang Abstract Background: Hepatic progenitor cells (HPC), a cell compartment capable of differentiating into hepatocytic and biliary lineages, may give rise to the formation of intermediate hepatobiliary cells (IHBC) or ductular reactions (DR). Aims: The aim of this study was to analyse the gene expression profiles of DR in cirrhosis and further investigate novel proteins expressed by HPC and their intermediate progeny. Methods: DR in hepatitis B virus (HBV)-positive cirrhotic liver tissues adjacent to hepatocellular carcinoma and interlobular bile ducts (ILBDs) in normal liver tissues were isolated by laser capture microdissection and then subjected to microarray analysis. Differential gene expression patterns were verified by quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry on serial sections. HPC and their intermediate progeny were recognized by immunostaining with hepatocytic and biliary markers [HepPar1, cytokeratin (CK)7, CK19, neural cell adhesion molecule (NCAM), epithelial cell adhesion molecule (EpCAM)]. Results: A total of 88 genes showed upregulation in DR compared with ILBDs. Gene ontology analyses revealed that these upregulated genes were mostly associated with cell adhesion, immune response and the metabolic process. Contactin associated protein-like 2 (CNTNAP2) was first confirmed to be a novel protein expressed in a subpopulation of DR that was positive for CK7, NCAM or EpCAM. In addition, immunoreactivity for CNTNAP2 was also noted in a subset of isolated CK7-positive HPC as well as some ductular IHBC positive for CK19 and HepPar1 in DR. Conclusion: CNTNAP2 is specifically associated with the emergence of ductular populations and may be identified as a novel protein for defining a subset of HPC and their intermediate progeny in cirrhosis. [source] Retinoic acid signalling induces the differentiation of mouse fetal liver-derived hepatic progenitor cellsLIVER INTERNATIONAL, Issue 10 2009Jiayi Huang Abstract Background: Hepatic progenitor cells (HPCs) can be isolated from fetal liver and extrahepatic tissues. Retinoic acid (RA) signalling plays an important role in development, although the role of RA signalling in liver-specific progenitors is poorly understood. Aims: We sought to determine the role of RA in regulating hepatic differentiation. Methods: RNA was isolated from liver tissues of various developmental stages. Liver marker expression was assessed by reverse transcriptase-polymerase chain reaction and immunofluorescence staining. Reversibly immortalized HPCs derived from mouse embryonic day 14.5 (E14.5) liver (aka, HP14.5) were established. Albumin promoter-driven reporter (Alb-GLuc) was used to monitor hepatic differentiation. Glycogen synthesis was assayed as a marker for terminal hepatic differentiation. Results: Retinoic acid receptor (RAR)-,, retinoid X receptor (RXR)-, and RXR-, expressed in E12.5 to postnatal day 28 liver samples. Expression of RAR-, and RXR-, was low perinatally, whereas RAR-, was undetectable in prenatal tissues and increased postnatally. Retinal dehydrogenase 1 and 2 (Raldh1 and Raldh2) were expressed in all tissues, while Raldh3 was weakly expressed in prenatal samples but was readily detected postnatally. Nuclear receptor corepressors were highly expressed in all tissues, while expression of nuclear co-activators decreased in perinatal tissues and increased after birth. HP14.5 cells expressed high levels of early liver stem cell markers. Expression of RA signalling components and coregulators was readily detected in HP14.5. RA was shown to induce Alb-GLuc activity and late hepatocyte markers. RA was further shown to induce glycogen synthesis in HP14.5 cells, an important function of mature hepatocytes. Conclusions: Our results strongly suggest that RA signalling may play an important role in regulating hepatic differentiation. [source] Combined hepatocellular cholangiocarcinoma originating from hepatic progenitor cells: immunohistochemical and double-fluorescence immunostaining evidenceHISTOPATHOLOGY, Issue 2 2008F Zhang Aims:, Combined hepatocellular cholangiocarcinoma (CHC) is a rare form of primary liver cancer, showing a mixture of hepatocellular and biliary features. Data suggest that most CHC arise from hepatic progenitor cells (HPCs). The aim was to investigate the origin of CHC. Methods and results:, Twelve cases of CHC were studied by immunohistochemistry for hepatocytic (hepPar1, ,-fetoprotein), cholangiocytic cytokeratin [(CK) 7, CK19], hepatic progenitor cell (OV-6), haematopoietic stem cell (c-kit, CD34), as well as CD45 and chromogranin-A markers. The combination of double-fluorescence immunostaining consisted of HepPar1 with CK19, and c-kit with OV-6. All 12 cases demonstrated more or less transitional areas, with strands/trabeculae of small, uniform, oval-shaped cells including scant cytoplasm and hyperchromatic nuclei embedded within a thick, desmoplastic stroma; however, two cases were found to consist entirely of such transitional areas. Simultaneous co-expression of hepPar1 and CK7, or CK19, was demonstrated in 10/12 (83.3%) cases of CHC. c-kit expression was noted in 10/12 (83.3%) cases, of which 7/10 (70%) showed co-expression of OV-6. Conclusions:, The results suggest that CHC are of HPC origin, supporting the concept that human hepatocarcinogenesis may originate from the transformation of HPCs. [source] The amazing universe of hepatic microstructure,HEPATOLOGY, Issue 2 2009Valeer J. Desmet An informal review is presented by the author of his 50 years of involvement in practice and research in hepatopathology. Some background for the author's attitude and meandering pathway into his professional career serves as introduction to a short discussion of the main topics of his interest and expertise. Histogenesis of liver cancer was the theme of early work for a Ph.D. thesis, the results of which were lost into oblivion due to local rules and circumstances, but were rescued three decades later. His conclusions about the cells of origin of liver cancer remain concordant with the newer concepts in the field after nearly half a century. Studies in the field of chronic hepatitis became a long saga, involving the first classification of this syndrome by "the Gnomes" in 1968, histochemical investigations of viral antigens, lymphocyte subsets and adhesion molecules, and a quarter century later, the creation of a new classification presently in use. Cholestasis was a broadening field in diagnostic entities and involved the study of liver lesions, comprising pathways of bile regurgitation (including reversed secretory polarity of hepatocytes) and so-called ductular reaction. The latter topic has a high importance for the various roles it plays in modulating liver tissue of chronic cholestasis into biliary cirrhosis, and as the territory of hepatic progenitor cells, crucial for liver regeneration in adverse conditions and in development of liver cancer. Study of the embryology of intrahepatic bile ducts helped to clarify the strange appearance of the ducts in "ductal plate configuration" in several conditions, including some forms of biliary atresia with poor prognosis and all varieties of fibrocystic bile duct diseases with "ductal plate malformation" as the basic morphologic lesion. (HEPATOLOGY 2009;50:333,344.) [source] Pathology of peripheral intrahepatic cholangiocarcinoma with reference to tumorigenesisHEPATOLOGY RESEARCH, Issue 4 2008Yasuni Nakanuma Cholangiocarcinomas (CCs) are neoplasms with cholangiocyte differentiation, and may arise from cholangiocytes of the biliary tree and possibly cholangiocyte progenitor cells. Intrahepatic CCs can be divided into the perihilar and peripheral types. Peripheral CCs present grossly as a mass forming tumor, and histologically as an adenocarcinoma of varying shapes and phenotypes. Some peripheral CCs (ductular type) are characterized by: (i) a histological resemblance to reactive bile ductules; (ii) the expression of neural cell adhesion molecule (NCAM) and vimentin. This type shows: (i) grossly, a blurred border; and (ii) histologically, carcinoma cells replacing the adjoining hepatocytes at the border of the tumor. It is frequently associated with neutrophilic infiltration and also with granulocyte and granulocyte macrophage colony-stimulating factors. We propose to call this type "ductular CC." The other peripheral CC (duct type) includes ordinary adenocarcinoma with well to moderately differentiated tubular and micropapillary patterns and is negative for NCAM but positive for mucin. This type can be called "duct CC," and shows a rather compressive growth. Interestingly, CC components of combined hepatocellular CC share the features of ductular CC, suggesting that hepatic progenitor cells may be involved in the tumorigenesis of ductular CC. The biological behavior of ductular CC and duct CC remains obscure, and follow-up and molecular studies on these tumors are required in order for these two CCs to be recognized as disease entities, and so as to evaluate their carcinogenesis. [source] Combined hepatocellular cholangiocarcinoma originating from hepatic progenitor cells: immunohistochemical and double-fluorescence immunostaining evidenceHISTOPATHOLOGY, Issue 2 2008F Zhang Aims:, Combined hepatocellular cholangiocarcinoma (CHC) is a rare form of primary liver cancer, showing a mixture of hepatocellular and biliary features. Data suggest that most CHC arise from hepatic progenitor cells (HPCs). The aim was to investigate the origin of CHC. Methods and results:, Twelve cases of CHC were studied by immunohistochemistry for hepatocytic (hepPar1, ,-fetoprotein), cholangiocytic cytokeratin [(CK) 7, CK19], hepatic progenitor cell (OV-6), haematopoietic stem cell (c-kit, CD34), as well as CD45 and chromogranin-A markers. The combination of double-fluorescence immunostaining consisted of HepPar1 with CK19, and c-kit with OV-6. All 12 cases demonstrated more or less transitional areas, with strands/trabeculae of small, uniform, oval-shaped cells including scant cytoplasm and hyperchromatic nuclei embedded within a thick, desmoplastic stroma; however, two cases were found to consist entirely of such transitional areas. Simultaneous co-expression of hepPar1 and CK7, or CK19, was demonstrated in 10/12 (83.3%) cases of CHC. c-kit expression was noted in 10/12 (83.3%) cases, of which 7/10 (70%) showed co-expression of OV-6. Conclusions:, The results suggest that CHC are of HPC origin, supporting the concept that human hepatocarcinogenesis may originate from the transformation of HPCs. [source] Retinoic acid signalling induces the differentiation of mouse fetal liver-derived hepatic progenitor cellsLIVER INTERNATIONAL, Issue 10 2009Jiayi Huang Abstract Background: Hepatic progenitor cells (HPCs) can be isolated from fetal liver and extrahepatic tissues. Retinoic acid (RA) signalling plays an important role in development, although the role of RA signalling in liver-specific progenitors is poorly understood. Aims: We sought to determine the role of RA in regulating hepatic differentiation. Methods: RNA was isolated from liver tissues of various developmental stages. Liver marker expression was assessed by reverse transcriptase-polymerase chain reaction and immunofluorescence staining. Reversibly immortalized HPCs derived from mouse embryonic day 14.5 (E14.5) liver (aka, HP14.5) were established. Albumin promoter-driven reporter (Alb-GLuc) was used to monitor hepatic differentiation. Glycogen synthesis was assayed as a marker for terminal hepatic differentiation. Results: Retinoic acid receptor (RAR)-,, retinoid X receptor (RXR)-, and RXR-, expressed in E12.5 to postnatal day 28 liver samples. Expression of RAR-, and RXR-, was low perinatally, whereas RAR-, was undetectable in prenatal tissues and increased postnatally. Retinal dehydrogenase 1 and 2 (Raldh1 and Raldh2) were expressed in all tissues, while Raldh3 was weakly expressed in prenatal samples but was readily detected postnatally. Nuclear receptor corepressors were highly expressed in all tissues, while expression of nuclear co-activators decreased in perinatal tissues and increased after birth. HP14.5 cells expressed high levels of early liver stem cell markers. Expression of RA signalling components and coregulators was readily detected in HP14.5. RA was shown to induce Alb-GLuc activity and late hepatocyte markers. RA was further shown to induce glycogen synthesis in HP14.5 cells, an important function of mature hepatocytes. Conclusions: Our results strongly suggest that RA signalling may play an important role in regulating hepatic differentiation. [source] Immunohistochemical evidence for hepatic progenitor cells in liver diseasesLIVER INTERNATIONAL, Issue 5 2002Jianyou Tan Abstract:, Background/Aim: Proliferative bile ductular reactions occur in a variety of liver diseases in humans. It is a matter of debate whether such reactions result from progenitor cell proliferation with biliary and hepatocytic differentiation, versus biliary metaplasia of damaged hepatocytes. We investigated bile ductular reactions in liver diseases, paying particular attention to the presence of cells with intermediate (hepatocytic/biliary) features (oval-like cells). Methods: Five specimens each were selected of submassive hepatic necrosis and cirrhosis due to hepatitis B, hepatitis C, autoimmune hepatitis, alcohol injury, primary biliary cirrhosis and primary sclerosing cholangitis. Immunohistochemical stains were performed for biliary markers (cytokeratins [CKs] 7 and 19), as well as hepatocytic markers (HepParl and alpha-fetoprotein[AFP]) in sequential sections. The degree of staining of each cell type (biliary, hepatocytic, intermediate) was graded semiquantitatively. Results: Hepatocytes always stained diffusely for HepParl, occasionally for CK7, and rarely for CK19. Biliary cells were always diffusely positive for CK7 and CK19, and rarely for HepParl. Intermediate cells were identified in all cases and showed widespread staining for both HepParl and CK7, and less commonly for CK19. AFP was not expressed in any cell type. The morphologic and immunohistochemical features of bile ductular reactions were similar in the different diseases. Conclusions: Proliferating hepatic parenchymal cells with intermediate (hepatocytic/biliary) morphologic features and combined immunophenotype can be identified in a variety of acute and chronic liver diseases. The similarity of bile ductular reactions among chronic hepatitic, alcoholic and biliary diseases suggests that they result from proliferation of oval-like progenitor cells. [source] Sarcomatoid hepatocellular carcinoma with hepatoblastoma-like features in an adultPATHOLOGY INTERNATIONAL, Issue 6 2004Min-Sun Cho A mixed epithelial and mesenchymal tumor of the liver arising in an adult is rare and is mostly classified as sarcomatoid hepatocellular carcinoma (HCC). In this study, a case of sarcomatoid HCC in an adult with hepatoblastoma (HB)-like features, which produced difficulty in the differential diagnosis between sarcomatoid HCC and mixed HB, is presented. The epithelial component of the tumor composed of poorly differentiated HCC, Edmondson's grade III, and more primitive components, which were embryonal and small cell undifferentiated components of HB-like areas. The small undifferentiated cells surrounded HCC and the embryonal component of HB-like area, and revealed transition partly to areas of rhabdomyosarcoma. A small portion of chondrosarcoma was also noted. Immunohistochemical analysis showed that HCC and the embryonal component of HB-like areas expressed alpha-fetoprotein (AFP) and cytokeratin 8. The small undifferentiated cells were negative for AFP but stained with cytokeratin 8 as well as CD56, which is a marker of primitive cells in many sarcoma and HB. It is not certain whether small undifferentiated cells belong to hepatic progenitor cells or primitive mesenchymal cells. Polymerase chain reaction,single-strand conformation polymorphism analysis for beta-catenin mutation using microdissection revealed no mutation of any components. A review was undertaken of the cases previously reported as adult hepatoblastoma without detailed immunohistochemical study and consider many of them may be sarcomatoid HCC. These primitive and sarcomatoid components would be arising from the dedifferentiation process of HCC. [source] Progenitor cells in liver regeneration: molecular responses controlling their activation and expansion,APMIS, Issue 11-12 2005ERIC SANTONI-RUGIU Although normally quiescent, the adult mammalian liver possesses a great capacity to regenerate after different types of injuries in order to restore the lost liver mass and ensure maintenance of the multiple liver functions. Major players in the regeneration process are mature residual cells, including hepatocytes, cholangiocytes and stromal cells. However, if the regenerative capacity of mature cells is impaired by liver-damaging agents, hepatic progenitor cells are activated and expand into the liver parenchyma. Upon transit amplification, the progenitor cells may generate new hepatocytes and biliary cells to restore liver homeostasis. In recent years, hepatic progenitor cells have been the subject of increasing interest due to their therapeutic potential in numerous liver diseases as alternative or supportive/complementary tools to liver transplantation. While the first investigations on hepatic progenitor cells have focused on their origin and phenotypic characterization, recent attention has focused on the influence of the hepatic microenvironment on their activation and proliferation. This microenvironment comprises the extracellular matrix, epithelial and non-epithelial resident liver cells, and recruited inflammatory cells as well as the variety of growth-modulating molecules produced and/or harboured by these elements. The cellular and molecular responses to different regenerative stimuli seem to depend on the injury inflicted and consequently on the molecular microenvironment created in the liver by a certain insult. This review will focus on molecular responses controlling activation and expansion of the hepatic progenitor cell niche, emphasizing similarities and differences in the microenvironments orchestrating regeneration by recruitment of progenitor cell populations or by replication of mature cells. [source] | ||||||||||||||||||||||