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Oderberg IM, Goessling W. Biliary epithelial cells are facultative liver stem cells during liver regeneration in adult zebrafish. JCI Insight 2023; 8:163929. [PMID: 36625346 PMCID: PMC9870093 DOI: 10.1172/jci.insight.163929] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 11/22/2022] [Indexed: 01/11/2023] Open
Abstract
The liver is a highly regenerative organ, yet the presence of a dedicated stem cell population remains controversial. Here, we interrogate a severe hepatocyte injury model in adult zebrafish to define that regeneration involves a stem cell population. After near-total hepatocyte ablation, single-cell transcriptomic and high-resolution imaging analyses throughout the entire regenerative timeline reveal that biliary epithelial cells undergo transcriptional and morphological changes to become hepatocytes. As a population, biliary epithelial cells give rise to both hepatocytes and biliary epithelial cells. Biliary epithelial cells proliferate and dedifferentiate to express hepatoblast transcription factors prior to hepatocyte differentiation. This process is characterized by increased MAPK, PI3K, and mTOR signaling, and chemical inhibition of these pathways impairs biliary epithelial cell proliferation and fate conversion. We conclude that, upon severe hepatocyte ablation in the adult liver, biliary epithelial cells act as facultative liver stem cells in an EGFR-PI3K-mTOR-dependent manner.
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Affiliation(s)
- Isaac M. Oderberg
- Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Wolfram Goessling
- Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.,Harvard Stem Cell Institute, Cambridge, Massachusetts USA.,Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.,Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,Harvard-MIT Division of Health Sciences and Technology, Boston, Massachusetts, USA.,Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
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2
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Lazcanoiturburu N, García-Sáez J, González-Corralejo C, Roncero C, Sanz J, Martín-Rodríguez C, Valdecantos MP, Martínez-Palacián A, Almalé L, Bragado P, Calero-Pérez S, Fernández A, García-Bravo M, Guerra C, Montoliu L, Segovia JC, Valverde ÁM, Fabregat I, Herrera B, Sánchez A. Lack of EGFR catalytic activity in hepatocytes improves liver regeneration following DDC-induced cholestatic injury by promoting a pro-restorative inflammatory response. J Pathol 2022; 258:312-324. [PMID: 36148647 DOI: 10.1002/path.6002] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 07/22/2022] [Accepted: 08/15/2022] [Indexed: 01/03/2025]
Abstract
Despite the well-known hepatoprotective role of the epidermal growth factor receptor (EGFR) pathway upon acute damage, its specific actions during chronic liver disease, particularly cholestatic injury, remain ambiguous and unresolved. Here, we analyzed the consequences of inactivating EGFR signaling in the liver on the regenerative response following cholestatic injury. For that, transgenic mice overexpressing a dominant negative mutant human EGFR lacking tyrosine kinase activity (ΔEGFR) in albumin-positive cells were submitted to liver damage induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), an experimental model resembling human primary sclerosing cholangitis. Our results show an early activation of EGFR after 1-2 days of a DDC-supplemented diet, followed by a signaling switch-off. Furthermore, ΔEGFR mice showed less liver damage and a more efficient regeneration following DDC injury. Analysis of the mechanisms driving this effect revealed an enhanced activation of mitogenic/survival signals, AKT and ERK1/2-MAPKs, and changes in cell turnover consistent with a quicker resolution of damage in response to DDC. These changes were concomitant with profound differences in the profile of intrahepatic immune cells, consisting of a shift in the M1/M2 balance towards M2 polarity, and the Cd4/Cd8 ratio in favor of Cd4 lymphocytes, overall supporting an immune cell switch into a pro-restorative phenotype. Interestingly, ΔEGFR livers also displayed an amplified ductular reaction, with increased expression of EPCAM and an increased number of CK19-positive ductular structures in portal areas, demonstrating an overexpansion of ductular progenitor cells. In summary, our work supports the notion that hepatocyte-specific EGFR activity acts as a key player in the crosstalk between parenchymal and non-parenchymal hepatic cells, promoting the pro-inflammatory response activated during cholestatic injury and therefore contributing to the pathogenesis of cholestatic liver disease. © 2022 The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Nerea Lazcanoiturburu
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid (UCM), Health Research Institute of the 'Hospital Clínico San Carlos' (IdISSC), Madrid, Spain
| | - Juan García-Sáez
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid (UCM), Health Research Institute of the 'Hospital Clínico San Carlos' (IdISSC), Madrid, Spain
| | - Carlos González-Corralejo
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid (UCM), Health Research Institute of the 'Hospital Clínico San Carlos' (IdISSC), Madrid, Spain
| | - Cesáreo Roncero
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid (UCM), Health Research Institute of the 'Hospital Clínico San Carlos' (IdISSC), Madrid, Spain
| | - Julián Sanz
- Anatomical Pathology Service of the 'Clínica Universidad de Navarra', Madrid, Spain
- Department of Psychiatry, Legal Medicine and Anatomical Pathology, Faculty of Medicine, UCM, Madrid, Spain
| | - Carlos Martín-Rodríguez
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid (UCM), Health Research Institute of the 'Hospital Clínico San Carlos' (IdISSC), Madrid, Spain
| | - M Pilar Valdecantos
- 'Alberto Sols' Biomedical Research Institute, Spanish National Research Council and Autonomous University of Madrid (IIBM, CSIC-UAM), Madrid, Spain
- Biomedical Research Networking Center in Diabetes and Associated Metabolic Disorders of the Carlos III Health Institute (CIBERDEM-ISCIII), Madrid, Spain
| | - Adoración Martínez-Palacián
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid (UCM), Health Research Institute of the 'Hospital Clínico San Carlos' (IdISSC), Madrid, Spain
| | - Laura Almalé
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid (UCM), Health Research Institute of the 'Hospital Clínico San Carlos' (IdISSC), Madrid, Spain
| | - Paloma Bragado
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid (UCM), Health Research Institute of the 'Hospital Clínico San Carlos' (IdISSC), Madrid, Spain
| | - Silvia Calero-Pérez
- 'Alberto Sols' Biomedical Research Institute, Spanish National Research Council and Autonomous University of Madrid (IIBM, CSIC-UAM), Madrid, Spain
- Biomedical Research Networking Center in Diabetes and Associated Metabolic Disorders of the Carlos III Health Institute (CIBERDEM-ISCIII), Madrid, Spain
| | - Almudena Fernández
- National Center for Biotechnology (CNB-CSIC), Biomedical Research Networking Center on Rare Diseases (CIBERER-ISCIII), Madrid, Spain
| | - María García-Bravo
- Cell Technology Division, Research Center for Energy, Environment and Technology (CIEMAT), Biomedical Research Networking Center on Rare Diseases (CIBERER-ISCIII), Madrid, Spain
- Advanced Therapies Mixed Unit, 'Fundación Jiménez Díaz' University Hospital Health Research Institute (CIEMAT/IIS-FJD), Madrid, Spain
| | - Carmen Guerra
- Molecular Oncology Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain
| | - Lluis Montoliu
- National Center for Biotechnology (CNB-CSIC), Biomedical Research Networking Center on Rare Diseases (CIBERER-ISCIII), Madrid, Spain
| | - José Carlos Segovia
- Cell Technology Division, Research Center for Energy, Environment and Technology (CIEMAT), Biomedical Research Networking Center on Rare Diseases (CIBERER-ISCIII), Madrid, Spain
- Advanced Therapies Mixed Unit, 'Fundación Jiménez Díaz' University Hospital Health Research Institute (CIEMAT/IIS-FJD), Madrid, Spain
| | - Ángela M Valverde
- 'Alberto Sols' Biomedical Research Institute, Spanish National Research Council and Autonomous University of Madrid (IIBM, CSIC-UAM), Madrid, Spain
- Biomedical Research Networking Center in Diabetes and Associated Metabolic Disorders of the Carlos III Health Institute (CIBERDEM-ISCIII), Madrid, Spain
| | - Isabel Fabregat
- TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
- Oncology Program, Biomedical Research Networking Center in Hepatic and Digestive Diseases (CIBEREHD-ISCIII), Madrid, Spain
- Department of Physiological Sciences, Faculty of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Spain
| | - Blanca Herrera
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid (UCM), Health Research Institute of the 'Hospital Clínico San Carlos' (IdISSC), Madrid, Spain
| | - Aránzazu Sánchez
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid (UCM), Health Research Institute of the 'Hospital Clínico San Carlos' (IdISSC), Madrid, Spain
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3
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Elchaninov A, Fatkhudinov T, Makarov A, Vorobieva I, Lokhonina A, Usman N, Kananykhina E, Vishnyakova P, Nikitina M, Goldshtein D, Bolshakova G, Glinkina V, Sukhikh G. Inherent control of hepatocyte proliferation after subtotal liver resection. Cell Biol Int 2020; 44:80-88. [PMID: 31297922 DOI: 10.1002/cbin.11203] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Accepted: 07/09/2019] [Indexed: 02/05/2023]
Abstract
At the normal physiological conditions, hepatocytes predominantly reside in G0 phase of cell cycle; they actively proceed to G1 phase upon damage to the organ. As it was shown in experiments with restoration of liver mass in rats after subtotal hepatectomy (resection of 80% of the organ mass may be considered as a model of the 'small for size' liver syndrome), the growth inhibition is due to prolonged arrest of hepatocyte proliferation, molecular mechanisms of which remain understudied. In a rat model of liver regeneration after surgical removal of 80% of its mass, we observe a delayed onset of hepatocyte proliferation: Ki67+ hepatocytes begin to appear as late as at 30 h after liver subtotal resection. Their appearance coincides with the beginning of transcription of genes for cyclins A2, B1, D 1 , and E 1 at 24-30 h after surgery. The corresponding increase in concentrations of cyclin D 1 and E proteins is further delayed till 48 h after liver resection. We have also observed a prolonged decrease in the expression of proto-oncogene c-met (the hepatocyte growth factor receptor-encoding gene Met), an increase in expression of the transforming growth factor β1 (TGFβ 1 ) receptor-encoding gene Tgfbr2. At the same time, irreversible block of hepatocyte proliferation is prevented by expression of certain factors, notably of the TWEAK/Fn14 signaling pathway: concentrations of the corresponding proteins in remnant livers have peaked from 24 to 48 h after liver subtotal resection.
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Affiliation(s)
- Andrey Elchaninov
- National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I.Kulakov of Ministry of Healthcare of Russian Federation, 4 Oparina Street, Moscow, 117997, Russian Federation
- Peoples Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, Moscow, 117198, Russian Federation
| | - Timur Fatkhudinov
- National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I.Kulakov of Ministry of Healthcare of Russian Federation, 4 Oparina Street, Moscow, 117997, Russian Federation
- Peoples Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, Moscow, 117198, Russian Federation
| | - Andrey Makarov
- National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I.Kulakov of Ministry of Healthcare of Russian Federation, 4 Oparina Street, Moscow, 117997, Russian Federation
- Pirogov Russian National Research Medical University, Ministry of Healthcare of the Russian Federation, 1 Ostrovitianov Street, Moscow, 117997, Russian Federation
| | - Iva Vorobieva
- National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I.Kulakov of Ministry of Healthcare of Russian Federation, 4 Oparina Street, Moscow, 117997, Russian Federation
| | - Anastasia Lokhonina
- National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I.Kulakov of Ministry of Healthcare of Russian Federation, 4 Oparina Street, Moscow, 117997, Russian Federation
| | - Natalia Usman
- National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I.Kulakov of Ministry of Healthcare of Russian Federation, 4 Oparina Street, Moscow, 117997, Russian Federation
| | - Evgeniya Kananykhina
- Research Institute of Human Morphology, 3 Tsurupa Street, Moscow, 117418, Russian Federation
| | - Polina Vishnyakova
- National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I.Kulakov of Ministry of Healthcare of Russian Federation, 4 Oparina Street, Moscow, 117997, Russian Federation
| | - Maria Nikitina
- Research Institute of Human Morphology, 3 Tsurupa Street, Moscow, 117418, Russian Federation
| | - Dmitry Goldshtein
- Research Center of Medical Genetics, 1 Moscvorechie, Moscow, 115478, Russian Federation
| | - Galina Bolshakova
- Research Institute of Human Morphology, 3 Tsurupa Street, Moscow, 117418, Russian Federation
| | - Valeria Glinkina
- Pirogov Russian National Research Medical University, Ministry of Healthcare of the Russian Federation, 1 Ostrovitianov Street, Moscow, 117997, Russian Federation
| | - Gennady Sukhikh
- National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I.Kulakov of Ministry of Healthcare of Russian Federation, 4 Oparina Street, Moscow, 117997, Russian Federation
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4
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Crema A, Ledda M, Fioretti D, Lolli MG, Sanchez M, Carico E, Marchese R, Rinaldi M, Lisi A. Combination of cord blood-derived human hepatic progenitors and hepatogenic factors strongly improves recovery after acute liver injury in mice through modulation of the Wnt/β-catenin signaling. J Tissue Eng Regen Med 2019; 13:1031-1043. [PMID: 30942524 DOI: 10.1002/term.2854] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Revised: 03/15/2019] [Accepted: 03/15/2019] [Indexed: 01/10/2023]
Abstract
Cell therapy represents a promising alternative strategy for end-stage liver disease, and hepatic progenitors are the best candidates. The possibility to maximize the paracrine effects of transplanted cells represents a great potential benefit for cell therapy success. We studied how cell type and microenvironment modulate the Wnt/β-catenin signaling in vitro and in vivo. In vitro, the onset of hepatocyte commitment was characterized by the presence of nuclear truncated β-catenin. In vivo, we analyzed the effect of human hepatic progenitors on damage recovery and functional regeneration in a mouse model of acute liver injury, either in combination or in absence of a selected mix of hepatogenic factors. Animals injected with human hepatic progenitors and hepatogenic factors showed improved engraftment triggering the Wnt/β-catenin signaling cascade. Human hepatic progenitors expressing the human oval cell marker OV6 displayed a consistent colocalization with β-catenin and colocalized with Wnt1 main ligand of the canonical pathway. Wnt5a, on the contrary, was expressed in distinct liver cell populations. Epithelial mesenchymal transition-related markers showed enhanced expression and wider distribution, and the hepato-mesenchymal population Thy1 + CK19- was also present. Control animals injected with hepatogenic factors alone exhibited higher β-catenin, decreased Wnt5a levels, and persistent proliferation of the hepato-mesenchymal population. In conclusion, the combination of human hepatic progenitors with selected hepatogenic factors creates a positive synergy with local microenvironment, ameliorates cell engraftment, stimulates and accelerates regenerative process, and improves the rescue of hepatic function by modulating the Wnt/βcatenin signaling and activating hepato-mesenchymal population.
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Affiliation(s)
- Annalisa Crema
- Institute of Translational Pharmacology (IFT), Department of Biomedical Sciences, National Research Council (CNR), Rome, Italy
| | - Mario Ledda
- Institute of Translational Pharmacology (IFT), Department of Biomedical Sciences, National Research Council (CNR), Rome, Italy
| | - Daniela Fioretti
- Institute of Translational Pharmacology (IFT), Department of Biomedical Sciences, National Research Council (CNR), Rome, Italy
| | - Maria Grazia Lolli
- Institute of Translational Pharmacology (IFT), Department of Biomedical Sciences, National Research Council (CNR), Rome, Italy
| | - Massimo Sanchez
- Core Facilities, Cytometry Unit, Istituto Superiore di Sanità, Rome, Italy
| | - Elisabetta Carico
- Department of Clinical and Molecular Medicine, Sapienza University, Sant'Andrea Hospital, Rome, Italy
| | | | - Monica Rinaldi
- Institute of Translational Pharmacology (IFT), Department of Biomedical Sciences, National Research Council (CNR), Rome, Italy
| | - Antonella Lisi
- Institute of Translational Pharmacology (IFT), Department of Biomedical Sciences, National Research Council (CNR), Rome, Italy
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5
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Horodyska J, Hamill RM, Reyer H, Trakooljul N, Lawlor PG, McCormack UM, Wimmers K. RNA-Seq of Liver From Pigs Divergent in Feed Efficiency Highlights Shifts in Macronutrient Metabolism, Hepatic Growth and Immune Response. Front Genet 2019; 10:117. [PMID: 30838035 PMCID: PMC6389832 DOI: 10.3389/fgene.2019.00117] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Accepted: 02/04/2019] [Indexed: 12/14/2022] Open
Abstract
Liver is a metabolically complex organ that influences nutrient partitioning and potentially modulates the efficiency of converting energy acquired from macronutrients ingestion into a muscle and/or adipose tissue (referred to as feed efficiency, FE). The objective of this study was to sequence the hepatic tissue transcriptome of closely related but differently feed efficient pigs (n = 16) and identify relevant biological processes that underpin the differences in liver phenotype between FE groups. Liver weight did not significantly differ between the FE groups, however, blood parameters showed that total protein, glucose, cholesterol and percentage of lymphocytes were significantly greater in high-FE pigs. Ontology analysis revealed carbohydrate, lipid and protein metabolism to be significantly enriched with differentially expressed genes. In particular, high-FE pigs exhibited gene expression patterns suggesting improved absorption of carbohydrates and cholesterol as well as enhanced reverse cholesterol transport. Furthermore, the inferred decrease in bile acid synthesis in high-FE pigs may contribute to the observed greater levels of serum glucose, which can be then delivered to cells and utilized for growth and maintenance. Gene ontology analysis also suggested that livers of more efficient pigs may be characterized by higher protein turnover and increased epithelial cell differentiation, whereby an enhanced quantity of invariant natural killer T-cells and viability of natural killer cells could induce a quicker and more effective hepatic response to inflammatory stimuli. Our findings suggest that this prompt hepatic response to inflammation in high-FE group may contribute to the more efficient utilization of nutrients for growth in these animals.
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Affiliation(s)
- Justyna Horodyska
- Teagasc, Food Research Centre, Ashtown, Ireland.,Leibniz Institute for Farm Animal Biology (FBN), Institute for Genome Biology, Dummerstorf, Germany
| | | | - Henry Reyer
- Leibniz Institute for Farm Animal Biology (FBN), Institute for Genome Biology, Dummerstorf, Germany
| | - Nares Trakooljul
- Leibniz Institute for Farm Animal Biology (FBN), Institute for Genome Biology, Dummerstorf, Germany
| | - Peadar G Lawlor
- Teagasc, Pig Production Department, AGRIC, Moorepark, Fermoy, Co. Cork, Ireland
| | - Ursula M McCormack
- Teagasc, Pig Production Department, AGRIC, Moorepark, Fermoy, Co. Cork, Ireland
| | - Klaus Wimmers
- Leibniz Institute for Farm Animal Biology (FBN), Institute for Genome Biology, Dummerstorf, Germany.,Faculty of Agricultural and Environmental Sciences, University Rostock, Rostock, Germany
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6
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Elchaninov AV, Makarov AV, Vorobieva IG, Kananykhina EY, Lokhonina AV, Bolshakova GB, Glinkina VV, Goldshtein DV, Fatkhudinov TK. Regulation of hepatocyte proliferation after subtotal liver resection in rats. GENES & CELLS 2018; 13:37-42. [DOI: 10.23868/201812045] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Hepatocyte proliferation is the main cellular mechanism of liver regeneration. However, after removal of more than 80 % of the liver mass, a temporary block of hepatocyte proliferation is observed, which may be the cause of impaired regeneration during transplantation and liver resection in the clinical practice. The current study aims to analyze the molecular mechanisms of hepatocyte proliferation impairment after subtotal liver resection in rats. In male Wistar rats, a model of liver regeneration after subtotal resection is reproduced - removal of more than 80 % of liver mass. Using the methods of immunohistochemistry, PCR-RT, western blot, possible molecular mechanisms of slowing down the proliferation of hepatocytes were studied. It was found that expression of cyclin D1 and E increased only 30 hours after surgery. Their appearance coincides with the beginning of transcription of genes for Cyclins D1 and E1 at 30 h after surgery. The corresponding increase in concentrations of cyclin D, and E proteins is further delayed till 48 h after surgery. These results indicate that, in this particular model, hepatocytes are reluctant to undergo transition between G0- and G1 -phases of cell cycle. We have observed a prolonged decrease in the expression of protooncogene C-met (the hepatocyte growth factor receptor-encoding gene Met). We have also observed an increase in expression of the transforming growth factor beta-1 receptor-encoding gene TgfbrII. At the same time, irreversible block of hepatocyte proliferation was prevented by expression of certain factors, notably of the TWEAK/ Fn14 signaling pathway: concentrations of the corresponding proteins in remnant livers have peaked from 24 h to 48 h after surgery. Thus, after subtotal liver resection, the remaining hepatocytes are exposed to a large scope of both mitogenic and antimitogenic factors. Proliferative behavior of hepatocytes in remnant livers is determined by fine balance of these factors. The prevalence of antimitogenic factors in the early period after surgery delays the onset of hepatocyte proliferation.
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7
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Matondo RB, Toussaint MJ, Govaert KM, van Vuuren LD, Nantasanti S, Nijkamp MW, Pandit SK, Tooten PC, Koster MH, Holleman K, Schot A, Gu G, Spee B, Roskams T, Rinkes IB, Schotanus B, Kranenburg O, de Bruin A. Surgical resection and radiofrequency ablation initiate cancer in cytokeratin-19+- liver cells deficient for p53 and Rb. Oncotarget 2016; 7:54662-54675. [PMID: 27323406 PMCID: PMC5342371 DOI: 10.18632/oncotarget.9952] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2015] [Accepted: 05/28/2016] [Indexed: 01/22/2023] Open
Abstract
The long term prognosis of liver cancer patients remains unsatisfactory because of cancer recurrence after surgical interventions, particularly in patients with viral infections. Since hepatitis B and C viral proteins lead to inactivation of the tumor suppressors p53 and Retinoblastoma (Rb), we hypothesize that surgery in the context of p53/Rb inactivation initiate de novo tumorigenesis. We, therefore, generated transgenic mice with hepatocyte and cholangiocyte/liver progenitor cell (LPC)-specific deletion of p53 and Rb, by interbreeding conditional p53/Rb knockout mice with either Albumin-cre or Cytokeratin-19-cre transgenic mice. We show that liver cancer develops at the necrotic injury site after surgical resection or radiofrequency ablation in p53/Rb deficient livers. Cancer initiation occurs as a result of specific migration, expansion and transformation of cytokeratin-19+-liver (CK-19+) cells. At the injury site migrating CK-19+ cells formed small bile ducts and adjacent cells strongly expressed the transforming growth factor β (TGFβ). Isolated cytokeratin-19+ cells deficient for p53/Rb were resistant against hypoxia and TGFβ-mediated growth inhibition. CK-19+ specific deletion of p53/Rb verified that carcinomas at the injury site originates from cholangiocytes or liver progenitor cells. These findings suggest that human liver patients with hepatitis B and C viral infection or with mutations for p53 and Rb are at high risk to develop tumors at the surgical intervention site.
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Affiliation(s)
- Ramadhan B Matondo
- Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Mathilda Jm Toussaint
- Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Klaas M Govaert
- Department of Surgical Oncology, Cancer Centre, UMC Utrecht, Utrecht, The Netherlands
| | - Luciel D van Vuuren
- Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Sathidpak Nantasanti
- Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.,Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Maarten W Nijkamp
- Department of Surgical Oncology, Cancer Centre, UMC Utrecht, Utrecht, The Netherlands
| | - Shusil K Pandit
- Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Peter Cj Tooten
- Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Mirjam H Koster
- Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Kaylee Holleman
- Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.,Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Arend Schot
- Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Guoqiang Gu
- Program in Developmental Biology and the Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Bart Spee
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Tania Roskams
- Translational Cell and Tissue Research, University of Leuven, Leuven, Belgium
| | - Inne Borel Rinkes
- Department of Surgical Oncology, Cancer Centre, UMC Utrecht, Utrecht, The Netherlands
| | - Baukje Schotanus
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Onno Kranenburg
- Department of Surgical Oncology, Cancer Centre, UMC Utrecht, Utrecht, The Netherlands
| | - Alain de Bruin
- Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.,Department of Pediatrics, Division of Molecular Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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8
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Reibetanz U, Hübner D, Jung M, Liebert UG, Claus C. Influence of Growth Characteristics of Induced Pluripotent Stem Cells on Their Uptake Efficiency for Layer-by-Layer Microcarriers. ACS NANO 2016; 10:6563-6573. [PMID: 27362252 DOI: 10.1021/acsnano.6b00999] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
Induced pluripotent stem cells (iPSCs) have the ability to differentiate into any specialized somatic cell type, which makes them an attractive tool for a wide variety of scientific approaches, including regenerative medicine. However, their pluripotent state and their growth in compact colonies render them difficult to access and, therefore, restrict delivery of specific agents for cell manipulation. Thus, our investigation focus was set on the evaluation of the capability of layer-by-layer (LbL) designed microcarriers to serve as a potential drug delivery system to iPSCs, as they offer several appealing advantages. Most notably, these carriers allow for the transport of active agents in a protected environment and for a rather specific delivery through surface modifications. As we could show, charge and mode of LbL carrier application as well as the size of the iPSC colonies determine the interaction with and the uptake rate by iPSCs. None of the examined conditions had an influence on iPSC colony properties such as colony morphology and size or maintenance of pluripotent properties. An overall interaction rate of LbL carriers with iPSCs of up to 20% was achieved. Those data emphasize the applicability of LbL carriers for stem cell research. Additionally, the potential use of LbL carriers as a promising delivery tool for iPSCs was contrasted to viral particles and liposomes. The identified differences among those delivery tools have substantiated our major conclusion that LbL carrier uptake rate is influenced by characteristic features of the iPSC colonies (most notably colony size) in addition to their surface charges.
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Affiliation(s)
- Uta Reibetanz
- Institute for Medical Physics and Biophysics, Faculty of Medicine, University of Leipzig , 04107 Leipzig, Germany
| | - Denise Hübner
- Institute of Virology, University of Leipzig , 04103 Leipzig, Germany
| | - Matthias Jung
- Department of Psychiatry, University of Halle-Wittenberg , Halle, Germany
| | - Uwe Gerd Liebert
- Institute of Virology, University of Leipzig , 04103 Leipzig, Germany
| | - Claudia Claus
- Institute of Virology, University of Leipzig , 04103 Leipzig, Germany
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Environmental Ligands of the Aryl Hydrocarbon Receptor and Their Effects in Models of Adult Liver Progenitor Cells. Stem Cells Int 2016; 2016:4326194. [PMID: 27274734 PMCID: PMC4870370 DOI: 10.1155/2016/4326194] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Accepted: 04/07/2016] [Indexed: 12/20/2022] Open
Abstract
The toxicity of environmental and dietary ligands of the aryl hydrocarbon receptor (AhR) in mature liver parenchymal cells is well appreciated, while considerably less attention has been paid to their impact on cell populations exhibiting phenotypic features of liver progenitor cells. Here, we discuss the results suggesting that the consequences of the AhR activation in the cellular models derived from bipotent liver progenitors could markedly differ from those in hepatocytes. In contact-inhibited liver progenitor cells, the AhR agonists induce a range of effects potentially linked with tumor promotion. They can stimulate cell cycle progression/proliferation and deregulate cell-to-cell communication, which is associated with downregulation of proteins forming gap junctions, adherens junctions, and desmosomes (such as connexin 43, E-cadherin, β-catenin, and plakoglobin), as well as with reduced cell adhesion and inhibition of intercellular communication. At the same time, toxic AhR ligands may affect the activity of the signaling pathways contributing to regulation of liver progenitor cell activation and/or differentiation, such as downregulation of Wnt/β-catenin and TGF-β signaling, or upregulation of transcriptional targets of YAP/TAZ, the effectors of Hippo signaling pathway. These data illustrate the need to better understand the potential role of liver progenitors in the AhR-mediated liver carcinogenesis and tumor promotion.
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10
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Giannelli G, Mikulits W, Dooley S, Fabregat I, Moustakas A, ten Dijke P, Portincasa P, Winter P, Janssen R, Leporatti S, Herrera B, Sanchez A. The rationale for targeting TGF-β in chronic liver diseases. Eur J Clin Invest 2016; 46:349-361. [PMID: 26823073 DOI: 10.1111/eci.12596] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2015] [Accepted: 01/25/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND Transforming growth factor (TGF)-β is a pluripotent cytokine that displays several tissue-specific biological activities. In the liver, TGF-β is considered a fundamental molecule, controlling organ size and growth by limiting hepatocyte proliferation. It is involved in fibrogenesis and, therefore, in worsening liver damage, as well as in triggering the development of hepatocellular carcinoma (HCC). TGF-β is known to act as an oncosuppressor and also as a tumour promoter in HCC, but its role is still unclear. DESIGN In this review, we discuss the potential role of TGF-β in regulating the tumoural progression of HCC, and therefore the rationale for targeting this molecule in patients with HCC. RESULTS A considerable amount of experimental preclinical evidence suggests that TGF-β is a promising druggable target in patients with HCC. To support this hypothesis, a phase II clinical trial is currently ongoing using a TGF-β pathway inhibitor, and results will soon be available. CONCLUSIONS The identification of new TGF-β related biomarkers will help to select those patients most likely to benefit from therapy aimed at inhibiting the TGF-β pathway. New formulations that may provide a more controlled and sustained delivery of the drug will improve the therapeutic success of such treatments.
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Affiliation(s)
- Gianluigi Giannelli
- Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy
| | - Wolfgang Mikulits
- Department of Medicine I, Institute of Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Steven Dooley
- Department of Medicine II, Medical Faculty, Mannheim Heidelberg University, Heidelberg, Germany
| | - Isabel Fabregat
- Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Spain
| | - Aristidis Moustakas
- Department of Medical Biochemistry and Microbiology and Ludwig Institute for Cancer Research, Biomedical Center, Uppsala University, Uppsala, Sweden
| | - Peter ten Dijke
- Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands, Leiden University Medical Center, Leiden, the Netherlands
| | - Piero Portincasa
- Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy
| | | | | | | | - Blanca Herrera
- Dep. Bioquímica y Biología Molecular II, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Universidad Complutense, Madrid, Spain
| | - Aranzazu Sanchez
- Dep. Bioquímica y Biología Molecular II, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Universidad Complutense, Madrid, Spain
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11
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Katselis C, Apostolou K, Feretis T, Papanikolaou IG, Zografos GC, Toutouzas K, Papalois A. Role of Stem Cells Transplantation in Tissue Regeneration After Acute or Chronic Acetaminophen Induced Liver Injury. J INVEST SURG 2015; 29:112-20. [PMID: 26650889 DOI: 10.3109/08941939.2015.1086040] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
PURPOSE Acetaminophen-induced liver injury (APAP) is recognized as a frequent etiologic factor responsible for hepatic damage in the developed world. Management remains still elusive as treatment options are limited and their results are inconclusive. Consequently new strategies are explored at the experimental level. Mesenchymal stem cells (MSCs) present a promising modality as they can promote liver regeneration (LG) and compensate acute liver injury (ALI). MATERIALS AND METHODS Our research was focused on articles related to drug-induced liver injury, mechanisms of liver regeneration (LG) after Acute Liver Injury (ALI) and recent experimental protocols of Mesenchymal Stem Cells (MSCs) transplantation after chemical insult. All these studies are cited on Pubmed and MedLine. RESULTS This review has three distinct sections. First recent developments in ALI pathogenesis are presented. The second section covers cellular pathways and histological findings relevant to liver regeneration. The final chapter analyzes MSCs transplantation protocols after ALI and interrelation between liver regeneration and hepatic differentiation of MSCs. CONCLUSION Adipose tissue stem cells (ADSCs) and (MSCs) transplantation represents a promising modality in severe ALI management although many aspects remain to be clarified.
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Affiliation(s)
- Charalampos Katselis
- a Department of Propaedeutic Surgery , University of Athens, School of Medicine, General Hospital of Athens "Hippocration" , Athens , Greece.,b Experimental - Research Center , ELPEN Pharmaceuticals , Pikermi , Attica
| | - Konstantinos Apostolou
- a Department of Propaedeutic Surgery , University of Athens, School of Medicine, General Hospital of Athens "Hippocration" , Athens , Greece.,b Experimental - Research Center , ELPEN Pharmaceuticals , Pikermi , Attica
| | - Themistoklis Feretis
- a Department of Propaedeutic Surgery , University of Athens, School of Medicine, General Hospital of Athens "Hippocration" , Athens , Greece.,b Experimental - Research Center , ELPEN Pharmaceuticals , Pikermi , Attica
| | - Ioannis G Papanikolaou
- a Department of Propaedeutic Surgery , University of Athens, School of Medicine, General Hospital of Athens "Hippocration" , Athens , Greece.,b Experimental - Research Center , ELPEN Pharmaceuticals , Pikermi , Attica
| | - George C Zografos
- a Department of Propaedeutic Surgery , University of Athens, School of Medicine, General Hospital of Athens "Hippocration" , Athens , Greece
| | - Konstantinos Toutouzas
- a Department of Propaedeutic Surgery , University of Athens, School of Medicine, General Hospital of Athens "Hippocration" , Athens , Greece
| | - Apostolos Papalois
- a Department of Propaedeutic Surgery , University of Athens, School of Medicine, General Hospital of Athens "Hippocration" , Athens , Greece.,b Experimental - Research Center , ELPEN Pharmaceuticals , Pikermi , Attica
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12
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Suárez-Causado A, Caballero-Díaz D, Bertrán E, Roncero C, Addante A, García-Álvaro M, Fernández M, Herrera B, Porras A, Fabregat I, Sánchez A. HGF/c-Met signaling promotes liver progenitor cell migration and invasion by an epithelial-mesenchymal transition-independent, phosphatidyl inositol-3 kinase-dependent pathway in an in vitro model. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2015; 1853:2453-63. [PMID: 26001768 DOI: 10.1016/j.bbamcr.2015.05.017] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 12/29/2014] [Revised: 05/08/2015] [Accepted: 05/13/2015] [Indexed: 12/11/2022]
Abstract
Oval cells constitute an interesting hepatic cell population. They contribute to sustain liver regeneration during chronic liver damage, but in doing this they can be target of malignant conversion and become tumor-initiating cells and drive hepatocarcinogenesis. The molecular mechanisms beneath either their pro-regenerative or pro-tumorigenic potential are still poorly understood. In this study, we have investigated the role of the HGF/c-Met pathway in regulation of oval cell migratory and invasive properties. Our results show that HGF induces c-Met-dependent oval cell migration both in normal culture conditions and after in vitro wounding. HGF-triggered migration involves F-actin cytoskeleton reorganization, which is also evidenced by activation of Rac1. Furthermore, HGF causes ZO-1 translocation from cell-cell contact sites to cytoplasm and its concomitant activation by phosphorylation. However, no loss of expression of cell-cell adhesion proteins, including E-cadherin, ZO-1 and Occludin-1, is observed. Additionally, migration does not lead to cell dispersal but to a characteristic organized pattern in rows, in turn associated with Golgi compaction, providing strong evidence of a morphogenic collective migration. Besides migration, HGF increases oval cell invasion through extracellular matrix, a process that requires PI3K activation and is at least partly mediated by expression and activation of metalloproteases. Altogether, our findings provide novel insights into the cellular and molecular mechanisms mediating the essential role of HGF/c-Met signaling during oval cell-mediated mouse liver regeneration.
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Affiliation(s)
- A Suárez-Causado
- Dep. Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
| | - D Caballero-Díaz
- Dep. Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
| | - E Bertrán
- Laboratori d'Oncologia Molecular, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain.
| | - C Roncero
- Dep. Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
| | - A Addante
- Dep. Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
| | - M García-Álvaro
- Dep. Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
| | - M Fernández
- Dep. Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
| | - B Herrera
- Dep. Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
| | - A Porras
- Dep. Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
| | - I Fabregat
- Laboratori d'Oncologia Molecular, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain; Departament de Ciències Fisiològiques II, Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain.
| | - A Sánchez
- Dep. Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
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13
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Han LL, Lv Y, Guo H, Ruan ZP, Nan KJ. Implications of biomarkers in human hepatocellular carcinoma pathogenesis and therapy. World J Gastroenterol 2014; 20:10249-10261. [PMID: 25132742 PMCID: PMC4130833 DOI: 10.3748/wjg.v20.i30.10249] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Revised: 03/21/2014] [Accepted: 04/29/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most frequent tumors worldwide and accounts for approximately one-third of all malignancies. In the past decade, advances have been made to improve the prognosis of HCC, including improvement in the clinical diagnosis of early-stage HCC using molecular biomarkers and molecular-targeted therapy to treat advanced HCC. However, the diagnosis, pathogenesis and targeted therapy of HCC are not completely independent, and should be comprehensively studied. For example, a number of tumor markers provide useful clinical information not only for prognosis, but also in pathogenesis and treatment efficacy. Therefore, this review will focus on the role of several specific biomarkers implicated in the pathogenesis of HCC and several promising molecular-targeted drugs that target the biomarkers of HCC.
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14
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High efficient differentiation of functional hepatocytes from porcine induced pluripotent stem cells. PLoS One 2014; 9:e100417. [PMID: 24949734 PMCID: PMC4065042 DOI: 10.1371/journal.pone.0100417] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2014] [Accepted: 05/23/2014] [Indexed: 01/15/2023] Open
Abstract
Hepatocyte transplantation is considered to be a promising therapy for patients with liver diseases. Induced pluripotent stem cells (iPSCs) provide an unlimited source for the generation of functional hepatocytes. In this study, we generated iPSCs from porcine ear fibroblasts (PEFs) by overexpressing Sox2, Klf4, Oct4, and c-Myc (SKOM), and developed a novel strategy for the efficient differentiation of hepatocyte-like cells from porcine iPSCs by following the processes of early liver development. The differentiated cells displayed the phenotypes of hepatocytes, exhibited classic hepatocyte-associated bio-functions, such as LDL uptake, glycogen storage and urea secretion, as well as possessed the metabolic activities of cytochrome P-450 (CYP) 3A and 2C. Furthermore, we compared the hepatocyte differentiation efficacy of our protocol with another published method, and the results demonstrated that our differentiation strategy could significantly improve the generation of morphological and functional hepatocyte-like cells from porcine iPSCs. In conclusion, this study establishes an efficient method for in vitro generation of functional hepatocytes from porcine iPSCs, which could represent a promising cell source for preclinical testing of cell-based therapeutics for liver failure and for pharmacological applications.
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15
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Ding ZY, Liang HF, Jin GN, Chen WX, Wang W, Datta PK, Zhang MZ, Zhang B, Chen XP. Smad6 suppresses the growth and self-renewal of hepatic progenitor cells. J Cell Physiol 2014; 229:651-660. [PMID: 24446200 DOI: 10.1002/jcp.24488] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2013] [Accepted: 10/02/2013] [Indexed: 12/16/2022]
Abstract
Activation of hepatic progenitor cells (HPCs) is commonly observed in chronic liver disease and Wnt/β-catenin signaling plays a crucial role in the expansion of HPCs. However, the molecular mechanisms that regulate the activation of Wnt/β-catenin signaling in the liver, especially in HPCs, remain largely elusive. Here, we reported that ectopic expression of Smad6 suppressed the proliferation and self-renewal of WB-F344 cells, a HPC cell line. Mechanistically, we found that Smad6 inhibited Wnt/β-catenin signaling through promoting the interaction of C-terminal binding protein (CtBP) with β-catenin/T-cell factor (TCF) complex to inhibit β-catenin mediated transcriptional activation in WB-F344 cells. We used siRNA targeting β-catenin to demonstrate that Wnt/β-catenin signaling was required for the proliferation and self-renewal of HPCs. Taken together, these results suggest that Smad6 is a regulatory molecule which regulates the proliferation, self-renewal and Wnt/β-catenin signaling in HPCs.
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Affiliation(s)
- Ze-Yang Ding
- Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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16
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Chen L, Zhang W, Liang HF, Zhou QD, Ding ZY, Yang HQ, Liu WB, Wu YH, Man Q, Zhang BX, Chen XP. Activin A induces growth arrest through a SMAD- dependent pathway in hepatic progenitor cells. Cell Commun Signal 2014; 12:18. [PMID: 24628936 PMCID: PMC3995548 DOI: 10.1186/1478-811x-12-18] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2013] [Accepted: 03/08/2014] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Activin A, an important member of transforming growth factor-β superfamily, is reported to inhibit proliferation of mature hepatocyte. However, the effect of activin A on growth of hepatic progenitor cells is not fully understood. To that end, we attempted to evaluate the potential role of activin A in the regulation of hepatic progenitor cell proliferation. RESULTS Using the 2-acetaminofluorene/partial hepatectomy model, activin A expression decreased immediately after partial hepatectomy and then increased from the 9th to 15th day post surgery, which is associated with the attenuation of oval cell proliferation. Activin A inhibited oval cell line LE6 growth via activating the SMAD signaling pathway, which manifested as the phosphorylation of SMAD2/3, the inhibition of Rb phosphorylation, the suppression of cyclinD1 and cyclinE, and the promotion of p21WAF1/Cip1 and p15INK4B expression. Treatment with activin A antagonist follistatin or blocking SMAD signaling could diminish the anti-proliferative effect of activin A. By contrast, inhibition of the MAPK pathway did not contribute to this effect. Antagonizing activin A activity by follistatin administration enhanced oval cell proliferation in the 2-acetylaminofluorene/partial hepatectomy model. CONCLUSION Activin A, acting through the SMAD pathway, negatively regulates the proliferation of hepatic progenitor cells.
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Affiliation(s)
- Lin Chen
- Hepatic surgery centre, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Wei Zhang
- Hepatic surgery centre, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Hui-fang Liang
- Hepatic surgery centre, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Qiao-dan Zhou
- Department of Nephrology, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Ze-yang Ding
- Hepatic surgery centre, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Hong-qiang Yang
- Hepatic surgery centre, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Medical College of Shihezi University, Shihezi, China
| | - Wei-bo Liu
- Hepatic surgery centre, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Yan-hui Wu
- Hepatic surgery centre, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Quan Man
- Hepatic surgery centre, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Bi-xiang Zhang
- Hepatic surgery centre, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Xiao-ping Chen
- Hepatic surgery centre, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
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17
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Hartman TR, Strochlic TI, Ji Y, Zinshteyn D, O'Reilly AM. Diet controls Drosophila follicle stem cell proliferation via Hedgehog sequestration and release. ACTA ACUST UNITED AC 2013; 201:741-57. [PMID: 23690177 PMCID: PMC3664720 DOI: 10.1083/jcb.201212094] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Dietary cholesterol levels control follicle stem cell proliferation in the Drosophila ovary via regulation of Hedgehog protein localization. A healthy diet improves adult stem cell function and delays diseases such as cancer, heart disease, and neurodegeneration. Defining molecular mechanisms by which nutrients dictate stem cell behavior is a key step toward understanding the role of diet in tissue homeostasis. In this paper, we elucidate the mechanism by which dietary cholesterol controls epithelial follicle stem cell (FSC) proliferation in the fly ovary. In nutrient-restricted flies, the transmembrane protein Boi sequesters Hedgehog (Hh) ligand at the surface of Hh-producing cells within the ovary, limiting FSC proliferation. Upon feeding, dietary cholesterol stimulates S6 kinase–mediated phosphorylation of the Boi cytoplasmic domain, triggering Hh release and FSC proliferation. This mechanism enables a rapid, tissue-specific response to nutritional changes, tailoring stem cell divisions and egg production to environmental conditions sufficient for progeny survival. If conserved in other systems, this mechanism will likely have important implications for studies on molecular control of stem cell function, in which the benefits of low calorie and low cholesterol diets are beginning to emerge.
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Affiliation(s)
- Tiffiney R Hartman
- Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
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18
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Laliena A, San Miguel B, Crespo I, Alvarez M, González-Gallego J, Tuñón MJ. Melatonin attenuates inflammation and promotes regeneration in rabbits with fulminant hepatitis of viral origin. J Pineal Res 2012; 53:270-8. [PMID: 22506987 DOI: 10.1111/j.1600-079x.2012.00995.x] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
The objective of the present study was to investigate the effect of melatonin on the liver inflammatory and regenerative response in an animal model of fulminant hepatic failure (FHF) of viral origin. Rabbits were experimentally infected with 2×10(4) hemagglutination units of a rabbit hemorrhagic disease virus (RHDV) isolate and received melatonin at two concentrations of 10 or 20mg/kg at 0, 12 and 24hr postinfection. RHDV infection induced an inflammatory response, with increased expression of toll-like receptor 4, high-mobility group box (HMGB)1, interleukin (IL)-1β, IL-6, tumor necrosis factor-α, and C-reactive protein, and decreased expression of decay accelerating factor (DAF/CD55). These effects were significantly reduced by melatonin. Matrix metalloproteinase-9 expression was also lowered in melatonin-treated rabbits. RHDV infection inhibited the hepatic regenerative/proliferative response, with a reduced expression of hepatocyte growth factor (HGF), epidermal growth factor, platelet-derived growth factor (PDGF)-B and vascular endothelial growth factor and their receptors; these responses were prevented by melatonin administration. Melatonin treatment also resulted in reduced expression of phosphorylated Janus kinase and enhanced expression of extracellular mitogen-activated protein kinase (ERK) and signal transducer and activator of transcription (STAT) 3. Our findings show that anti-inflammatory effects and stimulation of regenerative mechanisms contribute to the beneficial effects of melatonin in rabbits with experimental infection by RHDV and support a potential hepatoprotective role of melatonin in FHF.
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Abstract
The incidence of nonalcoholic fatty liver disease is increasing at an astonishing rate in the US population. Although only a small proportion of these patients develop steatohepatitis (NASH), those who do have a greater likelihood of developing end-stage liver disease and complications. Research on liver fibrosis and NASH progression shows that hedgehog (Hh) is reactivated after liver injury to assist in liver repair and regeneration. When the process of tissue repair and regeneration is prolonged or when Hh ligand and related genes are aberrantly regulated and excessive, tissue repair goes awry and NASH progresses to cirrhosis and hepatocellular carcinoma.
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Affiliation(s)
- Brittany N Bohinc
- Department of Endocrinology, Diabetes and Metabolism, Duke University Hospital, Durham, NC 27710, USA
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20
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Chen L, Zhang W, Zhou QD, Yang HQ, Liang HF, Zhang BX, Long X, Chen XP. HSCs play a distinct role in different phases of oval cell-mediated liver regeneration. Cell Biochem Funct 2012; 30:588-96. [PMID: 22535704 DOI: 10.1002/cbf.2838] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2011] [Revised: 03/07/2012] [Accepted: 04/11/2012] [Indexed: 12/29/2022]
Affiliation(s)
- Lin Chen
- Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College; Huazhong University of Science and Technology; Wuhan; China
| | - Wei Zhang
- Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College; Huazhong University of Science and Technology; Wuhan; China
| | - Qiao-dan Zhou
- Department of Nephrology, Tongji Hospital, Tongji Medical College; Huazhong University of Science and Technology; Wuhan; China
| | | | - Hui-fang Liang
- Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College; Huazhong University of Science and Technology; Wuhan; China
| | - Bi-xiang Zhang
- Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College; Huazhong University of Science and Technology; Wuhan; China
| | - Xin Long
- Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College; Huazhong University of Science and Technology; Wuhan; China
| | - Xiao-ping Chen
- Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College; Huazhong University of Science and Technology; Wuhan; China
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21
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Zhang W, Li W, Liu B, Wang P, Li W, Zhang H. Efficient generation of functional hepatocyte-like cells from human fetal hepatic progenitor cells in vitro. J Cell Physiol 2012; 227:2051-8. [PMID: 21751216 DOI: 10.1002/jcp.22934] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Differentiation of human hepatic progenitor cells to functional hepatocytes holds great potential to develop new therapeutic strategies for liver disease and to provide a platform for drug toxicity screens and identification of novel pharmaceuticals. We report here that human fetal hepatic progenitor cells (hFHPCs) efficiently differentiate to hepatocyte-like cells by continuous exposure to a combination of soluble factors for 7 days in vitro. We compared the effect of hepatocyte growth factor (HGF), oncostatin M (OSM), dexamethasone (DEX), or a combination on the expression of a liver-specific marker, albumin (ALB). Real-time RT-PCR analysis showed that, upon exposure to a combination of OSM, DEX, and HGF, the expression of ALB gradually increased in a time-dependent manner. In contrast, the level of the hepatic progenitor cell marker alpha-fetoprotein (AFP) decreased as differentiation progressed. Moreover, cells exposed to the combination of OSM, DEX, and HGF gradually featured highly differentiated hepatic functions, including ALB secretion, glycogen storage, urea production, and cytochrome P450 (CYP) activity. The effect of these factors on the differentiation of hFHPCs may be blocked by U0126, an inhibitor of the ERK1/2 signaling pathway. In conclusion, we demonstrate that a combination of soluble factors facilitates the efficient generation of highly differentiated hepatocyte-like cells from hFHPCs and ERK1/2 signaling pathway involved in this process. Results suggest that this system will be useful for generating functional hepatocytes and, hence, may serve as a cell source suitable for preclinical pharmacological research and testing.
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Affiliation(s)
- Weitao Zhang
- Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing, China
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Sengupta B, Siddiqi S. Hepatocellular carcinoma: important biomarkers and their significance in molecular diagnostics and therapy. Curr Med Chem 2012; 19:3722-9. [PMID: 22680921 PMCID: PMC11447867 DOI: 10.2174/092986712801661059] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2011] [Revised: 02/06/2012] [Accepted: 02/28/2012] [Indexed: 11/22/2022]
Abstract
The increasing incidence of hepatocellular carcinoma (HCC) is of great concern not only in the United States but throughout the world because of two major reasons: firstly, HCC is one of the most lethal form of malignancies with less than 10% survival rate and secondly, a lack of prudent diagnostics makes early detection of HCC nearly impossible. The poor prognosis of HCC accentuates the need to develop new diagnostic markers and therapeutic approaches. In this review we discuss recent advances made in the discovery of molecular biomarkers and their significance in the detection of HCC. We focus on three major classes of biomarkers: serological, tumor, peri-tumoral tissue and cancer stem cell markers. Considerable progress has been made recently in our understanding of HCC at the molecular level increasing the potential of molecular targeted therapy. A number of molecular targets have been identified that have been showing promising results. Of particular interest is Sorafenib, a multi-tyrosine kinase inhibitor that has been approved for the HCC treatment. Inhibitors of other molecular targets such as VEGF, EGFR, mTOR etc. are emerging as plausible therapeutic agents for the treatment of HCC and are discussed in this review.
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Affiliation(s)
- B. Sengupta
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827, USA
| | - S.A. Siddiqi
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827, USA
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Participation of liver progenitor cells in liver regeneration: lack of evidence in the AAF/PH rat model. J Transl Med 2012; 92:72-81. [PMID: 21912377 DOI: 10.1038/labinvest.2011.136] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
When hepatocyte proliferation is impaired, liver progenitor cells (LPC) are activated to participate in liver regeneration. We used the 2-acetaminofluorene/partial hepatectomy (AAF/PH) model to evaluate the contribution of LPC to liver cell replacement and function restoration. Fischer rats subjected to AAF/PH (or PH alone) were investigated 7, 10 and 14 days post-hepatectomy. Liver mass recovery (LMR) was estimated, and the liver mass to body weight ratio calculated. We used serum albumin and bilirubin levels, and liver albumin mRNA levels to assess the liver function. LPC expansion was analyzed by cytokeratin 19 (CK19), glutathione S-transferase protein (GSTp) immunohistochemistry and by CK19, CD133, transforming growth factor-β1 and hepatocyte growth factor mRNA expression in livers. Cell proliferation was evaluated by Ki67 and BrdU immunostaining. Compared with PH alone where LMR was ∼100% 14 days post-PH, LMR was defective in AAF/PH rats (64.1±15.5%, P=0.0004). LPC expansion was scarce in PH livers (0.5±0.4% of CK19(+) area), but significant in AAF/PH livers (8.5±7.2% of CK19(+)), and inversely correlated to LMR (r(2)=0.63, P<0.0001). A quarter of AAF/PH animals presented liver failure (low serum albumin and high serum bilirubin) 14 days post-PH. Compared with animals with preserved function, this was associated with a lower LMR (50±6.8 vs 74.6±9.4%, P=0.0005), a decreased liver to body weight ratio (2±0.3 vs 3.5±0.6%, P=0.001), and a larger LPC expansion such as proliferating Ki67(+) LPC covered 17.4±4.2% of the liver parenchyma vs 3.1±1.5%, (P<0.0001). Amongst those, rare LPC with an intermediate hepatocyte-like phenotype were seen. Also, less than 2% of hepatocytes were engaged into the cell cycle (Ki67(+)), while more numerous (∼25% of hepatocytes) in the livers with preserved function. These observations suggest that, in this model, the efficient recovery of the liver function was ensured rather by the proliferation of mature hepatocytes than by the LPC expansion and differentiation into hepatocytes.
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Assimakopoulos SF, Tsamandas AC, Alexandris IH, Georgiou C, Vagianos CE, Scopa CD. Stimulation of oval cell and hepatocyte proliferation by exogenous bombesin and neurotensin in partially hepatectomized rats. World J Gastrointest Pathophysiol 2011; 2:146-54. [PMID: 22180848 PMCID: PMC3240906 DOI: 10.4291/wjgp.v2.i6.146] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2011] [Revised: 11/07/2011] [Accepted: 11/14/2011] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effect of the neuropeptides bombesin (BBS) and neurotensin (NT) on oval cell proliferation in partially hepatectomized rats not pretreated with a known hepatocyte inhibitor.
METHODS: Seventy male Wistar rats were randomly divided into five groups: I = controls, II = sham operated, III = partial hepatectomy 70% (PHx), IV = PHx + BBS (30 μg/kg per day), V = PHx + NT (300 μg/kg per day). Forty eight hours after liver resection, portal endotoxin levels and hepatic glutathione redox state were determined. α-fetoprotein (AFP) mRNA (in situ hybridisation), cytokeratin-19 and Ki67 antigen expression (immunohistochemistry) and apoptosis (TUNEL) were evaluated on liver tissue samples. Cells with morphological features of oval cells that were cytokeratin-19 (+) and AFP mRNA (+) were scored in morphometric analysis and their proliferation was recorded. In addition, the proliferation and apoptotic rates of hepatocytes were determined.
RESULTS: In the control and sham operated groups, oval cells were significantly less compared to groups III, IV and V (P < 0.001). The neuropeptides BBS and NT significantly increased the proliferation of oval cells compared to group III (P < 0.001). In addition, BBS and NT induced a significant increase of hepatocyte proliferation (P < 0.001), whereas it decreased their apoptotic activity (P < 0.001) compared to group III. BBS and NT significantly decreased portal endotoxemia (P < 0.001) and increased the hepatic GSH: GSSG ratio (P < 0.05 and P < 0.001, respectively) compared to group III.
CONCLUSION: BBS and NT stimulated oval cell proliferation in a model of liver regeneration, without use of concomitant suppression of hepatocyte proliferation as oval cell activation stimuli, and improved the hepatocyte regenerative response. This peptides-induced combined stimulation of oval cell and hepatocyte proliferation might serve as a possible treatment modality for several liver diseases.
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An epistatic mini-circuitry between the transcription factors Snail and HNF4α controls liver stem cell and hepatocyte features exhorting opposite regulation on stemness-inhibiting microRNAs. Cell Death Differ 2011; 19:937-46. [PMID: 22139130 DOI: 10.1038/cdd.2011.175] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Preservation of the epithelial state involves the stable repression of epithelial-to-mesenchymal transition program, whereas maintenance of the stem compartment requires the inhibition of differentiation processes. A simple and direct molecular mini-circuitry between master elements of these biological processes might provide the best device to keep balanced such complex phenomena. In this work, we show that in hepatic stem cell Snail, a transcriptional repressor of the hepatocyte differentiation master gene HNF4α, directly represses the expression of the epithelial microRNAs (miRs)-200c and -34a, which in turn target several stem cell genes. Notably, in differentiated hepatocytes HNF4α, previously identified as a transcriptional repressor of Snail, induces the miRs-34a and -200a, b, c that, when silenced, causes epithelial dedifferentiation and reacquisition of stem traits. Altogether these data unveiled Snail, HNF4α and miRs-200a, b, c and -34a as epistatic elements controlling hepatic stem cell maintenance/differentiation.
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Sa-ngiamsuntorn K, Wongkajornsilp A, Kasetsinsombat K, Duangsa-ard S, Nuntakarn L, Borwornpinyo S, Akarasereenont P, Limsrichamrern S, Hongeng S. Upregulation of CYP 450s expression of immortalized hepatocyte-like cells derived from mesenchymal stem cells by enzyme inducers. BMC Biotechnol 2011; 11:89. [PMID: 21961524 PMCID: PMC3198927 DOI: 10.1186/1472-6750-11-89] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2011] [Accepted: 09/30/2011] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND The strenuous procurement of cultured human hepatocytes and their short lives have constrained the cell culture model of cytochrome P450 (CYP450) induction, xenobiotic biotransformation, and hepatotoxicity. The development of continuous non-tumorous cell line steadily containing hepatocyte phenotypes would substitute the primary hepatocytes for these studies. RESULTS The hepatocyte-like cells have been developed from hTERT plus Bmi-1-immortalized human mesenchymal stem cells to substitute the primary hepatocytes. The hepatocyte-like cells had polygonal morphology and steadily produced albumin, glycogen, urea and UGT1A1 beyond 6 months while maintaining proliferative capacity. Although these hepatocyte-like cells had low basal expression of CYP450 isotypes, their expressions could be extensively up regulated to 80 folds upon the exposure to enzyme inducers. Their inducibility outperformed the classical HepG2 cells. CONCLUSION The hepatocyte-like cells contained the markers of hepatocytes including CYP450 isotypes. The high inducibility of CYP450 transcripts could serve as a sensitive model for profiling xenobiotic-induced expression of CYP450.
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Affiliation(s)
- Khanit Sa-ngiamsuntorn
- Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Prannok Road, Bangkoknoi, Bangkok 10700, Thailand
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Sancho-Bru P. [Therapeutic possibilities of stem cells in the treatment of liver diseases]. GASTROENTEROLOGIA Y HEPATOLOGIA 2011; 34:701-10. [PMID: 21640436 DOI: 10.1016/j.gastrohep.2011.03.012] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/08/2011] [Accepted: 03/09/2011] [Indexed: 12/19/2022]
Abstract
Cell therapy and the use of stem cells in the treatment of liver diseases is still in the research phase. Nevertheless, the diversity of stem cells in terms of their origin, characteristics and potential for differentiation provides a wide spectrum of possibilities for the treatment of liver diseases. The present article describes the main types of stem cells and their potential for the treatment of liver diseases, as well as the main therapeutic strategies that are currently being explored for the treatment of these diseases through cell therapy. In addition, the main preclinical and clinical studies suggesting that stem cells could become an effective therapeutic alternative in distinct liver diseases are discussed.
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Affiliation(s)
- Pau Sancho-Bru
- Unidad de Hepatología, Hospital Clínic de Barcelona, Centro de Investigación Biológica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, España.
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