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Li SY, Liu ST, Wang CY, Bai YZ, Yuan ZW, Tang XB. Comprehensive circRNA expression profile and hub genes screening during human liver development. Ann Med 2025; 57:2497111. [PMID: 40285372 PMCID: PMC12035923 DOI: 10.1080/07853890.2025.2497111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 01/08/2025] [Accepted: 01/31/2025] [Indexed: 04/29/2025] Open
Abstract
BACKGROUND Understanding the expression of non-coding RNA in the liver during embryonic development provides important insights into liver diseases. Therefore, we investigated circular RNA (circRNA) roles in human liver development, an unexplored research domain. METHODS Using high-throughput sequencing and bioinformatics, we analysed foetal liver samples across developmental stages (7-20 weeks post-conception). Differentially expressed (DE) genes were identified and subjected to enrichment analysis using Gene Ontology (GO), Kyoto Encyclopaedia of Genes and Genomes (KEGG), and Disease Ontology (DO). Modular analysis was performed using the Search Tool for Retrieval of Interacting Genes (STRING), followed by construction of a protein-protein interaction (PPI) network using Cytoscape software. The key genes were screened using Molecular Complex Detection (MCODE). The mRNA levels of hub genes were validated using quantitative reverse transcription polymerase chain reaction (qRT-PCR). RESULTS There were 645 DE circRNAs and 5,145 DE mRNAs between human livers at the three growth stages (HB, EH, and LH). It was found that the activity of circRNAs was boosted remarkably in the hepatoblastic stage. Enrichment analysis found they mainly involved in nervous system regulation of liver function, embryonic organ development and digestive system development. In addition, DE circRNAs were primarily involved in the PI3K-AKT, MAPK and calcium pathways, potentially contributing to adult liver diseases. Notably, only hsa_circ_001471 and novel_circ_017382 were simultaneously identified at all stages and were persistently downregulated. A co-expression regulatory network involving these circRNAs was established. Three hub genes (LGR5, FOXL1 and RSPO3) were identified from the PPI network of 167 genes and may play key roles in human liver development. The RT-qPCR validation results were in agreement with the sequencing data. CONCLUSIONS Our findings provide the first insights into the roles and regulatory networks of circRNAs in human liver development, laying the groundwork for further investigations of molecular and signalling networks.
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Affiliation(s)
- Si Ying Li
- Department of Pediatric Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Shu Ting Liu
- Department of Pediatric Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Chen Yi Wang
- Department of Pediatric Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Yu Zuo Bai
- Department of Pediatric Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Zheng Wei Yuan
- The Key Laboratory of Health Ministry for Congenital Malformation, Shenyang, Liaoning Province, China
| | - Xiao Bing Tang
- Department of Pediatric Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China
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Zhao S, Feng Y, Zhang J, Zhang Q, Wang J, Cui S. Comparative analysis of gene expression between mice and humans in acetaminophen-induced liver injury by integrating bioinformatics analysis. BMC Med Genomics 2024; 17:80. [PMID: 38549107 PMCID: PMC10976682 DOI: 10.1186/s12920-024-01848-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 03/18/2024] [Indexed: 04/02/2024] Open
Abstract
OBJECTIVE Mice are routinely utilized as animal models of drug-induced liver injury (DILI), however, there are significant differences in the pathogenesis between mice and humans. This study aimed to compare gene expression between humans and mice in acetaminophen (APAP)-induced liver injury (AILI), and investigate the similarities and differences in biological processes between the two species. METHODS A pair of public datasets (GSE218879 and GSE120652) obtained from GEO were analyzed using "Limma" package in R language, and differentially expressed genes (DEGs) were identified, including co-expressed DEGs (co-DEGs) and specific-expressed DEGS (specific-DEGs). Analysis of Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were performed analyses for specific-DEGs and co-DEGs. The co-DEGs were also used to construct transcription factor (TF)-gene network, gene-miRNA interactions network and protein-protein interaction (PPI) network for analyzing hub genes. RESULTS Mouse samples contained 1052 up-regulated genes and 1064 down-regulated genes, while human samples contained 1156 up-regulated genes and 1557 down-regulated genes. After taking the intersection between the DEGs, only 154 co-down-regulated and 89 co-up-regulated DEGs were identified, with a proportion of less than 10%. It was suggested that significant differences in gene expression between mice and humans in drug-induced liver injury. Mouse-specific-DEGs predominantly engaged in processes related to apoptosis and endoplasmic reticulum stress, while human-specific-DEGs were concentrated around catabolic process. Analysis of co-regulated genes reveals showed that they were mainly enriched in biosynthetic and metabolism-related processes. Then a PPI network which contains 189 nodes and 380 edges was constructed from the co-DEGs and two modules were obtained by Mcode. We screened out 10 hub genes by three algorithms of Degree, MCC and MNC, including CYP7A1, LSS, SREBF1, FASN, CD44, SPP1, ITGAV, ANXA5, LGALS3 and PDGFRA. Besides, TFs such as FOXC1, HINFP, NFKB1, miRNAs like mir-744-5p, mir-335-5p, mir-149-3p, mir-218-5p, mir-10a-5p may be the key regulatory factors of hub genes. CONCLUSIONS The DEGs of AILI mice models and those of patients were compared, and common biological processes were identified. The signaling pathways and hub genes in co-expression were identified between mice and humans through a series of bioinformatics analyses, which may be more valuable to reveal molecular mechanisms of AILI.
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Affiliation(s)
- Shanmin Zhao
- Department of Laboratory Animal Sciences, School of Basic Medicine, Naval Medical University, NO. 800 Xiangyin Road, 200433, Shanghai, China
| | - Yan Feng
- Department of Laboratory Animal Sciences, School of Basic Medicine, Naval Medical University, NO. 800 Xiangyin Road, 200433, Shanghai, China
| | - Jingyuan Zhang
- Department of Laboratory Animal Sciences, School of Basic Medicine, Naval Medical University, NO. 800 Xiangyin Road, 200433, Shanghai, China
| | - Qianqian Zhang
- Department of Laboratory Animal Sciences, School of Basic Medicine, Naval Medical University, NO. 800 Xiangyin Road, 200433, Shanghai, China
| | - Junyang Wang
- Department of Laboratory Animal Sciences, School of Basic Medicine, Naval Medical University, NO. 800 Xiangyin Road, 200433, Shanghai, China
| | - Shufang Cui
- Department of Laboratory Animal Sciences, School of Basic Medicine, Naval Medical University, NO. 800 Xiangyin Road, 200433, Shanghai, China.
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Hrncir HR, Gracz AD. Cellular and transcriptional heterogeneity in the intrahepatic biliary epithelium. GASTRO HEP ADVANCES 2022; 2:108-120. [PMID: 36593993 PMCID: PMC9802653 DOI: 10.1016/j.gastha.2022.07.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 07/19/2022] [Indexed: 01/05/2023]
Abstract
Epithelial tissues comprise heterogeneous cellular subpopulations, which often compartmentalize specialized functions like absorption and secretion to distinct cell types. In the liver, hepatocytes and biliary epithelial cells (BECs; also called cholangiocytes) are the two major epithelial lineages and play distinct roles in (1) metabolism, protein synthesis, detoxification, and (2) bile transport and modification, respectively. Recent technological advances, including single cell transcriptomic assays, have shed new light on well-established heterogeneity among hepatocytes, endothelial cells, and immune cells in the liver. However, a "ground truth" understanding of molecular heterogeneity in BECs has remained elusive, and the field currently lacks a set of consensus biomarkers for identifying BEC subpopulations. Here, we review long-standing definitions of BEC heterogeneity as well as emerging studies that aim to characterize BEC subpopulations using next generation single cell assays. Understanding cellular heterogeneity in the intrahepatic bile ducts holds promise for expanding our foundational mechanistic knowledge of BECs during homeostasis and disease.
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Affiliation(s)
- Hannah R. Hrncir
- Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia
- Graduate Program in Biochemistry, Cell and Developmental Biology, Emory University, Atlanta, Georgia
| | - Adam D. Gracz
- Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia
- Graduate Program in Biochemistry, Cell and Developmental Biology, Emory University, Atlanta, Georgia
- Graduate Program in Genetics and Molecular Biology, Emory University, Atlanta, Georgia
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4
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Immune-related biomarkers shared by inflammatory bowel disease and liver cancer. PLoS One 2022; 17:e0267358. [PMID: 35452485 PMCID: PMC9032416 DOI: 10.1371/journal.pone.0267358] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 04/04/2022] [Indexed: 12/24/2022] Open
Abstract
It has been indicated that there is an association between inflammatory bowel disease (IBD) and hepatocellular carcinoma (HCC). However, the molecular mechanism underlying the risk of developing HCC among patients with IBD is not well understood. The current study aimed to identify shared genes and potential pathways and regulators between IBD and HCC using a system biology approach. By performing the different gene expression analyses, we identified 871 common differentially expressed genes (DEGs) between IBD and HCC. Of these, 112 genes overlapped with immune genes were subjected to subsequent bioinformatics analyses. The results revealed four hub genes (CXCL2, MMP9, SPP1 and SRC) and several other key regulators including six transcription factors (FOXC1, FOXL1, GATA2, YY1, ZNF354C and TP53) and five microRNAs (miR-124-3p, miR-34a-5p, miR-1-3p, miR-7-5p and miR-99b-5p) for these disease networks. Protein-drug interaction analysis discovered the interaction of the hub genes with 46 SRC-related and 11 MMP9- related drugs that may have a therapeutic effect on IBD and HCC. In conclusion, this study sheds light on the potential connecting mechanisms of HCC and IBD.
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Tsuchiya A, Lu WY. Liver stem cells: Plasticity of the liver epithelium. World J Gastroenterol 2019; 25:1037-1049. [PMID: 30862993 PMCID: PMC6406190 DOI: 10.3748/wjg.v25.i9.1037] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Revised: 01/21/2019] [Accepted: 01/26/2019] [Indexed: 02/06/2023] Open
Abstract
The liver has a high regenerative capacity after acute liver injury, but this is often impaired during chronic liver injury. The existence of a dedicated liver stem cell population that acts as a source of regeneration during chronic liver injury has been controversial. Recent advances in transgenic models and cellular reprogramming have provided new insights into the plasticity of the liver epithelium and directions for the development of future therapies. This article will highlight recent findings about the cellular source of regeneration during liver injury and the advances in promoting liver regeneration.
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Affiliation(s)
- Atsunori Tsuchiya
- Division of Gastroenterology and Hepatology, Graduate school of medical and dental sciences, Niigata University, Chuo-ku, Niigata 951-8510, Japan
| | - Wei-Yu Lu
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, the University of Birmingham, Birmingham B15 2TT, United Kingdom
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Perugorria MJ, Olaizola P, Labiano I, Esparza-Baquer A, Marzioni M, Marin JJG, Bujanda L, Banales JM. Wnt-β-catenin signalling in liver development, health and disease. Nat Rev Gastroenterol Hepatol 2019; 16:121-136. [PMID: 30451972 DOI: 10.1038/s41575-018-0075-9] [Citation(s) in RCA: 396] [Impact Index Per Article: 66.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The canonical Wnt-β-catenin pathway is a complex, evolutionarily conserved signalling mechanism that regulates fundamental physiological and pathological processes. Wnt-β-catenin signalling tightly controls embryogenesis, including hepatobiliary development, maturation and zonation. In the mature healthy liver, the Wnt-β-catenin pathway is mostly inactive but can become re-activated during cell renewal and/or regenerative processes, as well as in certain pathological conditions, diseases, pre-malignant conditions and cancer. In hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), the two most prevalent primary liver tumours in adults, Wnt-β-catenin signalling is frequently hyperactivated and promotes tumour growth and dissemination. A substantial proportion of liver tumours (mainly HCC and, to a lesser extent, CCA) have mutations in genes encoding key components of the Wnt-β-catenin signalling pathway. Likewise, hepatoblastoma, the most common paediatric liver cancer, is characterized by Wnt-β-catenin activation, mostly as a result of β-catenin mutations. In this Review, we discuss the most relevant molecular mechanisms of action and regulation of Wnt-β-catenin signalling in liver development and pathophysiology. Moreover, we highlight important preclinical and clinical studies and future directions in basic and clinical research.
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Affiliation(s)
- Maria J Perugorria
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital - University of the Basque Country (UPV/EHU), San Sebastian, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health (ISCIII), Madrid, Spain
- Ikerbasque, Basque Foundation for Science, Bilbao, Spain
| | - Paula Olaizola
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital - University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Ibone Labiano
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital - University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Aitor Esparza-Baquer
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital - University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Marco Marzioni
- Department of Gastroenterology, Università Politecnica delle Marche, Ancona, Italy
| | - Jose J G Marin
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health (ISCIII), Madrid, Spain
- Experimental Hepatology and Drug Targeting (HEVEFARM), Biomedical Research Institute of Salamanca (IBSAL), University of Salamanca, Salamanca, Spain
| | - Luis Bujanda
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital - University of the Basque Country (UPV/EHU), San Sebastian, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health (ISCIII), Madrid, Spain
| | - Jesus M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital - University of the Basque Country (UPV/EHU), San Sebastian, Spain.
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health (ISCIII), Madrid, Spain.
- Ikerbasque, Basque Foundation for Science, Bilbao, Spain.
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Fabris L, Spirli C, Cadamuro M, Fiorotto R, Strazzabosco M. Emerging concepts in biliary repair and fibrosis. Am J Physiol Gastrointest Liver Physiol 2017; 313:G102-G116. [PMID: 28526690 PMCID: PMC5582882 DOI: 10.1152/ajpgi.00452.2016] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2016] [Revised: 04/20/2017] [Accepted: 05/11/2017] [Indexed: 01/31/2023]
Abstract
Chronic diseases of the biliary tree (cholangiopathies) represent one of the major unmet needs in clinical hepatology and a significant knowledge gap in liver pathophysiology. The common theme in cholangiopathies is that the target of the disease is the biliary tree. After damage to the biliary epithelium, inflammatory changes stimulate a reparative response with proliferation of cholangiocytes and restoration of the biliary architecture, owing to the reactivation of a variety of morphogenetic signals. Chronic damage and inflammation will ultimately result in pathological repair with generation of biliary fibrosis and clinical progression of the disease. The hallmark of pathological biliary repair is the appearance of reactive ductular cells, a population of cholangiocyte-like epithelial cells of unclear and likely mixed origin that are able to orchestrate a complex process that involves a number of different cell types, under joint control of inflammatory and morphogenetic signals. Several questions remain open concerning the histogenesis of reactive ductular cells, their role in liver repair, their mechanism of activation, and the signals exchanged with the other cellular elements cooperating in the reparative process. This review contributes to the current debate by highlighting a number of new concepts derived from the study of the pathophysiology of chronic cholangiopathies, such as congenital hepatic fibrosis, biliary atresia, and Alagille syndrome.
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Affiliation(s)
- Luca Fabris
- Department of Molecular Medicine, University of Padua School of Medicine, Padua, Italy; .,Liver Center, Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut.,International Center for Digestive Health, University of Milan-Bicocca School of Medicine, Milan, Italy; and
| | - Carlo Spirli
- 2Liver Center, Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut; ,3International Center for Digestive Health, University of Milan-Bicocca School of Medicine, Milan, Italy; and
| | - Massimiliano Cadamuro
- 3International Center for Digestive Health, University of Milan-Bicocca School of Medicine, Milan, Italy; and ,4Department of Medicine and Surgery, University of Milan-Bicocca School of Medicine, Milan, Italy
| | - Romina Fiorotto
- 2Liver Center, Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut; ,3International Center for Digestive Health, University of Milan-Bicocca School of Medicine, Milan, Italy; and
| | - Mario Strazzabosco
- 2Liver Center, Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut; ,3International Center for Digestive Health, University of Milan-Bicocca School of Medicine, Milan, Italy; and ,4Department of Medicine and Surgery, University of Milan-Bicocca School of Medicine, Milan, Italy
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8
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Khamphaya T, Chansela P, Piyachaturawat P, Suksamrarn A, Nathanson MH, Weerachayaphorn J. Effects of andrographolide on intrahepatic cholestasis induced by alpha-naphthylisothiocyanate in rats. Eur J Pharmacol 2016; 789:254-264. [PMID: 27475677 PMCID: PMC10804355 DOI: 10.1016/j.ejphar.2016.07.032] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Revised: 07/18/2016] [Accepted: 07/20/2016] [Indexed: 12/28/2022]
Abstract
Cholestasis is a cardinal manifestation of liver diseases but effective therapeutic approaches are limited. Therefore, alternative therapy for treating and preventing cholestatic liver diseases is necessary. Andrographolide, a promising anticancer drug derived from the medicinal plant Andrographis paniculata, has diverse pharmacological properties and multi-spectrum therapeutic applications. However, it is unknown whether andrographolide has a hepatoprotective effect on intrahepatic cholestasis. The aims of this study were to investigate the protective effect and possible mechanisms of andrographolide in a rat model of acute intrahepatic cholestasis induced by alpha-naphthylisothiocyanate (ANIT). Andrographolide was administered intragastrically for four consecutive days, with a single intraperitoneal injection of ANIT on the second day. Liver injury was evaluated biochemically and histologically together with hepatic gene and protein expression analysis. Rats pretreated with andrographolide prior to ANIT injection demonstrated lower levels of serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyltransferase, as well as bilirubin and bile acids as compared to rats treated with ANIT alone. Andrographolide also decreased the incidence and extent of periductular fibrosis and bile duct proliferation. Analysis of protein expression in livers from andrographolide-treated cholestatic rats revealed markedly decreased expression of alpha-smooth muscle actin and nuclear factor kappa-B (NF-κB). In conclusion, andrographolide has a potent protective property against ANIT-induced cholestatic liver injury. The mechanisms that underlie this protective effect are mediated through down-regulation of NF-κB expression and inhibition of hepatic stellate cell activation. These findings suggest that andrographolide could be a promising therapeutic option in prevention and slowing down the progression of cholestatic liver diseases.
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Affiliation(s)
- Tanaporn Khamphaya
- Toxicology Graduate Program, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Piyachat Chansela
- Department of Anatomy, Phramongkutklao College of Medicine, Bangkok, Thailand
| | | | - Apichart Suksamrarn
- Department of Chemistry, Faculty of Science, Ramkhamhaeng University, Bangkok, Thailand
| | - Michael H Nathanson
- Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Jittima Weerachayaphorn
- Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand; Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
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9
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Dollé L, Theise ND, Schmelzer E, Boulter L, Gires O, van Grunsven LA. EpCAM and the biology of hepatic stem/progenitor cells. Am J Physiol Gastrointest Liver Physiol 2015; 308:G233-50. [PMID: 25477371 PMCID: PMC4329473 DOI: 10.1152/ajpgi.00069.2014] [Citation(s) in RCA: 94] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein, which is frequently and highly expressed on carcinomas, tumor-initiating cells, selected tissue progenitors, and embryonic and adult stem cells. During liver development, EpCAM demonstrates a dynamic expression, since it can be detected in fetal liver, including cells of the parenchyma, whereas mature hepatocytes are devoid of EpCAM. Liver regeneration is associated with a population of EpCAM-positive cells within ductular reactions, which gradually lose the expression of EpCAM along with maturation into hepatocytes. EpCAM can be switched on and off through a wide panel of strategies to fine-tune EpCAM-dependent functional and differentiative traits. EpCAM-associated functions relate to cell-cell adhesion, proliferation, maintenance of a pluripotent state, regulation of differentiation, migration, and invasion. These functions can be conferred by the full-length protein and/or EpCAM-derived fragments, which are generated upon regulated intramembrane proteolysis. Control by EpCAM therefore not only depends on the presence of full-length EpCAM at cellular membranes but also on varying rates of the formation of EpCAM-derived fragments that have their own regulatory properties and on changes in the association of EpCAM with interaction partners. Thus spatiotemporal localization of EpCAM in immature liver progenitors, transit-amplifying cells, and mature liver cells will decisively impact the regulation of EpCAM functions and might be one of the triggers that contributes to the adaptive processes in stem/progenitor cell lineages. This review will summarize EpCAM-related molecular events and how they relate to hepatobiliary differentiation and regeneration.
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Affiliation(s)
- Laurent Dollé
- Department of Biomedical Sciences, Liver Cell Biology Lab, Vrije Universiteit Brussel, Brussels, Belgium;
| | - Neil D. Theise
- 2Departments of Pathology and Medicine, Beth Israel Medical Center of Albert Einstein College of Medicine, New York, New York;
| | - Eva Schmelzer
- 3McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania;
| | - Luke Boulter
- 4Medical Research Council Human Genetics Unit, Institute for Genetics and Molecular Medicine, Edinburgh, Scotland; and
| | - Olivier Gires
- 5Department of Otorhinolaryngology, Head and Neck Surgery, Grosshadern Medical Center, Ludwig-Maximilians-University of Munich, Munich, Germany
| | - Leo A. van Grunsven
- 1Department of Biomedical Sciences, Liver Cell Biology Lab, Vrije Universiteit Brussel, Brussels, Belgium;
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Shin S, Kaestner KH. The origin, biology, and therapeutic potential of facultative adult hepatic progenitor cells. Curr Top Dev Biol 2014; 107:269-92. [PMID: 24439810 DOI: 10.1016/b978-0-12-416022-4.00010-x] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
The liver plays an essential role in glucose and lipid metabolism, synthesis of plasma proteins, and detoxification of xenobiotics and other toxins. Chronic disease of this important organ is one of the leading causes of death in the United States. Following loss of tissue, liver mass can be restored by two mechanisms. Under normal conditions, or after massive loss of parenchyma by surgical resection, liver mass is maintained by division of hepatocytes. After chronic injury, or when proliferation of hepatocytes is impaired, facultative adult hepatic progenitor cells (HPCs) proliferate and differentiate into hepatocytes and cholangiocytes (biliary epithelial cells). HPCs are attractive candidates for cell transplantation because of their potential contribution to liver regeneration. However, until recently, the lack of highly specific markers has hampered efforts to better understand the origin and physiology of HPCs. Recent advances in cell isolation methods and genetic lineage tracing have enabled investigators to explore multiple aspects of HPC biology. In this review, we describe the potential origins of HPCs, the markers used to detect them, the contribution of HPCs to recovery, and the signaling pathways that regulate their biology. We end with an examination of the therapeutic potential of HPCs and their derivatives.
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Affiliation(s)
- Soona Shin
- Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
| | - Klaus H Kaestner
- Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
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11
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Nejak-Bowen KN, Monga SPS. Wnt drives stem cell-mediated repair response after hepatic injury. Hepatology 2013; 58:1847-50. [PMID: 23788312 DOI: 10.1002/hep.26579] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2013] [Revised: 05/06/2013] [Accepted: 06/06/2013] [Indexed: 12/28/2022]
Affiliation(s)
- Kari N Nejak-Bowen
- Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, PA
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12
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Cui S, Leyva-Vega M, Tsai EA, Eauclaire SF, Glessner JT, Hakonarson H, Devoto M, Haber BA, Spinner NB, Matthews RP. Evidence from human and zebrafish that GPC1 is a biliary atresia susceptibility gene. Gastroenterology 2013; 144:1107-1115.e3. [PMID: 23336978 PMCID: PMC3736559 DOI: 10.1053/j.gastro.2013.01.022] [Citation(s) in RCA: 95] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2012] [Revised: 01/03/2013] [Accepted: 01/07/2013] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Biliary atresia (BA) is a progressive fibroinflammatory disorder of infants involving the extrahepatic and intrahepatic biliary tree. Its etiology is unclear but is believed to involve exposure of a genetically susceptible individual to certain environmental factors. BA occurs exclusively in the neonatal liver, so variants of genes expressed during hepatobiliary development could affect susceptibility. Genome-wide association studies previously identified a potential region of interest at 2q37. We continued these studies to narrow the region and identify BA susceptibility genes. METHODS We searched for copy number variants that were increased among patients with BA (n = 61) compared with healthy individuals (controls; n = 5088). After identifying a candidate gene, we investigated expression patterns of orthologues in zebrafish liver and the effects of reducing expression, with morpholino antisense oligonucleotides, on biliary development, gene expression, and signal transduction. RESULTS We observed a statistically significant increase in deletions at 2q37.3 in patients with BA that resulted in deletion of one copy of GPC1, which encodes glypican 1, a heparan sulfate proteoglycan that regulates Hedgehog signaling and inflammation. Knockdown of gpc1 in zebrafish led to developmental biliary defects. Exposure of the gpc1 morphants to cyclopamine, a Hedgehog antagonist, partially rescued the gpc1-knockdown phenotype. Injection of zebrafish with recombinant Sonic Hedgehog led to biliary defects similar to those of the gpc1 morphants. Liver samples from patients with BA had reduced levels of apical GPC1 in cholangiocytes compared with samples from controls. CONCLUSIONS Based on genetic analysis of patients with BA and zebrafish, GPC1 appears to be a BA susceptibility gene. These findings also support a role for Hedgehog signaling in the pathogenesis of BA.
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Affiliation(s)
- Shuang Cui
- Division of Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Melissa Leyva-Vega
- Division of Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Ellen A. Tsai
- Department of Pathology and Laboratory Medicine, The Children’s Hospital of Philadelphia Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania,Genomics and Computational Biology Graduate Group, The Children’s Hospital of Philadelphia Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Steven F. Eauclaire
- Division of Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Joseph T. Glessner
- Center for Applied Genomics, The Children’s Hospital of Philadelphia Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Hakon Hakonarson
- Center for Applied Genomics, The Children’s Hospital of Philadelphia Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania,Department of Pediatrics, The Children’s Hospital of Philadelphia Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania,Department of Genetics, The Children’s Hospital of Philadelphia Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Marcella Devoto
- Department of Pediatrics, The Children’s Hospital of Philadelphia Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania,Department of Biostatistics and Epidemiology, The Children’s Hospital of Philadelphia Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania,Department of Molecular Medicine, University of Rome La Sapienza, Rome, Italy
| | - Barbara A. Haber
- Division of Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania,Department of Pediatrics, The Children’s Hospital of Philadelphia Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Nancy B. Spinner
- Department of Pathology and Laboratory Medicine, The Children’s Hospital of Philadelphia Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Randolph P. Matthews
- Division of Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania,Department of Pediatrics, The Children’s Hospital of Philadelphia Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
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13
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Bai H, Zhang N, Xu Y, Chen Q, Khan M, Potter JJ, Nayar SK, Cornish T, Alpini G, Bronk S, Pan D, Anders RA. Yes-associated protein regulates the hepatic response after bile duct ligation. Hepatology 2012; 56:1097-107. [PMID: 22886419 PMCID: PMC3431197 DOI: 10.1002/hep.25769] [Citation(s) in RCA: 144] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2011] [Accepted: 03/31/2012] [Indexed: 12/11/2022]
Abstract
UNLABELLED Human chronic cholestatic liver diseases are characterized by cholangiocyte proliferation, hepatocyte injury, and fibrosis. Yes-associated protein (YAP), the effector of the Hippo tumor-suppressor pathway, has been shown to play a critical role in promoting cholangiocyte and hepatocyte proliferation and survival during embryonic liver development and hepatocellular carcinogenesis. Therefore, the aim of this study was to examine whether YAP participates in the regenerative response after cholestatic injury. First, we examined human liver tissue from patients with chronic cholestasis. We found more-active nuclear YAP in the bile ductular reactions of primary sclerosing cholangitis and primary biliary cirrhosis patient liver samples. Next, we used the murine bile duct ligation (BDL) model to induce cholestatic liver injury. We found significant changes in YAP activity after BDL in wild-type mice. The function of YAP in the hepatic response after BDL was further evaluated with liver-specific Yap conditional deletion in mice. Ablating Yap in the mouse liver not only compromised bile duct proliferation, but also enhanced hepatocyte necrosis and suppressed hepatocyte proliferation after BDL. Furthermore, primary hepatocytes and cholangiocytes isolated from Yap-deficient livers showed reduced proliferation in response to epidermal growth factor in vitro. Finally, we demonstrated that YAP likely mediates its biological effects through the modulation of Survivin expression. CONCLUSION Our data suggest that YAP promotes cholangiocyte and hepatocyte proliferation and prevents parenchymal damage after cholestatic injury in mice and thus may mediate the response to cholestasis-induced human liver disease.
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Affiliation(s)
- Haibo Bai
- Department of Pathology, Johns Hopkins University School of MedicineBaltimore, MD
| | - Nailing Zhang
- Howard Hughes Medical Institute, Johns Hopkins University School of MedicineBaltimore, MD,Department of Molecular Biology and Genetics, Johns Hopkins University School of MedicineBaltimore, MD
| | - Yang Xu
- Department of Pathology, Johns Hopkins University School of MedicineBaltimore, MD
| | - Qian Chen
- Howard Hughes Medical Institute, Johns Hopkins University School of MedicineBaltimore, MD,Department of Molecular Biology and Genetics, Johns Hopkins University School of MedicineBaltimore, MD
| | - Mehtab Khan
- Department of Pathology, Johns Hopkins University School of MedicineBaltimore, MD
| | - James J Potter
- Department of Medicine, Johns Hopkins University School of MedicineBaltimore, MD
| | - Suresh K Nayar
- Department of Pathology, Johns Hopkins University School of MedicineBaltimore, MD
| | - Toby Cornish
- Department of Pathology, Johns Hopkins University School of MedicineBaltimore, MD
| | - Gianfranco Alpini
- Department of Medicine and Scott & White Digestive Disease Research Center, Texas A&M Health Science Center, College of Medicine, and Scott & White Hospital, and Research Service, Central Texas Veterans Health Care SystemTemple, TX
| | - Steven Bronk
- Division of Gastroenterology and Hepatology, Mayo Clinic School of MedicineRochester, MN
| | - Duojia Pan
- Howard Hughes Medical Institute, Johns Hopkins University School of MedicineBaltimore, MD,Department of Molecular Biology and Genetics, Johns Hopkins University School of MedicineBaltimore, MD
| | - Robert A Anders
- Department of Pathology, Johns Hopkins University School of MedicineBaltimore, MD
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14
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Strazzabosco M, Fabris L. Development of the bile ducts: essentials for the clinical hepatologist. J Hepatol 2012; 56:1159-1170. [PMID: 22245898 PMCID: PMC3328609 DOI: 10.1016/j.jhep.2011.09.022] [Citation(s) in RCA: 128] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2011] [Revised: 09/08/2011] [Accepted: 09/13/2011] [Indexed: 02/07/2023]
Abstract
Several cholangiopathies result from a perturbation of developmental processes. Most of these cholangiopathies are characterised by the persistence of biliary structures with foetal configuration. Developmental processes are also relevant in acquired liver diseases, as liver repair mechanisms exploit a range of autocrine and paracrine signals transiently expressed in embryonic life. We briefly review the ontogenesis of the intra- and extrahepatic biliary tree, highlighting the morphogens, growth factors, and transcription factors that regulate biliary development, and the relationships between developing bile ducts and other branching biliary structures. Then, we discuss the ontogenetic mechanisms involved in liver repair, and how these mechanisms are recapitulated in ductular reaction, a common reparative response to many forms of biliary and hepatocellular damage. Finally, we discuss the pathogenic aspects of the most important primary cholangiopathies related to altered biliary development, i.e. polycystic and fibropolycystic liver diseases, Alagille syndrome.
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Affiliation(s)
- Mario Strazzabosco
- Section of Digestive Diseases, Yale University, New Haven, CT, USA; Department of Clinical Medicine, University of Milan-Bicocca, Milan, Italy.
| | - Luca Fabris
- Department of Clinical Medicine, University of Milan-Bicocca, Milan, Italy,Department of Surgical and Gastroenterological Sciences, University of Padova, Italy
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15
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Affiliation(s)
- Laurent Dollé
- Liver Cell Biology Lab, Department of Cell Biology, Vrije Universiteit Brussel, Brussels, Belgium
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16
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Vanderpool C, Sparks EE, Huppert KA, Gannon M, Means AL, Huppert SS. Genetic interactions between hepatocyte nuclear factor-6 and Notch signaling regulate mouse intrahepatic bile duct development in vivo. Hepatology 2012; 55:233-43. [PMID: 21898486 PMCID: PMC3235248 DOI: 10.1002/hep.24631] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/07/2022]
Abstract
UNLABELLED Notch signaling and hepatocyte nuclear factor-6 (HNF-6) are two genetic factors known to affect lineage commitment in the bipotential hepatoblast progenitor cell (BHPC) population. A genetic interaction involving Notch signaling and HNF-6 in mice has been inferred through separate experiments showing that both affect BHPC specification and bile duct morphogenesis. To define the genetic interaction between HNF-6 and Notch signaling in an in vivo mouse model, we examined the effects of BHPC-specific loss of HNF-6 alone and within the background of BHPC-specific loss of recombination signal binding protein immunoglobulin kappa J (RBP-J), the common DNA-binding partner of all Notch receptors. Isolated loss of HNF-6 in this mouse model fails to demonstrate a phenotypic variance in bile duct development compared to control. However, when HNF-6 loss is combined with RBP-J loss, a phenotype consisting of cholestasis, hepatic necrosis, and fibrosis is observed that is more severe than the phenotype seen with Notch signaling loss alone. This phenotype is associated with significant intrahepatic biliary system abnormalities, including an early decrease in biliary epithelial cells, evolving to ductular proliferation and a decrease in the density of communicating peripheral bile duct branches. In this in vivo model, simultaneous loss of both HNF-6 and RBP-J results in down-regulation of both HNF-1β and Sox9 (sex determining region Y-related HMG box transcription factor 9). CONCLUSION HNF-6 and Notch signaling interact in vivo to control expression of downstream mediators essential to the normal development of the intrahepatic biliary system. This study provides a model to investigate genetic interactions of factors important to intrahepatic bile duct development and their effect on cholestatic liver disease phenotypes.
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Affiliation(s)
- Charles Vanderpool
- Department of Pediatrics, D. Brent Polk Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Erin E. Sparks
- Department of Cell and Developmental Biology and Center for Stem Cell Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Kari A. Huppert
- Department of Cell and Developmental Biology and Center for Stem Cell Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Maureen Gannon
- Department of Medicine and Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Anna L. Means
- Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Stacey S. Huppert
- Department of Cell and Developmental Biology and Center for Stem Cell Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
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17
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Dorrell C, Erker L, Schug J, Kopp JL, Canaday PS, Fox AJ, Smirnova O, Duncan AW, Finegold MJ, Sander M, Kaestner KH, Grompe M. Prospective isolation of a bipotential clonogenic liver progenitor cell in adult mice. Genes Dev 2011; 25:1193-203. [PMID: 21632826 PMCID: PMC3110957 DOI: 10.1101/gad.2029411] [Citation(s) in RCA: 185] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2011] [Accepted: 04/08/2011] [Indexed: 12/19/2022]
Abstract
The molecular identification of adult hepatic stem/progenitor cells has been hampered by the lack of truly specific markers. To isolate putative adult liver progenitor cells, we used cell surface-marking antibodies, including MIC1-1C3, to isolate subpopulations of liver cells from normal adult mice or those undergoing an oval cell response and tested their capacity to form bilineage colonies in vitro. Robust clonogenic activity was found to be restricted to a subset of biliary duct cells antigenically defined as CD45(-)/CD11b(-)/CD31(-)/MIC1-1C3(+)/CD133(+)/CD26(-), at a frequency of one of 34 or one of 25 in normal or oval cell injury livers, respectively. Gene expression analyses revealed that Sox9 was expressed exclusively in this subpopulation of normal liver cells and was highly enriched relative to other cell fractions in injured livers. In vivo lineage tracing using Sox9creER(T2)-R26R(YFP) mice revealed that the cells that proliferate during progenitor-driven liver regeneration are progeny of Sox9-expressing precursors. A comprehensive array-based comparison of gene expression in progenitor-enriched and progenitor-depleted cells from both normal and DDC (3,5-diethoxycarbonyl-1,4-dihydrocollidine or diethyl1,4-dihydro-2,4,6-trimethyl-3,5-pyridinedicarboxylate)-treated livers revealed new potential regulators of liver progenitors.
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Affiliation(s)
- Craig Dorrell
- Oregon Stem Cell Center, Oregon Health and Science University, Portland, Oregon 97239, USA
| | - Laura Erker
- Oregon Stem Cell Center, Oregon Health and Science University, Portland, Oregon 97239, USA
| | - Jonathan Schug
- Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
- Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
| | - Janel L. Kopp
- Department of Pediatrics, University of California at San Diego, La Jolla, California 92093, USA
- Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California 92093, USA
| | - Pamela S. Canaday
- Oregon Stem Cell Center, Oregon Health and Science University, Portland, Oregon 97239, USA
| | - Alan J. Fox
- Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
- Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
| | - Olga Smirnova
- Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
- Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
| | - Andrew W. Duncan
- Oregon Stem Cell Center, Oregon Health and Science University, Portland, Oregon 97239, USA
| | - Milton J. Finegold
- Department of Pathology, Baylor College of Medicine, Houston, Texas 77030, USA
| | - Maike Sander
- Department of Pediatrics, University of California at San Diego, La Jolla, California 92093, USA
- Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California 92093, USA
| | - Klaus H. Kaestner
- Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
- Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
| | - Markus Grompe
- Oregon Stem Cell Center, Oregon Health and Science University, Portland, Oregon 97239, USA
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18
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Shin S, Walton G, Aoki R, Brondell K, Schug J, Fox A, Smirnova O, Dorrell C, Erker L, Chu AS, Wells RG, Grompe M, Greenbaum LE, Kaestner KH. Foxl1-Cre-marked adult hepatic progenitors have clonogenic and bilineage differentiation potential. Genes Dev 2011; 25:1185-92. [PMID: 21632825 PMCID: PMC3110956 DOI: 10.1101/gad.2027811] [Citation(s) in RCA: 129] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2011] [Accepted: 03/31/2011] [Indexed: 12/22/2022]
Abstract
Isolation of hepatic progenitor cells is a promising approach for cell replacement therapy of chronic liver disease. The winged helix transcription factor Foxl1 is a marker for progenitor cells and their descendants in the mouse liver in vivo. Here, we purify progenitor cells from Foxl1-Cre; RosaYFP mice and evaluate their proliferative and differentiation potential in vitro. Treatment of Foxl1-Cre; RosaYFP mice with a 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet led to an increase of the percentage of YFP-labeled Foxl1(+) cells. Clonogenic assays demonstrated that up to 3.6% of Foxl1(+) cells had proliferative potential. Foxl1(+) cells differentiated into cholangiocytes and hepatocytes in vitro, depending on the culture condition employed. Microarray analyses indicated that Foxl1(+) cells express stem cell markers such as Prom1 as well as differentiation markers such as Ck19 and Hnf4a. Thus, the Foxl1-Cre; RosaYFP model allows for easy isolation of adult hepatic progenitor cells that can be expanded and differentiated in culture.
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Affiliation(s)
- Soona Shin
- Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, USA
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19
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Abstract
In most cholangiopathies, liver diseases of different etiologies in which the biliary epithelium is the primary target in the pathogenic sequence, the central mechanism involves inflammation. Inflammation, characterized by pleomorphic peribiliary infiltrate containing fibroblasts, macrophages, lymphocytes, as well as endothelial cells and pericytes, is associated to the emergence of "reactive cholangiocytes." These biliary cells do not possess bile secretory functions, are in contiguity with terminal cholangioles, and are of a less-differentiated phenotype. They have acquired several mesenchymal properties, including motility and ability to secrete a vast number of proinflammatory chemo/cytokines and growth factors along with de novo expression of a rich receptor machinery. These functional properties enable reactive cholangiocytes to establish intimate contacts and to mutually exchange a variety of paracrine signals with the different mesenchymal cell types populating the portal infiltrate. The extensive crosstalk between the epithelial and mesenchymal compartments is the driver of liver repair mechanisms in cholangiopathies, ultimately evolving toward portal fibrosis. Herein, the authors first review the properties of the different cell types involved in their interaction, and then analyze the underlying molecular mechanisms as they relate to liver repair in cholangiopathies.
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Affiliation(s)
- Luca Fabris
- Department of Surgical and Gastroenterological Sciences, University of Padua, Padova, Italy
- Center for Liver Research (CeLiveR), Bergamo, Italy
| | - Mario Strazzabosco
- Center for Liver Research (CeLiveR), Bergamo, Italy
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut
- Department of Clinical Medicine, University of Milano-Bicocca, Milan, Italy
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20
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Onori P, Gaudio E, Franchitto A, Alpini G, Francis H. Histamine regulation of hyperplastic and neoplastic cell growth in cholangiocytes. World J Gastrointest Pathophysiol 2010; 1:38-49. [PMID: 21607141 PMCID: PMC3097946 DOI: 10.4291/wjgp.v1.i2.38] [Citation(s) in RCA: 6] [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: 02/09/2010] [Revised: 04/03/2010] [Accepted: 04/10/2010] [Indexed: 02/06/2023] Open
Abstract
Histamine has long been known to be involved in inflammatory events. The discovery of antihistamines dates back to the first half of the 20th century when a Swiss-Italian pharmacologist, Daniel Bovet began his work. In 1957 he was awarded a Nobel Prize for his production of antihistamines for allergy relief. Since that time, histamine has been found to play a role in other events besides allergic reaction. Possibly unbelievable to Bovet and his peers, histamine has now been marked as playing a role in liver pathologies including hepatobiliary diseases.
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21
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Glaser S, Onori P, Wise C, Yang F, Marzioni M, Alvaro D, Franchitto A, Mancinelli R, Alpini G, Munshi MK, Gaudio E. Recent advances in the regulation of cholangiocyte proliferation and function during extrahepatic cholestasis. Dig Liver Dis 2010; 42:245-52. [PMID: 20153989 PMCID: PMC2836402 DOI: 10.1016/j.dld.2010.01.008] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2010] [Accepted: 01/08/2010] [Indexed: 12/11/2022]
Abstract
Bile duct epithelial cells (i.e., cholangiocytes), which line the intrahepatic biliary epithelium, are the target cells in a number of human cholestatic liver diseases (termed cholangiopathies). Cholangiocyte proliferation and death is present in virtually all human cholangiopathies. A number of recent studies have provided insights into the key mechanisms that regulate the proliferation and function of cholangiocytes during the pathogenesis of cholestatic liver diseases. In our review, we have summarised the most important of these recent studies over the past 3 years with a focus on those performed in the animal model of extrahepatic bile duct ligation. In the first part of the review, we provide relevant background on the biliary ductal system. We then proceed with a general discussion of the factors regulating biliary proliferation performed in the cholestatic animal model of bile duct ligation. Further characterisation of the factors that regulate cholangiocyte proliferation and function will help in elucidating the mechanisms regulating the pathogenesis of biliary tract diseases in humans and in devising new treatment approaches for these devastating diseases.
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Affiliation(s)
- S.S. Glaser
- Digestive Disease Research Center, Scott & White, TX, United States
- Department of Medicine, Division of Gastroenterology, Scott & White and Texas A&M Health Science Center, College of Medicine, Temple, TX, United States
| | - P. Onori
- Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy
| | - C. Wise
- Department of Medicine, Division of Gastroenterology, Scott & White and Texas A&M Health Science Center, College of Medicine, Temple, TX, United States
| | - F. Yang
- Department of Medicine, Division of Gastroenterology, Scott & White and Texas A&M Health Science Center, College of Medicine, Temple, TX, United States
- Shengjing Hospital, China Medical University, Shenyang City, Liaoning Province, China
| | - M. Marzioni
- Department of Gastroenterology, Universita' Politecnica delle Marche, Ancona, Italy
| | - D. Alvaro
- Gastroenterology, University of Rome “La Sapienza”, Rome, Italy
| | - A. Franchitto
- Department of Human Anatomy, University of Rome “La Sapienza”, Rome, Italy
| | - R. Mancinelli
- Department of Human Anatomy, University of Rome “La Sapienza”, Rome, Italy
| | - G. Alpini
- Digestive Disease Research Center, Scott & White, TX, United States
- Department of Medicine, Division of Gastroenterology, Scott & White and Texas A&M Health Science Center, College of Medicine, Temple, TX, United States
- Central Texas Veterans Health Care System, Temple, TX, United States
| | - Md. K. Munshi
- Department of Medicine, Division of Gastroenterology, Scott & White and Texas A&M Health Science Center, College of Medicine, Temple, TX, United States
| | - E. Gaudio
- Department of Human Anatomy, University of Rome “La Sapienza”, Rome, Italy
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