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Neil D. Theise - One of the best experts on this subject based on the ideXlab platform.
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keratin 19 and mesenchymal markers for evaluation of epithelial mesenchymal transition and stem cell niche components in primary biliary cholangitis by sequential elution stripping multiplex immunohistochemistry
Journal of Histotechnology, 2020Co-Authors: John David Paulsen, Neil D. Theise, Briana Zeck, Katherine Sun, Camila Simoes, Luis ChiribogaAbstract:Multiplexed immunohistochemical techniques give insight into contextual cellular relationships by offering the ability to collect cell-specific data with spatial information from formalin-fixed, paraffin-embedded tissue sections. We established an automated sequential elution-stripping multiplex immunohistochemical assay to address two controversial scientific questions in the field of hepatopathology: 1) whether epithelial-to-mesenchymal transition or mesenchymal-to-epithelial transition occurs during liver injury and repair of a chronic liver disease and 2) if there is a stromal:epithelial relationship along the Canals of Hering that would support the concept of this biliary structure being a stem/progenitor cell niche. Our 4-plex assay includes both epithelial and mesenchymal clinical immunohistochemical markers and was performed on clinical human liver specimens in patients with primary biliary cholangitis. The assay demonstrated that in each specimen, co-expression of epithelial and mesenchymal markers was observed in extraportal cholangiocytes. In regard to possible mesenchymal components in a stem cell niche, 82.3% ± 5.5% of extraportal cholangiocytes were intimately associated with a vimentin-positive cell. Co-expression of epithelial and mesenchymal markers by extraportal cholangiocytes is evidence for epithelial to mesenchymal transition in primary biliary cholangitis. Vimentin-positive stromal cells are frequently juxtaposed to extraportal cholangiocytes, supporting an epithelial:mesenchymal relationship within the hepatobiliary stem cell niche. Our automated sequential elution-stripping multiplex immunohistochemical assay is a cost-effective multiplexing technique that can be readily applied to a small series of clinical pathology samples in order to answer scientific questions involving cell:cell relationships and cellular antibody expression.
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Canal of Hering loss is an initiating step for primary biliary cholangitis (PBC): A hypothesis.
Medical hypotheses, 2020Co-Authors: Neil D. Theise, Yasuni Nakanuma, James M. Crawford, Alberto QuagliaAbstract:Abstract The origin and initiating features of PBC remain obscure despite decades of study. However, recent papers have demonstrated loss of Canals of Hering (CoH) to be the earliest histologic change in liver biopsy specimens from patients with primary biliary cholangitis (PBC). We posit that CoH loss prior to significant inflammation or evidence of bile duct injury might be a very early, perhaps even an initiating lesion of PBC. As a potential target of inflammatory or toxic injury, CoH loss may initiate rather than follow the cascade of events leading to duct injury and loss and their sequelae. Toxins may be exogenous in origin, such as environmental toxins or drug exposures, or endogenous, resulting from genetic or epigenetic alterations in canalicular bile transporters upstream from the CoH. In turn, this hypothesis suggests that loss of CoH would lead to altered bile flow and composition injurious to downstream bile ducts, because bile composition has not been modulated by normal CoH physiologic functions or because, in the absence of CoH, canalicular fluid flow into the biliary tree is disrupted interfering with soluble trophic factors important for bile duct integrity. Regardless of the pathogenic mechanism causing CoH loss, only following such loss would the characteristic diagnostic findings of PBC become evident: damage to downstream interlobular and sub-lobular bile ducts. To the extent that the causal mechanisms for CoH loss can be identified, clinical identification (as through early identification of CoH loss) and intervention (depending on the inciting cause) may offer promise for treatment of this enigmatic disease.
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MEETING ABSTRACT Open Access Hepato-biliary stem cells: facts and fancies
2016Co-Authors: Neil D. TheiseAbstract:The Canals of Hering and stem cells At the close of the 20th century, a decades long questions was finally settled: both rodent and human livers had facultative hepato-biliary stem cells. The stem cell niche in which these cells ’ activities were identified was the canal of Hering (CoH) [1] – the link between hepatocyte canaliculi and the biliary tree. This structure had been functionally demonstrated by Ewald Hering in 1857, but its anatomic structure was merely inferred, but not visualized. Hering’s suggested that the link was located at the limiting plate, where hepatic parenchyma encountered portal tract stroma. His initial drawings depicted that hypothesis. The first direct imagings of the CoH were via electron micro-scopy, which confirmed that the CoH, as Hering intuited, was comprised of hepatocytes on one side and the smalles
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The Canals of Hering and Hepatic Stem Cells in Humans
2013Co-Authors: Neil D. Theise, Romil Saxena, Bernard C. Portmann, Swan N. Thung, Herman Yee, Luis Chiriboga, Ashok Kumar, James M. CrawfordAbstract:for biliary-type cytokeratins, may represent hepatic stem cells, Canals of Hering (CoH), and/or ductal plate remnants. We evaluated these cells 3 dimensionally in normal human liver and massive necrosis. Tissues from normal human livers and from 1 liver with acetaminophen-induced massive necrosis were serially sectioned, immunostained for cytokeratin 19 (CK19), and sequentially photographed. Images were examined to determine 3-dimensional relationships among CK19–positive cells. Immunostains for other hepatocyte and progenitor cell markers were examined. In normal livers, intraparenchymal CK19–positive cells lined up as linear arrays in sequential levels. One hundred of 106 (94.3%) defined, complete arrays within levels examined, most having 1 terminus at a bile duct, the other in the lobule, beyond the limiting plate. In massive necrosis, ther
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Keratin 19 demonstration of canal of Hering loss in primary biliary cirrhosis: "minimal change PBC"?
Hepatology, 2013Co-Authors: Fahad M. Khan, Arathi Rajendra Komarla, Paulo Giovanni Mendoza, Henry C. Bodenheimer, Neil D. TheiseAbstract:Liver biopsy is important for diagnosing primary biliary cirrhosis (PBC). Prior investigations suggest that immunostaining for biliary keratin 19 (K19) may show the earliest changes suspicious for PBC, namely, loss of the Canals of Hering (CoH). We aimed to study the clinical outcomes of patients whose biopsy specimens appeared histologically near normal or with minimal inflammatory changes, but in which K19 staining revealed widespread periportal CoH loss, a finding we termed “minimal change PBC.” Ten patients were identified prospectively as having nearly normal or mildly inflamed biopsy specimens without diagnostic or suggestive histologic features of PBC, but with near complete CoH loss; six had available follow-up clinical data, one had follow-up biopsy. Controls for clinical and/or K19 analysis included six normal livers and biopsy specimens from 10 patients with confirmed early PBC, 10 with early stage chronic hepatitis C (CHC), and nine with resolving, self-limited hepatitis (RSLH). Staining for K19 in normal controls, livers with “minimal change” PBC, CHC, and RSLH showed 9.2 ± 6.0, 0.44 ± 0.37 (P < 0.0001), 5.7 ± 4.6 (n.s.), 4.1 ± 2.1 (P < 0.02) CoH per portal tract, respectively. Patients with available clinical follow up, compared to patients with diagnostic early-stage PBC biopsies, showed identical treatment responses to ursodeoxycholic acid, similar rates and types of nonhepatic autoimmune diseases, and/or subsequent development of autoimmune hepatitis overlap syndrome. Conclusion: We suggest that CoH loss demonstrated by K19 immunostaining is an early feature in PBC. Clinical findings in the years following biopsy, including response to ursodeoxycholic acid, show identical changes to patients with biopsy confirmed PBC. We suggest that this “minimal change” feature may support a clinical diagnosis of PBC even in the absence of characteristic, granulomatous, duct destructive lesions. (HEPATOLOGY 2013)
Guido Carpino - One of the best experts on this subject based on the ideXlab platform.
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Hepatic Progenitor Cells and Biliary Tree Stem Cells
Liver Diseases, 2020Co-Authors: Guido Carpino, Sergio Morini, Simone Carotti, Eugenio GaudioAbstract:In the adult human liver, hepatic stem/progenitor cells (HPCs) are facultative bipotential stem cells which reside in the Canals of Hering and in bile ductules. HPCs have a unique phenotype and are capable to differentiate towards hepatocytes and cholangiocytes. The differentiation toward a more mature phenotype is characterized by the progressive acquisition of mature traits and the appearance of a progeny with an intermediate phenotype.
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Contribution of Resident Stem Cells to Liver and Biliary Tree Regeneration in Human Diseases.
International journal of molecular sciences, 2018Co-Authors: Diletta Overi, Antonio Franchitto, Guido Carpino, Vincenzo Cardinale, Paolo Onori, Domenico Alvaro, S. Safarikia, Eugenio GaudioAbstract:Two distinct stem/progenitor cell populations of biliary origin have been identified in the adult liver and biliary tree. Hepatic Stem/progenitor Cells (HpSCs) are bipotent progenitor cells located within the Canals of Hering and can be differentiated into mature hepatocytes and cholangiocytes; Biliary Tree Stem/progenitor Cells (BTSCs) are multipotent stem cells located within the peribiliary glands of large intrahepatic and extrahepatic bile ducts and able to differentiate into hepatic and pancreatic lineages. HpSCs and BTSCs are endowed in a specialized niche constituted by supporting cells and extracellular matrix compounds. The actual contribution of these stem cell niches to liver and biliary tree homeostatic regeneration is marginal; this is due to the high replicative capabilities and plasticity of mature parenchymal cells (i.e., hepatocytes and cholangiocytes). However, the study of human liver and biliary diseases disclosed how these stem cell niches are involved in the regenerative response after extensive and/or chronic injuries, with the activation of specific signaling pathways. The present review summarizes the contribution of stem/progenitor cell niches in human liver diseases, underlining mechanisms of activation and clinical implications, including fibrogenesis and disease progression.
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the hepatic biliary and pancreatic network of stem progenitor cell niches in humans a new reference frame for disease and regeneration
Hepatology, 2016Co-Authors: Giacomo Lanzoni, Vincenzo Cardinale, Guido CarpinoAbstract:Stem/progenitors for liver, biliary tree, and pancreas exist at early stages of development in the definitive ventral endoderm forming the foregut. In humans, they persist postnatally as part of a network, with evidence supporting their contributions to hepatic and pancreatic organogenesis throughout life. Multiple stem cell niches persist in specific anatomical locations within the human biliary tree and pancreatic ducts. In liver and pancreas, replication of mature parenchymal cells ensures the physiological turnover and the restoration of parenchyma after minor injuries. Although actively debated, multiple observations indicate that stem/progenitor cells contribute to repair pervasive, chronic injuries. The most primitive of the stem/progenitor cells, biliary tree stem cells, are found in peribiliary glands within extrahepatic and large intrahepatic bile ducts. Biliary tree stem cells are comprised of multiple subpopulations with traits suggestive of maturational lineage stages and yet capable of self-replication and multipotent differentiation, being able to differentiate to mature liver cells (hepatocytes, cholangiocytes) and mature pancreatic cells (including functional islet endocrine cells). Hepatic stem cells are located within Canals of Hering and bile ductules and are capable of differentiating to hepatocyte and cholangiocyte lineages. The existence, phenotype, and anatomical location of stem/progenitors in the adult pancreas are actively debated. Ongoing studies suggest that pancreatic stem cells reside within the biliary tree, primarily the hepatopancreatic common duct, and are rare in the pancreas proper. Pancreatic ducts and pancreatic duct glands harbor committed pancreatic progenitors. Conclusion: The hepatic, biliary, and pancreatic network of stem/progenitor cell niches should be considered as a framework for understanding liver and pancreatic regeneration after extensive or chronic injuries and for the study of human chronic diseases affecting these organs. (Hepatology 2016;64:277-286)
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Stem/Progenitor Cell Niches Involved in Hepatic and Biliary Regeneration
Stem cells international, 2016Co-Authors: Guido Carpino, Antonio Franchitto, Anastasia Renzi, Vincenzo Cardinale, Paolo Onori, Domenico Alvaro, Lola M. Reid, Eugenio GaudioAbstract:Niches containing stem/progenitor cells are present in different anatomical locations along the human biliary tree and within liver acini. The most primitive stem/progenitors, biliary tree stem/progenitor cells (BTSCs), reside within peribiliary glands located throughout large extrahepatic and intrahepatic bile ducts. BTSCs are multipotent and can differentiate towards hepatic and pancreatic cell fates. These niches' matrix chemistry and other characteristics are undefined. Canals of Hering (bile ductules) are found periportally and contain hepatic stem/progenitor cells (HpSCs), participating in the renewal of small intrahepatic bile ducts and being precursors to hepatocytes and cholangiocytes. The niches also contain precursors to hepatic stellate cells and endothelia, macrophages, and have a matrix chemistry rich in hyaluronans, minimally sulfated proteoglycans, fetal collagens, and laminin. The microenvironment furnishes key signals driving HpSC activation and differentiation. Newly discovered third niches are pericentral within hepatic acini, contain Axin2+ unipotent hepatocytic progenitors linked on their lateral borders to endothelia forming the central vein, and contribute to normal turnover of mature hepatocytes. Their relationship to the other stem/progenitors is undefined. Stem/progenitor niches have important implications in regenerative medicine for the liver and biliary tree and in pathogenic processes leading to diseases of these tissues.
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Stem Cell Populations Giving Rise to Liver, Biliary Tree, and Pancreas
Stem Cells Handbook, 2013Co-Authors: Mark E. Furth, Guido Carpino, Vincenzo Cardinale, Yunfang Wang, Giacomo Lanzoni, Cai Bin Cui, Eliane Wauthier, David A. Gerber, Tsunekazu Oikawa, Juan Domínguez-bendalaAbstract:Determined stem cells for liver and pancreas are present in stem cell niches, peribiliary glands (PBGs), throughout the biliary tree. PBGs are connected to intrahepatic stem cell niches, Canals of Hering, and niches of committed progenitors, pancreatic duct glands. The phenotypic traits in the most primitive populations comprise both liver and pancreatic markers (transcription factors, pluripotency genes, endodermal genes), and their highest numbers are in large intrahepatic bile ducts and the hepato-pancreatic common duct. Their descendants have phenotypic traits implicating maturational lineages along a radial axis within bile duct walls and a proximal-to-distal axis from duodenum to mature cells near or in the liver or pancreas. The stem cells and lineages constitute a biological framework for hepatic and pancreatic organogenesis throughout life.
Vincenzo Cardinale - One of the best experts on this subject based on the ideXlab platform.
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Contribution of Resident Stem Cells to Liver and Biliary Tree Regeneration in Human Diseases.
International journal of molecular sciences, 2018Co-Authors: Diletta Overi, Antonio Franchitto, Guido Carpino, Vincenzo Cardinale, Paolo Onori, Domenico Alvaro, S. Safarikia, Eugenio GaudioAbstract:Two distinct stem/progenitor cell populations of biliary origin have been identified in the adult liver and biliary tree. Hepatic Stem/progenitor Cells (HpSCs) are bipotent progenitor cells located within the Canals of Hering and can be differentiated into mature hepatocytes and cholangiocytes; Biliary Tree Stem/progenitor Cells (BTSCs) are multipotent stem cells located within the peribiliary glands of large intrahepatic and extrahepatic bile ducts and able to differentiate into hepatic and pancreatic lineages. HpSCs and BTSCs are endowed in a specialized niche constituted by supporting cells and extracellular matrix compounds. The actual contribution of these stem cell niches to liver and biliary tree homeostatic regeneration is marginal; this is due to the high replicative capabilities and plasticity of mature parenchymal cells (i.e., hepatocytes and cholangiocytes). However, the study of human liver and biliary diseases disclosed how these stem cell niches are involved in the regenerative response after extensive and/or chronic injuries, with the activation of specific signaling pathways. The present review summarizes the contribution of stem/progenitor cell niches in human liver diseases, underlining mechanisms of activation and clinical implications, including fibrogenesis and disease progression.
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the hepatic biliary and pancreatic network of stem progenitor cell niches in humans a new reference frame for disease and regeneration
Hepatology, 2016Co-Authors: Giacomo Lanzoni, Vincenzo Cardinale, Guido CarpinoAbstract:Stem/progenitors for liver, biliary tree, and pancreas exist at early stages of development in the definitive ventral endoderm forming the foregut. In humans, they persist postnatally as part of a network, with evidence supporting their contributions to hepatic and pancreatic organogenesis throughout life. Multiple stem cell niches persist in specific anatomical locations within the human biliary tree and pancreatic ducts. In liver and pancreas, replication of mature parenchymal cells ensures the physiological turnover and the restoration of parenchyma after minor injuries. Although actively debated, multiple observations indicate that stem/progenitor cells contribute to repair pervasive, chronic injuries. The most primitive of the stem/progenitor cells, biliary tree stem cells, are found in peribiliary glands within extrahepatic and large intrahepatic bile ducts. Biliary tree stem cells are comprised of multiple subpopulations with traits suggestive of maturational lineage stages and yet capable of self-replication and multipotent differentiation, being able to differentiate to mature liver cells (hepatocytes, cholangiocytes) and mature pancreatic cells (including functional islet endocrine cells). Hepatic stem cells are located within Canals of Hering and bile ductules and are capable of differentiating to hepatocyte and cholangiocyte lineages. The existence, phenotype, and anatomical location of stem/progenitors in the adult pancreas are actively debated. Ongoing studies suggest that pancreatic stem cells reside within the biliary tree, primarily the hepatopancreatic common duct, and are rare in the pancreas proper. Pancreatic ducts and pancreatic duct glands harbor committed pancreatic progenitors. Conclusion: The hepatic, biliary, and pancreatic network of stem/progenitor cell niches should be considered as a framework for understanding liver and pancreatic regeneration after extensive or chronic injuries and for the study of human chronic diseases affecting these organs. (Hepatology 2016;64:277-286)
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Stem/Progenitor Cell Niches Involved in Hepatic and Biliary Regeneration
Stem cells international, 2016Co-Authors: Guido Carpino, Antonio Franchitto, Anastasia Renzi, Vincenzo Cardinale, Paolo Onori, Domenico Alvaro, Lola M. Reid, Eugenio GaudioAbstract:Niches containing stem/progenitor cells are present in different anatomical locations along the human biliary tree and within liver acini. The most primitive stem/progenitors, biliary tree stem/progenitor cells (BTSCs), reside within peribiliary glands located throughout large extrahepatic and intrahepatic bile ducts. BTSCs are multipotent and can differentiate towards hepatic and pancreatic cell fates. These niches' matrix chemistry and other characteristics are undefined. Canals of Hering (bile ductules) are found periportally and contain hepatic stem/progenitor cells (HpSCs), participating in the renewal of small intrahepatic bile ducts and being precursors to hepatocytes and cholangiocytes. The niches also contain precursors to hepatic stellate cells and endothelia, macrophages, and have a matrix chemistry rich in hyaluronans, minimally sulfated proteoglycans, fetal collagens, and laminin. The microenvironment furnishes key signals driving HpSC activation and differentiation. Newly discovered third niches are pericentral within hepatic acini, contain Axin2+ unipotent hepatocytic progenitors linked on their lateral borders to endothelia forming the central vein, and contribute to normal turnover of mature hepatocytes. Their relationship to the other stem/progenitors is undefined. Stem/progenitor niches have important implications in regenerative medicine for the liver and biliary tree and in pathogenic processes leading to diseases of these tissues.
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Stem Cell Populations Giving Rise to Liver, Biliary Tree, and Pancreas
Stem Cells Handbook, 2013Co-Authors: Mark E. Furth, Guido Carpino, Vincenzo Cardinale, Yunfang Wang, Giacomo Lanzoni, Cai Bin Cui, Eliane Wauthier, David A. Gerber, Tsunekazu Oikawa, Juan Domínguez-bendalaAbstract:Determined stem cells for liver and pancreas are present in stem cell niches, peribiliary glands (PBGs), throughout the biliary tree. PBGs are connected to intrahepatic stem cell niches, Canals of Hering, and niches of committed progenitors, pancreatic duct glands. The phenotypic traits in the most primitive populations comprise both liver and pancreatic markers (transcription factors, pluripotency genes, endodermal genes), and their highest numbers are in large intrahepatic bile ducts and the hepato-pancreatic common duct. Their descendants have phenotypic traits implicating maturational lineages along a radial axis within bile duct walls and a proximal-to-distal axis from duodenum to mature cells near or in the liver or pancreas. The stem cells and lineages constitute a biological framework for hepatic and pancreatic organogenesis throughout life.
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Concise review: Clinical programs of stem cell therapies for liver and pancreas
'Wiley', 2013Co-Authors: Giacomo Lanzoni, Guido Carpino, Vincenzo Cardinale, Yunfang Wang, Tsunekazu Oikawa, Juan Domínguez-bendala, Cai-bin Cui, David Gerber, Mara Gabriel, Mark E. FurthAbstract:Regenerative medicine is transitioning into clinical programs using stem/progenitor cell therapies for repair of damaged organs. We summarize those for liver and pancreas, organs that share endodermal stem cell populations, biliary tree stem cells (hBTSCs), located in peribiliary glands. They are precursors to hepatic stem/progenitors in Canals of Hering and to committed progenitors in pancreatic duct glands. They give rise to maturational lineages along a radial axis within bile duct walls and a proximal-to-distal axis starting at the duodenum and ending with mature cells in the liver or pancreas. Clinical trials have been ongoing for years assessing effects of determined stem cells (fetal-liver-derived hepatic stem/progenitors) transplanted into the hepatic artery of patients with various liver diseases. Immunosuppression was not required. Control subjects, those given standard of care for a given condition, all died within a year or deteriorated in their liver functions. Subjects transplanted with 100-150 million hepatic stem/progenitor cells had improved liver functions and survival extending for several years. Full evaluations of safety and efficacy of transplants are still in progress. Determined stem cell therapies for diabetes using hBTSCs remain to be explored but are likely to occur following ongoing preclinical studies. In addition, mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs) are being used for patients with chronic liver conditions or with diabetes. MSCs have demonstrated significant effects through paracrine signaling of trophic and immunomodu-latory factors, and there is limited evidence for inefficient lineage restriction into mature parenchymal or islet cells. HSCs' effects are primarily via modulation of immune mechanisms. © AlphaMed Press
Roberto Brunelli - One of the best experts on this subject based on the ideXlab platform.
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biliary tree stem progenitor cells in glands of extrahepatic and intraheptic bile ducts an anatomical in situ study yielding evidence of maturational lineages
Journal of Anatomy, 2012Co-Authors: Guido Carpino, Antonio Franchitto, Vincenzo Cardinale, Paolo Onori, Pasquale Berloco, Massimo Rossi, Yunfang Wang, R Semeraro, M M Anceschi, Roberto BrunelliAbstract:Stem/progenitors have been identified intrahepatically in the Canals of Hering and extrahepatically in glands of the biliary tree. Glands of the biliary tree (peribiliary glands) are tubulo-alveolar glands with mucinous and serous acini, located deep within intrahepatic and extrahepatic bile ducts. We have shown that biliary tree stem/progenitors (BTSCs) are multipotent, giving rise in vitro and in vivo to hepatocytes, cholangiocytes or pancreatic islets. Cells with the phenotype of BTSCs are located at the bottom of the peribiliary glands near the fibromuscular layer. They are phenotypically heterogeneous, expressing transcription factors as well as surface and cytoplasmic markers for stem/progenitors of liver (e.g. SOX9/17), pancreas (e.g. PDX1) and endoderm (e.g. SOX17, EpCAM, NCAM, CXCR4, Lgr5, OCT4) but not for mature markers (e.g. albumin, secretin receptor or insulin). Subpopulations co-expressing liver and pancreatic markers (e.g. PDX1+/SOX17+) are EpCAM+/−, and are assumed to be the most primitive of the BTSC subpopulations. Their descendants undergo a maturational lineage process from the interior to the surface of ducts and vary in the mature cells generated: pancreatic cells in hepatopancreatic ducts, liver cells in large intrahepatic bile ducts, and bile duct cells along most of the biliary tree. We hypothesize that there is ongoing organogenesis throughout life, with BTSCs giving rise to hepatic stem cells in the Canals of Hering and to committed progenitors within the pancreas. The BTSCs are likely to be central to normal tissue turnover and injury repair and to be key elements in the pathophysiology of liver, pancreas and biliary tree diseases, including oncogenesis.
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Biliary tree stem/progenitor cells in glands of extrahepatic and intraheptic bile ducts: an anatomical in situ study yielding evidence of maturational lineages.
Journal of anatomy, 2011Co-Authors: Guido Carpino, Antonio Franchitto, Vincenzo Cardinale, Paolo Onori, Pasquale Berloco, Massimo Rossi, Yunfang Wang, R Semeraro, M M Anceschi, Roberto BrunelliAbstract:Stem/progenitors have been identified intrahepatically in the Canals of Hering and extrahepatically in glands of the biliary tree. Glands of the biliary tree (peribiliary glands) are tubulo-alveolar glands with mucinous and serous acini, located deep within intrahepatic and extrahepatic bile ducts. We have shown that biliary tree stem/progenitors (BTSCs) are multipotent, giving rise in vitro and in vivo to hepatocytes, cholangiocytes or pancreatic islets. Cells with the phenotype of BTSCs are located at the bottom of the peribiliary glands near the fibromuscular layer. They are phenotypically heterogeneous, expressing transcription factors as well as surface and cytoplasmic markers for stem/progenitors of liver (e.g. SOX9/17), pancreas (e.g. PDX1) and endoderm (e.g. SOX17, EpCAM, NCAM, CXCR4, Lgr5, OCT4) but not for mature markers (e.g. albumin, secretin receptor or insulin). Subpopulations co-expressing liver and pancreatic markers (e.g. PDX1+/SOX17+) are EpCAM+/−, and are assumed to be the most primitive of the BTSC subpopulations. Their descendants undergo a maturational lineage process from the interior to the surface of ducts and vary in the mature cells generated: pancreatic cells in hepatopancreatic ducts, liver cells in large intrahepatic bile ducts, and bile duct cells along most of the biliary tree. We hypothesize that there is ongoing organogenesis throughout life, with BTSCs giving rise to hepatic stem cells in the Canals of Hering and to committed progenitors within the pancreas. The BTSCs are likely to be central to normal tissue turnover and injury repair and to be key elements in the pathophysiology of liver, pancreas and biliary tree diseases, including oncogenesis.
Péter Nagy - One of the best experts on this subject based on the ideXlab platform.
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Expansion of Hepatic Stem Cell Compartment Boosts Liver Regeneration
Stem cells and development, 2013Co-Authors: Veronika Papp, Katalin Dezső, Sándor Paku, András Rókusz, Edina Bugyik, Vanessza Szabó, Zoltán Pávai, Péter NagyAbstract:The hepatic stem cells reside periportally forming the Canals of Hering in normal liver. They can be identified by their unique immunophenotype in rat. The oval cells, the progenies of stem cells invade deep the liver parenchyma after activation and differentiate into focally arranged small—and eventually trabecularly ordered regular hepatocytes. We have observed that upon the completion of intense oval cell reactions narrow ductular structures are present in the parenchyma, we propose to call them parenchymal ductules. These parenchymal ductules have the same immunophenotype [cytokeratin (CK)7−/CK19+/alpha-fetoprotein (AFP)−/delta-like protein (DLK)−] as the resting stem cells of the Canals of Hering, but different from them reside scattered in the parenchyma. In our present experiments, we have investigated in an in vivo functional assay if the presence of these parenchymal ductules has any impact on a progenitor cell driven regeneration process. Parenchymal ductules were induced either by an establishe...
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Architectural and immunohistochemical characterization of biliary ductules in normal human liver.
Stem cells and development, 2009Co-Authors: Katalin Dezső, Sándor Paku, Veronika Papp, Eszter Turányi, Péter NagyAbstract:The Canals of Hering or biliary ductules have been described to connect the bile canaliculi with the interlobular bile ducts, and thus forming the distal part of the biliary tree. Studies in the last two decades suggested that the cells constructing these ductules could behave as hepatic progenitor cells. The Canals of Hering are confined to the periportal space in the rat, while they have been reported to spread beyond the limiting plate in human liver. The distribution of the distal biliary ductules in normal human hepatic tissue has been investigated in our recent experiments. We could demonstrate the presence of interlobular connective tissue septa in a rudimentary form in healthy livers. The Canals of Hering run in these septa in line with the terminal branches of the portal vein and hepatic arteries. This arrangement develops in the postnatal period but regresses after early childhood. The Canals of Hering can be identified by the unique epithelial membrane antigen (EMA)−/CD56+/CD133+ immunophenotyp...
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immunohistochemical analysis of cytokeratin 7 expression in resting and proliferating biliary structures of rat liver
Hepatology, 2005Co-Authors: Sándor Paku, Katalin Dezső, László Kopper, Péter NagyAbstract:Cytokeratins are the largest subfamily of intermediate filament proteins and include more than 20 different gene products, which are expressed in an epithelial tissue-specific manner. We studied by immunohistochemistry and confocal microscopy the distribution of cytokeratin subtypes in the biliary system of adult rat liver. A cytokeratin (CK)19+/7− cholangiocyte population was observed in the smaller branches of the biliary tree including the Canals of Hering. They proliferated after 2-acetaminofluorene (AAF) administration, although later the typical oval cells expressed CK7. This observation suggests that cholangiocytes with this cytokeratin phenotype may harbor adult hepatic stem cells. The CK19+/7− cholangiocytes were not present in the rat liver at birth, but developed postnatally. Similar cell populations were not observed in human livers. In conclusion, we propose that the CK19+/7− phenotype may be characteristic for adult hepatic stem cells in rat liver and that these cells are generated de novo after birth. Supplementary material for this article can be found on the HEPATOLOGY website (http://www.interscience.wiley.com/jpages/0270-9139/suppmat/index.html). (HEPATOLOGY 2005;42:863–870.)
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Immunohistochemical analysis of cytokeratin 7 expression in resting and proliferating biliary structures of rat liver.
Hepatology (Baltimore Md.), 2005Co-Authors: Sándor Paku, Katalin Dezso, László Kopper, Péter NagyAbstract:Cytokeratins are the largest subfamily of intermediate filament proteins and include more than 20 different gene products, which are expressed in an epithelial tissue-specific manner. We studied by immunohistochemistry and confocal microscopy the distribution of cytokeratin subtypes in the biliary system of adult rat liver. A cytokeratin (CK)19+/7- cholangiocyte population was observed in the smaller branches of the biliary tree including the Canals of Hering. They proliferated after 2-acetaminofluorene (AAF) administration, although later the typical oval cells expressed CK7. This observation suggests that cholangiocytes with this cytokeratin phenotype may harbor adult hepatic stem cells. The CK19+/7- cholangiocytes were not present in the rat liver at birth, but developed postnatally. Similar cell populations were not observed in human livers. In conclusion, we propose that the CK19+/7- phenotype may be characteristic for adult hepatic stem cells in rat liver and that these cells are generated de novo after birth.
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Origin and structural evolution of the early proliferating oval cells in rat liver.
The American journal of pathology, 2001Co-Authors: Sándor Paku, Péter Nagy, Janos Schnur, Snorri S. ThorgeirssonAbstract:We have analyzed the histological changes in rat liver after 2-acetylaminofluorene (AAF) administration. The data demonstrate that AAF-induced oval cells were preferentially generated by proliferation of the terminal biliary ductules that we suggest constitute the primary hepatic stem cell niche. The oval cells formed ductular structures, representing an extension of the Canals of Hering. This histological organization provides continuous bile drainage of the hepatocytes and uninterrupted blood flow in the sinusoids. The oval cell ductules are surrounded by a continuous basement membrane that is intermittently disrupted by processes of stellate cells that form direct cell-cell contact with the oval cells. Although both AAF treatment and bile duct ligation results in proliferation of biliary epithelial cells, the mechanism(s) responsible for the proliferation of the biliary epithelium seems to differ in the two models. In contrast to the biliary proliferation stimulated by bile ligation, AAF-induced oval cell proliferation as well as the capacity of these cells to differentiate into hepatocytes, bile epithelial cells and possibly other cell lineages can be blocked by administration of dexamethasone.