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Derbeneva D, Pilmane M, Petersons A. Gene proteins, growth factors/their receptors in the wall of chronic calculous cholecystitis-affected gallbladder children. BMC Pediatr 2025; 25:288. [PMID: 40221697 PMCID: PMC11992698 DOI: 10.1186/s12887-025-05650-4] [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: 01/01/2025] [Accepted: 03/28/2025] [Indexed: 04/14/2025] Open
Abstract
BACKGROUND Chronic calculous cholecystitis is the main cause of cholecystectomies in children, and 50.5% of patients with gallstones are asymptomatic at the time of diagnosis. However, the morphopathogenesis of chronic cholecystitis with cholelithiasis is unclear and may involve various genes, gene proteins, and growth factors. METHODS Tissues were obtained from four males (aged 6-18 years) and two females (aged 15 and 14 years) during planned cholecystectomies. Five healthy gallbladder tissues were obtained from the archival postmortem tissue of children. SHH, IHH, HGF, IGF1, IGF1R, and HOXB3 were detected by immunohistochemistry and evaluated semiquantitatively. Statistical analysis was used to identify statistically significant differences and correlations between the factors. RESULTS Decreased numbers of SHH-, IHH-, and IGF1R-positive cells, along with an increased number of HOXB3-positive cells, were observed in patients. SHH-positive epitheliocytes and connective tissue cells; IHH-positive cells in all locations; IGF1R-positive epitheliocytes, endotheliocytes, and smooth muscle cells; and HOXB3-positive smooth muscle cells were significantly different among the groups. However, the strongest negative correlation was found between HOXB3-positive smooth myocytes and SHH- and IHH-positive connective tissues, and the strongest positive correlation was detected among epithelial IHH, SHH, and IGF1R, as well as between IGF1R in the epithelium and endothelium of the blood vessels. CONCLUSIONS The reduced number of cells positive for the primary endodermal proteins SHH/IHH and the decreased number of IGFR1-positive cells suggest their potential roles in the development of chronic calculous cholecystitis. Additionally, the increased number of HOXB3-positive cells under these conditions likely implies stimulated growth properties, whereas HGF and IGF1 appear to have a reduced contribution to the pathogenesis of chronic calculous cholecystitis.
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Affiliation(s)
- Darja Derbeneva
- Institute of Anatomy and Anthropology, Riga Stradins University, Kronvalda Boulevard 9, Riga, LV-1010, Latvia.
| | - Mara Pilmane
- Institute of Anatomy and Anthropology, Riga Stradins University, Kronvalda Boulevard 9, Riga, LV-1010, Latvia.
| | - Aigars Petersons
- Department of Paediatric Surgery, Riga Stradins University, Dzirciema street 16, Riga, LV-1007, Latvia
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2
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Chen TI, Chen MH, Yin SC, Lin CJ, Lam TK, Huang CW, Chen YT, Liu XR, Gao YZ, Hsu WL, Chen HY, Yeh TS, Koshiol J, Lee MH. Associations between metabolic syndrome and cholangiocarcinoma risk: A large-scale population-based cohort study. Hepatology 2025:01515467-990000000-01209. [PMID: 40117647 DOI: 10.1097/hep.0000000000001312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2025] [Accepted: 03/03/2025] [Indexed: 03/23/2025]
Abstract
BACKGROUND AND AIMS This large-scale, population-based cohort study examined the associations between metabolic syndrome and cholangiocarcinoma risk, including its intrahepatic and extrahepatic forms. APPROACH AND RESULTS A total of 4,932,211 adults aged ≥40 years participated in a government-initiated health checkup program (2012-2017), which collected lifestyle data, anthropometric measurements, and biochemical tests. Follow-up continued until 2021, with data linkage to National Cancer and Death Registries to ascertain the occurrence of cholangiocarcinoma and obtain vital status information. Fine and Gray models accounted for competing risks. During 35,879,371 person-years of follow-up, 6117 cholangiocarcinoma cases were identified, with an incidence rate of 17.05 (95% CI: 15.90-18.20) per 100,000 person-years. Individuals with metabolic syndrome had significantly higher incidences of both intrahepatic and extrahepatic cholangiocarcinoma ( p <0.0001). The multivariate-adjusted HR for cholangiocarcinoma among those with metabolic syndrome was 1.20 (1.14-1.27). Stratification analyses by age, sex, liver enzyme levels, and comorbidities consistently demonstrated an increased cholangiocarcinoma risk among individuals with metabolic syndrome. A dose-response relationship was observed, with a higher number of metabolic components correlating with an elevated cholangiocarcinoma risk, even after accounting for all-cause mortality as a competing risk. The adjusted subdistribution HRs ranged from 1.16 (95% CI: 1.02-1.32) for individuals with one metabolic component to 1.67 (95% CI: 1.45-1.94) for those with five ( p for trend <0.0001). CONCLUSIONS The positive association between metabolic syndrome and cholangiocarcinoma risk suggests that managing metabolic risk factors might reduce the occurrence of both intrahepatic and extrahepatic cholangiocarcinoma.
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Affiliation(s)
- Tzu-I Chen
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Data Science Center, College of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan
| | - Ming-Huang Chen
- Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Szu-Ching Yin
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chih-Jo Lin
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Tram Kim Lam
- Environmental Epidemiology Branch, Epidemiology and Genomics Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Rockville, Maryland, USA
| | - Chia-Wei Huang
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Advanced Therapeutics Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Institute of Brain Science, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yi-Ting Chen
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Xia-Rong Liu
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yun-Zheng Gao
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Wan-Lun Hsu
- Data Science Center, College of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan
- Master Program of Big Data in Medical Healthcare Industry, College of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan
| | - Hsuan-Yu Chen
- Institute of Statistical Science, Academia Sinica, Taipei, Taiwan
| | - Ta-Sen Yeh
- Department of Surgery, Chang Gung Memorial Hospital at Linko, Taiwan
| | - Jill Koshiol
- Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland, USA
| | - Mei-Hsuan Lee
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Environmental Epidemiology Branch, Epidemiology and Genomics Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Rockville, Maryland, USA
- Center of Excellence for Metabolic Associated Fatty Liver Disease, National Sun Yat-sen University, Kaohsiung, Taiwan
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3
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Kineman RD, Del Rio-Moreno M, Waxman DJ. Liver-specific actions of GH and IGF1 that protect against MASLD. Nat Rev Endocrinol 2025; 21:105-117. [PMID: 39322791 DOI: 10.1038/s41574-024-01037-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/29/2024] [Indexed: 09/27/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD; also known as nonalcoholic fatty liver disease) is a chronic condition associated with metabolic syndrome, a group of conditions that includes obesity, insulin resistance, hyperlipidaemia and cardiovascular disease. Primary growth hormone (GH) deficiency is associated with MASLD, and the decline in circulating levels of GH with weight gain might contribute to the development of MASLD. Raising endogenous GH secretion or administering GH replacement therapy in the context of MASLD enhances insulin-like growth factor 1 (IGF1) production and reduces steatosis and the severity of liver injury. GH and IGF1 indirectly control MASLD progression by regulating systemic metabolic function. Evidence supports the proposal that GH and IGF1 also have a direct role in regulating liver metabolism and health. This Review focuses on how GH acts on the hepatocyte in a sex-dependent manner to limit lipid accumulation, reduce stress, and promote survival and regeneration. In addition, we discuss how GH and IGF1 might regulate non-parenchymal cells of the liver to control inflammation and fibrosis, which have a major effect on hepatocyte survival and regeneration. Development of a better understanding of how GH and IGF1 coordinate the functions of specific, individual liver cell types might provide insight into the aetiology of MASLD initiation and progression and suggest novel approaches for the treatment of MASLD.
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Affiliation(s)
- Rhonda D Kineman
- Department of Medicine, Section of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago, Chicago, IL, USA.
- Jesse Brown VA Medical Center, Research and Development Division, Chicago, IL, USA.
| | - Mercedes Del Rio-Moreno
- Department of Medicine, Section of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago, Chicago, IL, USA
- Jesse Brown VA Medical Center, Research and Development Division, Chicago, IL, USA
| | - David J Waxman
- Department of Biology and Bioinformatics Program, Boston University, Boston, MA, USA
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Righini M, Mancini R, Busutti M, Buscaroli A. Autosomal Dominant Polycystic Kidney Disease: Extrarenal Involvement. Int J Mol Sci 2024; 25:2554. [PMID: 38473800 DOI: 10.3390/ijms25052554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 02/19/2024] [Accepted: 02/20/2024] [Indexed: 03/14/2024] Open
Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disorder, but kidneys are not the only organs involved in this systemic disorder. Individuals with the condition may display additional manifestations beyond the renal system, involving the liver, pancreas, and brain in the context of cystic manifestations, while involving the vascular system, gastrointestinal tract, bones, and cardiac valves in the context of non-cystic manifestations. Despite kidney involvement remaining the main feature of the disease, thanks to longer survival, early diagnosis, and better management of kidney-related problems, a new wave of complications must be faced by clinicians who treated patients with ADPKD. Involvement of the liver represents the most prevalent extrarenal manifestation and has growing importance in the symptom burden and quality of life. Vascular abnormalities are a key factor for patients' life expectancy and there is still debate whether to screen or not to screen all patients. Arterial hypertension is often the earliest onset symptom among ADPKD patients, leading to frequent cardiovascular complications. Although cardiac valvular abnormalities are a frequent complication, they rarely lead to relevant problems in the clinical history of polycystic patients. One of the newest relevant aspects concerns bone disorders that can exert a considerable influence on the clinical course of these patients. This review aims to provide the "state of the art" among the extrarenal manifestation of ADPKD.
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Affiliation(s)
- Matteo Righini
- Nephrology and Dialysis Unit, Santa Maria delle Croci Hospital, AUSL Romagna, 48121 Ravenna, Italy
- Nephrology, Dialysis and Transplantation Unit, IRCCS Azienda Ospedaliero Universitaria di Bologna, 40138 Bologna, Italy
| | - Raul Mancini
- Nephrology, Dialysis and Transplantation Unit, IRCCS Azienda Ospedaliero Universitaria di Bologna, 40138 Bologna, Italy
| | - Marco Busutti
- Nephrology, Dialysis and Transplantation Unit, IRCCS Azienda Ospedaliero Universitaria di Bologna, 40138 Bologna, Italy
| | - Andrea Buscaroli
- Nephrology and Dialysis Unit, Santa Maria delle Croci Hospital, AUSL Romagna, 48121 Ravenna, Italy
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Iqbal A, Van Hul N, Belicova L, Corbat AA, Hankeova S, Andersson ER. Spatially segregated defects and IGF1-responsiveness of hilar and peripheral biliary organoids from a model of Alagille syndrome. Liver Int 2024; 44:541-558. [PMID: 38014627 DOI: 10.1111/liv.15789] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Revised: 11/02/2023] [Accepted: 11/03/2023] [Indexed: 11/29/2023]
Abstract
BACKGROUND & AIMS Alagille syndrome (ALGS) manifests with peripheral intrahepatic bile duct (IHBD) paucity, which can spontaneously resolve. In a model for ALGS, Jag1Ndr/Ndr mice, this occurs with distinct architectural mechanisms in hilar and peripheral IHBDs. Here, we investigated region-specific IHBD characteristics and addressed whether IGF1, a cholangiocyte mitogen that is downregulated in ALGS and in Jag1Ndr/Ndr mice, can improve biliary outcomes. METHODS Intrahepatic cholangiocyte organoids (ICOs) were derived from hilar and peripheral adult Jag1+/+ and Jag1Ndr/Ndr livers (hICOs and pICOs, respectively). ICOs were grown in Matrigel or microwell arrays, and characterized using bulk RNA sequencing, immunofluorescence, and high throughput analyses of nuclear sizes. ICOs were treated with IGF1, followed by analyses of growth, proliferation, and death. CellProfiler and Python scripts were custom written for image analyses. Key results were validated in vivo by immunostaining. RESULTS Cell growth assays and transcriptomics demonstrated that Jag1Ndr/Ndr ICOs were less proliferative than Jag1+/+ ICOs. IGF1 specifically rescued survival and growth of Jag1Ndr/Ndr pICOs. Jag1Ndr/Ndr hICOs were the least proliferative, with lower Notch signalling and an enrichment of hepatocyte signatures and IGF uptake/transport pathways. In vitro (Jag1Ndr/Ndr hICOs) and in vivo (Jag1Ndr/Ndr hilar portal tracts) analyses revealed ectopic HNF4a+ hepatocytes. CONCLUSIONS Hilar and peripheral Jag1Ndr/Ndr ICOs exhibit differences in Notch signalling status, proliferation, and cholangiocyte commitment which may result in cholangiocyte-to-hepatocyte transdifferentiation. While Jag1Ndr/Ndr pICOs can be rescued by IGF1, hICOs are unresponsive, perhaps due to their hepatocyte-like state and/or expression of IGF transport components. IGF1 represents a potential therapeutic for peripheral bile ducts.
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Affiliation(s)
- Afshan Iqbal
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
| | - Noemi Van Hul
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
| | - Lenka Belicova
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
| | - Agustin A Corbat
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
| | - Simona Hankeova
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
| | - Emma R Andersson
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
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Cai X, Tacke F, Guillot A, Liu H. Cholangiokines: undervalued modulators in the hepatic microenvironment. Front Immunol 2023; 14:1192840. [PMID: 37261338 PMCID: PMC10229055 DOI: 10.3389/fimmu.2023.1192840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 05/02/2023] [Indexed: 06/02/2023] Open
Abstract
The biliary epithelial cells, also known as cholangiocytes, line the intra- and extrahepatic bile ducts, forming a barrier between intra- and extra-ductal environments. Cholangiocytes are mostly known to modulate bile composition and transportation. In hepatobiliary diseases, bile duct injury leads to drastic alterations in cholangiocyte phenotypes and their release of soluble mediators, which can vary depending on the original insult and cellular states (quiescence, senescence, or proliferation). The cholangiocyte-secreted cytokines (also termed cholangiokines) drive ductular cell proliferation, portal inflammation and fibrosis, and carcinogenesis. Hence, despite the previous consensus that cholangiocytes are bystanders in liver diseases, their diverse secretome plays critical roles in modulating the intrahepatic microenvironment. This review summarizes recent insights into the cholangiokines under both physiological and pathological conditions, especially as they occur during liver injury-regeneration, inflammation, fibrosis and malignant transformation processes.
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Affiliation(s)
- Xiurong Cai
- Department of Hematology, Oncology and Tumor Immunology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany
| | - Adrien Guillot
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany
| | - Hanyang Liu
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany
- Center of Gastrointestinal Diseases, Changzhou Second People's Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou, China
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7
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Oxley M, Francis H, Sato K. Growth Hormone Signaling in Liver Diseases: Therapeutic Potentials and Controversies. Semin Liver Dis 2023; 43:24-30. [PMID: 36652958 DOI: 10.1055/a-2015-1359] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Growth hormone (GH) and downstream insulin-like growth factor 1 (IGF1) signaling mediate growth and metabolism. GH deficiency causes short stature or dwarfism, and excess GH causes acromegaly. Although the association of GH/IGF1 signaling with liver diseases has been suggested previously, current studies are controversial and the functional roles of GH/IGF1 signaling are still undefined. GH supplementation therapy showed promising therapeutic effects in some patients, such as non-alcoholic fatty liver disease, but inhibition of GH signaling may be beneficial for other liver diseases, such as hepatocellular carcinoma. The functional roles of GH/IGF1 signaling and the effects of agonists/antagonists targeting this signaling may differ depending on the liver injury or animal models. This review summarizes current controversial studies of GH/IGF1 signaling in liver diseases and discusses therapeutic potentials of GH therapy.
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Affiliation(s)
- Madisyn Oxley
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Heather Francis
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
- Department of Research, Richard L. Roudebush VA Medical Center, Indianapolis, Indiana
| | - Keisaku Sato
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
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8
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Im C, Sapkota Y, Moon W, Kawashima M, Nakamura M, Tokunaga K, Yasui Y. Genome-wide haplotype association analysis of primary biliary cholangitis risk in Japanese. Sci Rep 2018; 8:7806. [PMID: 29773854 PMCID: PMC5958065 DOI: 10.1038/s41598-018-26112-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Accepted: 04/30/2018] [Indexed: 12/16/2022] Open
Abstract
Primary biliary cholangitis (PBC) susceptibility loci have largely been discovered through single SNP association testing. In this study, we report genic haplotype patterns associated with PBC risk genome-wide in two Japanese cohorts. Among the 74 genic PBC risk haplotype candidates we detected with a novel methodological approach in a discovery cohort of 1,937 Japanese, nearly two-thirds were replicated (49 haplotypes, Bonferroni-corrected P < 6.8 × 10-4) in an independent Japanese cohort (N = 949). Along with corroborating known PBC-associated loci (TNFSF15, HLA-DRA), risk haplotypes may potentially model cis-interactions that regulate gene expression. For example, one replicated haplotype association (9q32-9q33.1, OR = 1.7, P = 3.0 × 10-21) consists of intergenic SNPs outside of the human leukocyte antigen (HLA) region that overlap regulatory histone mark peaks in liver and blood cells, and are significantly associated with TNFSF8 expression in whole blood. We also replicated a novel haplotype association involving non-HLA SNPs mapped to UMAD1 (7p21.3; OR = 15.2, P = 3.9 × 10-9) that overlap enhancer peaks in liver and memory Th cells. Our analysis demonstrates the utility of haplotype association analyses in discovering and characterizing PBC susceptibility loci.
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Affiliation(s)
- Cindy Im
- School of Public Health, University of Alberta, Edmonton, Alberta, T6G 1C9, Canada.
| | - Yadav Sapkota
- Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
| | - Wonjong Moon
- Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
| | - Minae Kawashima
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan
| | - Minoru Nakamura
- Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences and Clinical Research Center, National Hospital Organization Nagasaki Medical Center, Omura, Nagasaki, 856-8562, Japan
| | - Katsushi Tokunaga
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan
| | - Yutaka Yasui
- School of Public Health, University of Alberta, Edmonton, Alberta, T6G 1C9, Canada. .,Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
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Andersson ER, Chivukula IV, Hankeova S, Sjöqvist M, Tsoi YL, Ramsköld D, Masek J, Elmansuri A, Hoogendoorn A, Vazquez E, Storvall H, Netušilová J, Huch M, Fischler B, Ellis E, Contreras A, Nemeth A, Chien KC, Clevers H, Sandberg R, Bryja V, Lendahl U. Mouse Model of Alagille Syndrome and Mechanisms of Jagged1 Missense Mutations. Gastroenterology 2018; 154:1080-1095. [PMID: 29162437 PMCID: PMC7007299 DOI: 10.1053/j.gastro.2017.11.002] [Citation(s) in RCA: 77] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2017] [Revised: 10/21/2017] [Accepted: 11/02/2017] [Indexed: 12/28/2022]
Abstract
BACKGROUND & AIMS Alagille syndrome is a genetic disorder characterized by cholestasis, ocular abnormalities, characteristic facial features, heart defects, and vertebral malformations. Most cases are associated with mutations in JAGGED1 (JAG1), which encodes a Notch ligand, although it is not clear how these contribute to disease development. We aimed to develop a mouse model of Alagille syndrome to elucidate these mechanisms. METHODS Mice with a missense mutation (H268Q) in Jag1 (Jag1+/Ndr mice) were outbred to a C3H/C57bl6 background to generate a mouse model for Alagille syndrome (Jag1Ndr/Ndr mice). Liver tissues were collected at different timepoints during development, analyzed by histology, and liver organoids were cultured and analyzed. We performed transcriptome analysis of Jag1Ndr/Ndr livers and livers from patients with Alagille syndrome, cross-referenced to the Human Protein Atlas, to identify commonly dysregulated pathways and biliary markers. We used species-specific transcriptome separation and ligand-receptor interaction assays to measure Notch signaling and the ability of JAG1Ndr to bind or activate Notch receptors. We studied signaling of JAG1 and JAG1Ndr via NOTCH 1, NOTCH2, and NOTCH3 and resulting gene expression patterns in parental and NOTCH1-expressing C2C12 cell lines. RESULTS Jag1Ndr/Ndr mice had many features of Alagille syndrome, including eye, heart, and liver defects. Bile duct differentiation, morphogenesis, and function were dysregulated in newborn Jag1Ndr/Ndr mice, with aberrations in cholangiocyte polarity, but these defects improved in adult mice. Jag1Ndr/Ndr liver organoids collapsed in culture, indicating structural instability. Whole-transcriptome sequence analyses of liver tissues from mice and patients with Alagille syndrome identified dysregulated genes encoding proteins enriched at the apical side of cholangiocytes, including CFTR and SLC5A1, as well as reduced expression of IGF1. Exposure of Notch-expressing cells to JAG1Ndr, compared with JAG1, led to hypomorphic Notch signaling, based on transcriptome analysis. JAG1-expressing cells, but not JAG1Ndr-expressing cells, bound soluble Notch1 extracellular domain, quantified by flow cytometry. However, JAG1 and JAG1Ndr cells each bound NOTCH2, and signaling from NOTCH2 signaling was reduced but not completely inhibited, in response to JAG1Ndr compared with JAG1. CONCLUSIONS In mice, expression of a missense mutant of Jag1 (Jag1Ndr) disrupts bile duct development and recapitulates Alagille syndrome phenotypes in heart, eye, and craniofacial dysmorphology. JAG1Ndr does not bind NOTCH1, but binds NOTCH2, and elicits hypomorphic signaling. This mouse model can be used to study other features of Alagille syndrome and organ development.
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Affiliation(s)
- Emma R. Andersson
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden,Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
| | - Indira V. Chivukula
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
| | - Simona Hankeova
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden,Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden,Institute of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Marika Sjöqvist
- Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
| | - Yat Long Tsoi
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
| | - Daniel Ramsköld
- Rheumatology Unit, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Jan Masek
- Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
| | - Aiman Elmansuri
- Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
| | - Anita Hoogendoorn
- Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
| | - Elenae Vazquez
- Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología-Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, México City, México
| | - Helena Storvall
- Karolinska University Hospital, CLINTEC, Karolinska Institutet, Stockholm, Sweden
| | - Julie Netušilová
- Institute of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Meritxell Huch
- Hubrecht Institute for Developmental Biology and Stem Cell Research, University Medical Centre Utrecht, Netherlands
| | - Björn Fischler
- Karolinska University Hospital, Department of Pediatrics, CLINTEC, Karolinska Institutet, Stockholm, Sweden
| | - Ewa Ellis
- Karolinska University Hospital, CLINTEC, Karolinska Institutet, Stockholm, Sweden
| | - Adriana Contreras
- Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología-Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, México City, México
| | - Antal Nemeth
- Karolinska University Hospital, Department of Pediatrics, CLINTEC, Karolinska Institutet, Stockholm, Sweden
| | - Kenneth C. Chien
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
| | - Hans Clevers
- Hubrecht Institute for Developmental Biology and Stem Cell Research, University Medical Centre Utrecht, Netherlands
| | - Rickard Sandberg
- Ludwig Institute for Cancer Research, Karolinska Institutet, Stockholm, Sweden
| | - Vitezslav Bryja
- Institute of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Urban Lendahl
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
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Cordero-Espinoza L, Huch M. The balancing act of the liver: tissue regeneration versus fibrosis. J Clin Invest 2018; 128:85-96. [PMID: 29293095 PMCID: PMC5749503 DOI: 10.1172/jci93562] [Citation(s) in RCA: 156] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Epithelial cell loss alters a tissue's optimal function and awakens evolutionarily adapted healing mechanisms to reestablish homeostasis. Although adult mammalian organs have a limited regeneration potential, the liver stands out as one remarkable exception. Following injury, the liver mounts a dynamic multicellular response wherein stromal cells are activated in situ and/or recruited from the bloodstream, the extracellular matrix (ECM) is remodeled, and epithelial cells expand to replenish their lost numbers. Chronic damage makes this response persistent instead of transient, tipping the system into an abnormal steady state known as fibrosis, in which ECM accumulates excessively and tissue function degenerates. Here we explore the cellular and molecular switches that balance hepatic regeneration and fibrosis, with a focus on uncovering avenues of disease modeling and therapeutic intervention.
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Yoo KS, Lim WT, Choi HS. Biology of Cholangiocytes: From Bench to Bedside. Gut Liver 2017; 10:687-98. [PMID: 27563020 PMCID: PMC5003190 DOI: 10.5009/gnl16033] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Revised: 02/14/2016] [Accepted: 03/09/2016] [Indexed: 12/11/2022] Open
Abstract
Cholangiocytes, the lining epithelial cells in bile ducts, are an important subset of liver cells. They are activated by endogenous and exogenous stimuli and are involved in the modification of bile volume and composition. They are also involved in damaging and repairing the liver. Cholangiocytes have many functions including bile production. They are also involved in transport processes that regulate the volume and composition of bile. Cholangiocytes undergo proliferation and cell death under a variety of conditions. Cholangiocytes have functional and morphological heterogenecity. The immunobiology of cholangiocytes is important, particularly for understanding biliary disease. Secretion of different proinflammatory mediators, cytokines, and chemokines suggests the major role that cholangiocytes play in inflammatory reactions. Furthermore, paracrine secretion of growth factors and peptides mediates extensive cross-talk with other liver cells, including hepatocytes, stellate cells, stem cells, subepithelial myofibroblasts, endothelial cells, and inflammatory cells. Cholangiopathy refers to a category of chronic liver diseases whose primary disease target is the cholangiocyte. Cholangiopathy usually results in end-stage liver disease requiring liver transplant. We summarize the biology of cholangiocytes and redefine the concept of cholangiopathy. We also discuss the recent progress that has been made in understanding the pathogenesis of cholangiopathy and how such progress has influenced therapy.
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Affiliation(s)
- Kyo-Sang Yoo
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea
| | - Woo Taek Lim
- Korea University School of Medicine, Seoul, Korea
| | - Ho Soon Choi
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea
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12
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Klungboonkrong V, Das D, McLennan G. Molecular Mechanisms and Targets of Therapy for Hepatocellular Carcinoma. J Vasc Interv Radiol 2017; 28:949-955. [PMID: 28416267 DOI: 10.1016/j.jvir.2017.03.002] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Revised: 03/01/2017] [Accepted: 03/01/2017] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. HCC develops through a multistep process that involves the local tumor microenvironment, intracellular signaling pathways, and altered metabolic system that allows the cancer proliferation. Understanding the mechanisms of tumor development and progression is critical to developing improved therapies aimed at better survival. This article reviews the molecular mechanisms of HCC development and highlights the potential therapeutic targets for treatments.
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Affiliation(s)
- Vivian Klungboonkrong
- Department of Interventional Radiology, Imaging Institute, Cleveland, OH 44195; Department of Radiology, KhonKaen University, KhonKaen, Thailand
| | - Dola Das
- Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195
| | - Gordon McLennan
- Department of Interventional Radiology, Imaging Institute, Cleveland, OH 44195.
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13
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Liberal R, Grant CR. Cirrhosis and autoimmune liver disease: Current understanding. World J Hepatol 2016; 8:1157-1168. [PMID: 27729952 PMCID: PMC5055585 DOI: 10.4254/wjh.v8.i28.1157] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Revised: 05/14/2016] [Accepted: 08/08/2016] [Indexed: 02/06/2023] Open
Abstract
Primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) constitute the classic autoimmune liver diseases (AILDs). While AIH target the hepatocytes, in PBC and PSC the targets of the autoimmune attack are the biliary epithelial cells. Persistent liver injury, associated with chronic AILD, leads to un-resolving inflammation, cell proliferation and the deposition of extracellular matrix proteins by hepatic stellate cells and portal myofibroblasts. Liver cirrhosis, and the resultant loss of normal liver function, inevitably ensues. Patients with cirrhosis have higher risks or morbidity and mortality, and that in the decompensated phase, complications of portal hypertension and/or liver dysfunction lead to rapid deterioration. Accurate diagnosis and monitoring of cirrhosis is, therefore of upmost importance. Liver biopsy is currently the gold standard technique, but highly promising non-invasive methodology is under development. Liver transplantation (LT) is an effective therapeutic option for the management of end-stage liver disease secondary to AIH, PBC and PSC. LT is indicated for AILD patients who have progressed to end-stage chronic liver disease or developed intractable symptoms or hepatic malignancy; in addition, LT may also be indicated for patients presenting with acute liver disease due to AIH who do not respond to steroids.
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14
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Dianat N, Weber A, Dubart-Kupperschmitt A. [Human pluripotent stem cells and liver disorders]. Biol Aujourdhui 2016; 210:19-26. [PMID: 27286577 DOI: 10.1051/jbio/2016006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2016] [Indexed: 11/14/2022]
Abstract
The liver is associated with many diseases including metabolic and cholestatic diseases, cirrhosis as well as chronic and acute hepatitis. However, knowledge about the mechanisms involved in the pathophysiology of these diseases remains limited due to the restricted access to liver biopsies and the lack of cellular models derived from patients. The liver is the main organ responsible for the elimination of xenobiotics and thus hepatocytes have a key role in toxicology and pharmacokinetics. The induced pluripotent stem cells generated from patients with monogenic metabolic disorders, for which the corresponding gene is identified, are relevant in vitro models for the study of the mechanisms involved in generation of pathologies and also for drug screening. Towards this aim, robust protocols for generating liver cells, such as hepatocytes and cholangiocytes, are essential. Our study focused on familial hypercholesterolemia disease modeling, as well as on establishing a protocol for generation of functional cholangiocytes from pluripotent stem cells.
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Affiliation(s)
- Noushin Dianat
- INSERM U1193, Hôpital Paul Brousse, 94807 Villejuif, France - UMR S1193, Université Paris-Sud, Hôpital Paul Brousse, 94800 Villejuif, France - Département hospitalo-universitaire Hepatinov, Hôpital Paul Brousse, 94807 Villejuif, France
| | - Anne Weber
- INSERM U1193, Hôpital Paul Brousse, 94807 Villejuif, France - UMR S1193, Université Paris-Sud, Hôpital Paul Brousse, 94800 Villejuif, France - Département hospitalo-universitaire Hepatinov, Hôpital Paul Brousse, 94807 Villejuif, France
| | - Anne Dubart-Kupperschmitt
- INSERM U1193, Hôpital Paul Brousse, 94807 Villejuif, France - UMR S1193, Université Paris-Sud, Hôpital Paul Brousse, 94800 Villejuif, France - Département hospitalo-universitaire Hepatinov, Hôpital Paul Brousse, 94807 Villejuif, France
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15
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Sun Y, Haapanen K, Li B, Zhang W, Van de Water J, Gershwin ME. Women and primary biliary cirrhosis. Clin Rev Allergy Immunol 2016; 48:285-300. [PMID: 25241227 DOI: 10.1007/s12016-014-8449-4] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Primary biliary cirrhosis occurs more frequently in women, and previous studies indicated that the average age of primary biliary cirrhosis (PBC) onset makes pregnancy in PBC patients uncommon. However, more recently, improved diagnostic testing has enabled detection of PBC in younger women, including those of childbearing age. This has led investigators to become increasingly interested in the relationship between the ontogeny of PBC and pregnancy. Published cases indicate that the typical age for pregnant women to be diagnosed with PBC is in the early 30s, and that during gestation, pruritus and jaundice are the most common symptoms. During gestation, susceptible women may experience onset of PBC resulting from the drastic changes in female hormones; this would include not only the mitochondrial damage due to accumulation of bile acids but also changes in the immune response during the different stages of pregnancy that might play an important role in the breakdown of self-tolerance. The mechanisms underlying the potential relationship between PBC and pregnancy warrant further investigation. For women first diagnosed with PBC during gestation, or those for whom first appearance of a flare up occurs during and postpartum, investigation of the immune response throughout gestation could provide new avenues for immunologic therapeutic intervention and the discovery of new treatment strategies for PBC.
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Affiliation(s)
- Ying Sun
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, 451 Health Sciences Drive, Suite 6510, Davis, CA, 95616, USA
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Franchitto A, Onori P, Renzi A, Carpino G, Mancinelli R, Alvaro D, Gaudio E. Recent advances on the mechanisms regulating cholangiocyte proliferation and the significance of the neuroendocrine regulation of cholangiocyte pathophysiology. ANNALS OF TRANSLATIONAL MEDICINE 2014; 1:27. [PMID: 25332971 DOI: 10.3978/j.issn.2305-5839.2012.10.03] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 09/10/2012] [Accepted: 10/15/2012] [Indexed: 12/14/2022]
Abstract
Cholangiocytes are epithelial cells lining the biliary epithelium. Cholangiocytes play several key roles in the modification of ductal bile and are also the target cells in chronic cholestatic liver diseases (i.e., cholangiopathies) such as PSC, PBC, polycystic liver disease (PCLD) and cholangiocarcinoma (CCA). During these pathologies, cholangiocytes (which in normal condition are in a quiescent state) begin to proliferate acquiring phenotypes of neuroendocrine cells, and start secreting different cytokines, growth factors, neuropeptides, and hormones to modulate cholangiocytes proliferation and interaction with the surrounding environment, trying to reestablish the balance between proliferation/loss of cholangiocytes for the maintenance of biliary homeostasis. The purpose of this review is to summarize the recent findings on the mechanisms regulating cholangiocyte proliferation and the significance of the neuroendocrine regulation of cholangiocyte pathophysiology. To clarify the mechanisms of action of these factors we will provide new potential strategies for the management of chronic liver diseases.
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Affiliation(s)
- Antonio Franchitto
- 1 Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, University of Rome "Sapienza", Rome, Italy ; 2 Eleonora Lorillard Spencer-Cenci Foundation, Rome, Italy ; 3 Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy ; 4 Department of Health Science, University of Rome "Foro Italico", Italy ; 5 Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Sapienza, University of Rome "Sapienza", Rome, Italy
| | - Paolo Onori
- 1 Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, University of Rome "Sapienza", Rome, Italy ; 2 Eleonora Lorillard Spencer-Cenci Foundation, Rome, Italy ; 3 Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy ; 4 Department of Health Science, University of Rome "Foro Italico", Italy ; 5 Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Sapienza, University of Rome "Sapienza", Rome, Italy
| | - Anastasia Renzi
- 1 Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, University of Rome "Sapienza", Rome, Italy ; 2 Eleonora Lorillard Spencer-Cenci Foundation, Rome, Italy ; 3 Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy ; 4 Department of Health Science, University of Rome "Foro Italico", Italy ; 5 Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Sapienza, University of Rome "Sapienza", Rome, Italy
| | - Guido Carpino
- 1 Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, University of Rome "Sapienza", Rome, Italy ; 2 Eleonora Lorillard Spencer-Cenci Foundation, Rome, Italy ; 3 Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy ; 4 Department of Health Science, University of Rome "Foro Italico", Italy ; 5 Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Sapienza, University of Rome "Sapienza", Rome, Italy
| | - Romina Mancinelli
- 1 Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, University of Rome "Sapienza", Rome, Italy ; 2 Eleonora Lorillard Spencer-Cenci Foundation, Rome, Italy ; 3 Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy ; 4 Department of Health Science, University of Rome "Foro Italico", Italy ; 5 Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Sapienza, University of Rome "Sapienza", Rome, Italy
| | - Domenico Alvaro
- 1 Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, University of Rome "Sapienza", Rome, Italy ; 2 Eleonora Lorillard Spencer-Cenci Foundation, Rome, Italy ; 3 Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy ; 4 Department of Health Science, University of Rome "Foro Italico", Italy ; 5 Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Sapienza, University of Rome "Sapienza", Rome, Italy
| | - Eugenio Gaudio
- 1 Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, University of Rome "Sapienza", Rome, Italy ; 2 Eleonora Lorillard Spencer-Cenci Foundation, Rome, Italy ; 3 Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy ; 4 Department of Health Science, University of Rome "Foro Italico", Italy ; 5 Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Sapienza, University of Rome "Sapienza", Rome, Italy
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Pivonello C, De Martino MC, Negri M, Cuomo G, Cariati F, Izzo F, Colao A, Pivonello R. The GH-IGF-SST system in hepatocellular carcinoma: biological and molecular pathogenetic mechanisms and therapeutic targets. Infect Agent Cancer 2014; 9:27. [PMID: 25225571 PMCID: PMC4164328 DOI: 10.1186/1750-9378-9-27] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2012] [Accepted: 06/23/2014] [Indexed: 12/15/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide. Different signalling pathways have been identified to be implicated in the pathogenesis of HCC; among these, GH, IGF and somatostatin (SST) pathways have emerged as some of the major pathways implicated in the development of HCC. Physiologically, GH-IGF-SST system plays a crucial role in liver growth and development since GH induces IGF1 and IGF2 secretion and the expression of their receptors, involved in hepatocytes cell proliferation, differentiation and metabolism. On the other hand, somatostatin receptors (SSTRs) are exclusively present on the biliary tract. Importantly, the GH-IGF-SST system components have been indicated as regulators of hepatocarcinogenesis. Reduction of GH binding affinity to GH receptor, decreased serum IGF1 and increased serum IGF2 production, overexpression of IGF1 receptor, loss of function of IGF2 receptor and appearance of SSTRs are frequently observed in human HCC. In particular, recently, many studies have evaluated the correlation between increased levels of IGF1 receptors and liver diseases and the oncogenic role of IGF2 and its involvement in angiogenesis, migration and, consequently, in tumour progression. SST directly or indirectly influences tumour growth and development through the inhibition of cell proliferation and secretion and induction of apoptosis, even though SST role in hepatocarcinogenesis is still opened to argument. This review addresses the present evidences suggesting a role of the GH-IGF-SST system in the development and progression of HCC, and describes the therapeutic perspectives, based on the targeting of GH-IGF-SST system, which have been hypothesised and experimented in HCC.
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Affiliation(s)
- Claudia Pivonello
- Dipartimento di Medicina Clinica e Chirurgia, Università Federico II di Napoli, Via Sergio Pansini, 5, Naples 80131, Italy
| | - Maria Cristina De Martino
- Dipartimento di Medicina Clinica e Chirurgia, Università Federico II di Napoli, Via Sergio Pansini, 5, Naples 80131, Italy
| | - Mariarosaria Negri
- Dipartimento di Medicina Clinica e Chirurgia, Università Federico II di Napoli, Via Sergio Pansini, 5, Naples 80131, Italy
| | | | - Federica Cariati
- Dipartimento di Medicina Clinica e Chirurgia, Università Federico II di Napoli, Via Sergio Pansini, 5, Naples 80131, Italy
| | - Francesco Izzo
- National Cancer Institute G Pascale Foundation, Naples, Italy
| | - Annamaria Colao
- Dipartimento di Medicina Clinica e Chirurgia, Università Federico II di Napoli, Via Sergio Pansini, 5, Naples 80131, Italy
| | - Rosario Pivonello
- Dipartimento di Medicina Clinica e Chirurgia, Università Federico II di Napoli, Via Sergio Pansini, 5, Naples 80131, Italy
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18
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Dianat N, Dubois-Pot-Schneider H, Steichen C, Desterke C, Leclerc P, Raveux A, Combettes L, Weber A, Corlu A, Dubart-Kupperschmitt A. Generation of functional cholangiocyte-like cells from human pluripotent stem cells and HepaRG cells. Hepatology 2014; 60:700-14. [PMID: 24715669 PMCID: PMC4315871 DOI: 10.1002/hep.27165] [Citation(s) in RCA: 153] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2013] [Accepted: 04/07/2014] [Indexed: 12/11/2022]
Abstract
UNLABELLED Cholangiocytes are biliary epithelial cells, which, like hepatocytes, originate from hepatoblasts during embryonic development. In this study we investigated the potential of human embryonic stem cells (hESCs) to differentiate into cholangiocytes and we report a new approach, which drives differentiation of hESCs toward the cholangiocytic lineage using feeder-free and defined culture conditions. After differentiation into hepatic progenitors, hESCs were differentiated further into cholangiocytes using growth hormone, epidermal growth factor, interleukin-6, and then sodium taurocholate. These conditions also allowed us to generate cholangiocytes from HepaRG-derived hepatoblasts. hESC- and HepaRG-derived cholangiocyte-like cells expressed markers of cholangiocytes including cytokeratin 7 and osteopontin, and the transcription factors SOX9 and hepatocyte nuclear factor 6. The cells also displayed specific proteins important for cholangiocyte functions including cystic fibrosis transmembrane conductance regulator, secretin receptor, and nuclear receptors. They formed primary cilia and also responded to hormonal stimulation by increase of intracellular Ca(2+) . We demonstrated by integrative genomics that the expression of genes, which signed hESC- or HepaRG-cholangiocytes, separates hepatocytic lineage from cholangiocyte lineage. When grown in a 3D matrix, cholangiocytes developed epithelial/apicobasal polarity and formed functional cysts and biliary ducts. In addition, we showed that cholangiocyte-like cells could also be generated from human induced pluripotent stem cells, demonstrating the efficacy of our approach with stem/progenitor cells of diverse origins. CONCLUSION We have developed a robust and efficient method for differentiating pluripotent stem cells into cholangiocyte-like cells, which display structural and functional similarities to bile duct cells in normal liver. These cells will be useful for the in vitro study of the molecular mechanisms of bile duct development and have important potential for therapeutic strategies, including bioengineered liver approaches.
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Affiliation(s)
- Noushin Dianat
- INSERM, U972, Paul Brousse HospitalVillejuif, France,Université Paris Sud, UMR-S 972Villejuif, France,IFR 93, Bicêtre HospitalKremlin-Bicêtre, France,DHU Hepatinov, Paul Brousse HospitalVillejuif, France
| | | | - Clara Steichen
- INSERM, U972, Paul Brousse HospitalVillejuif, France,Université Paris Sud, UMR-S 972Villejuif, France,IFR 93, Bicêtre HospitalKremlin-Bicêtre, France,DHU Hepatinov, Paul Brousse HospitalVillejuif, France
| | - Christophe Desterke
- INSERM, U972, Paul Brousse HospitalVillejuif, France,Université Paris Sud, UMR-S 972Villejuif, France,DHU Hepatinov, Paul Brousse HospitalVillejuif, France
| | | | - Aurélien Raveux
- INSERM, U972, Paul Brousse HospitalVillejuif, France,Université Paris Sud, UMR-S 972Villejuif, France,IFR 93, Bicêtre HospitalKremlin-Bicêtre, France
| | - Laurent Combettes
- DHU Hepatinov, Paul Brousse HospitalVillejuif, France,INSERM UMR-S 757UPS-Orsay, Orsay, France
| | - Anne Weber
- INSERM, U972, Paul Brousse HospitalVillejuif, France,Université Paris Sud, UMR-S 972Villejuif, France,IFR 93, Bicêtre HospitalKremlin-Bicêtre, France,DHU Hepatinov, Paul Brousse HospitalVillejuif, France
| | - Anne Corlu
- INSERM, UMR-S 991, Pontchaillou HospitalRennes, France,University of Rennes 1Rennes, France,
Address reprint requests to: Anne Corlu, Ph.D., INSERM, UMR-S 991, Pontchaillou Hospital, Rennes F-35033, France. E-mail: ; or Anne Dubart-Kupperschmitt, M.D., INSERM, U972, Paul Brousse Hospital, Villejuif, F-94807, France. ; fax: +33 (0)1 47 26 03 19, +33 (0)2 99 54 01 37
| | - Anne Dubart-Kupperschmitt
- INSERM, U972, Paul Brousse HospitalVillejuif, France,Université Paris Sud, UMR-S 972Villejuif, France,IFR 93, Bicêtre HospitalKremlin-Bicêtre, France,DHU Hepatinov, Paul Brousse HospitalVillejuif, France
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Han Y, Glaser S, Meng F, Francis H, Marzioni M, McDaniel K, Alvaro D, Venter J, Carpino G, Onori P, Gaudio E, Alpini G, Franchitto A. Recent advances in the morphological and functional heterogeneity of the biliary epithelium. Exp Biol Med (Maywood) 2013; 238:549-65. [PMID: 23856906 DOI: 10.1177/1535370213489926] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
This review focuses on the recent advances related to the heterogeneity of different-sized bile ducts with regard to the morphological and phenotypical characteristics, and the differential secretory, apoptotic and proliferative responses of small and large cholangiocytes to gastrointestinal hormones/peptides, neuropeptides and toxins. We describe several in vivo and in vitro models used for evaluating biliary heterogeneity. Subsequently, we discuss the heterogeneous proliferative and apoptotic responses of small and large cholangiocytes to liver injury and the mechanisms regulating the differentiation of small into large (more differentiated) cholangiocytes. Following a discussion on the heterogeneity of stem/progenitor cells in the biliary epithelium, we outline the heterogeneity of bile ducts in human cholangiopathies. After a summary section, we discuss the future perspectives that will further advance the field of the functional heterogeneity of the biliary epithelium.
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Affiliation(s)
- Yuyan Han
- Department of Medicine, Division Gastroenterology, Texas A&M Health Science Center, College of Medicine, TX, USA
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Onori P, Mancinelli R, Franchitto A, Carpino G, Renzi A, Brozzetti S, Venter J, Francis H, Glaser S, Jefferson DM, Alpini G, Gaudio E. Role of follicle-stimulating hormone on biliary cyst growth in autosomal dominant polycystic kidney disease. Liver Int 2013; 33:914-25. [PMID: 23617956 PMCID: PMC4064944 DOI: 10.1111/liv.12177] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2012] [Accepted: 03/11/2013] [Indexed: 12/20/2022]
Abstract
BACKGROUND Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder characterized by the progressive development of renal and hepatic cysts. Follicle-stimulating hormone (FSH) has been demonstrated to be a trophic factor for biliary cells in normal rats and experimental cholestasis induced by bile duct ligation (BDL). AIMS To assess the effect of FSH on cholangiocyte proliferation during ADPKD using both in vivo and in vitro models. METHODS Evaluation of FSH receptor (FSHR), FSH, phospho-extracellular-regulated kinase (pERK) and c-myc expression in liver fragments from normal patients and patients with ADPKD. In vitro, we studied proliferating cell nuclear antigen (PCNA) and cAMP levels in a human immortalized, non-malignant cholangiocyte cell line (H69) and in an immortalized cell line obtained from the epithelium lining the hepatic cysts from the patients with ADPKD (LCDE) with or without transient silencing of the FSH gene. RESULTS Follicle-stimulating hormone is linked to the active proliferation of the cystic wall and to the localization of p-ERK and c-myc. This hormone sustains the biliary growth by activation of the cAMP/ERK signalling pathway. CONCLUSION These results showed that FSH has an important function in cystic growth acting on the cAMP pathway, demonstrating that it provides a target for medical therapy of hepatic cysts during ADPKD.
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Affiliation(s)
- Paolo Onori
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, University of Rome ‘Sapienza’, Rome, Italy
| | - Romina Mancinelli
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, University of Rome ‘Sapienza’, Rome, Italy
| | - Antonio Franchitto
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, University of Rome ‘Sapienza’, Rome, Italy,Eleonora Lorillard Spencer-Cenci Foundation, Rome, Italy
| | - Guido Carpino
- Department of Health Science, University of Rome ‘Foro Italico’, Rome, Italy
| | - Anastasia Renzi
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, University of Rome ‘Sapienza’, Rome, Italy
| | - Stefania Brozzetti
- Department of Surgical Sciences, University of Rome ‘Sapienza’, Rome, Italy
| | - Julie Venter
- Scott & White Digestive Disease Research Center, Central Texas Veterans Health Care System and Texas A&M Health Science Center, College of Medicine, Temple, TX, USA
| | - Heather Francis
- Scott & White Digestive Disease Research Center, Central Texas Veterans Health Care System and Texas A&M Health Science Center, College of Medicine, Temple, TX, USA
| | - Shannon Glaser
- Scott & White Digestive Disease Research Center, Central Texas Veterans Health Care System and Texas A&M Health Science Center, College of Medicine, Temple, TX, USA
| | | | - Gianfranco Alpini
- Scott & White Digestive Disease Research Center, Central Texas Veterans Health Care System and Texas A&M Health Science Center, College of Medicine, Temple, TX, USA
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, University of Rome ‘Sapienza’, Rome, Italy
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Sokolović A, Rodriguez-Ortigosa CM, Bloemendaal LT, Oude Elferink RPJ, Prieto J, Bosma PJ. Insulin-like growth factor 1 enhances bile-duct proliferation and fibrosis in Abcb4(-/-) mice. BIOCHIMICA ET BIOPHYSICA ACTA 2013; 1832:697-704. [PMID: 23416526 DOI: 10.1016/j.bbadis.2013.02.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/04/2012] [Revised: 01/21/2013] [Accepted: 02/06/2013] [Indexed: 12/20/2022]
Abstract
Adamant progression of chronic cholangiopathies towards cirrhosis and limited therapeutic options leave a liver transplantation the only effective treatment. Insulin-like growth factor 1 (IGF1) effectively blocks fibrosis in acute models of liver damage in mice, and a phase I clinical trial suggested an improved liver function. IGF1 targets the biliary epithelium, but its potential benefit in chronic cholangiopathies has not been studied. To investigate the possible therapeutic effect of increased IGF1 expression, we crossed Abcb4(-/-) mice (a model for chronic cholangiopathy), with transgenic animals that overexpress IGF1. The effect on disease progression was studied in the resulting IGF1-overexpressing Abcb4(-/-) mice, and compared to that of Abcb4(-/-) littermates. The specificity of this effect was further studied in an acute model of fibrosis. The overexpression of IGF1 in transgenic Abcb4(-/-) mice resulted in stimulation of fibrogenic processes - as shown by increased expression of Tgfß, and collagens 1, 3 and 4, and confirmed by Sirius red staining and hydroxyproline measurements. Excessive extracellular matrix deposition was favored by raise in Timp1 and Timp2, while a reduction of tPA expression indicated lower tissue remodeling. These effects were accompanied by an increase in expression of inflammation markers like Tnfα, and higher presence of infiltrating macrophages. Finally, increased number of Ck19-expressing cells indicated proliferation of biliary epithelium. In contrast to liver fibrosis associated with hepatocellular damage, IGF1 overexpression does not inhibit liver fibrogenesis in chronic cholangiopathy.
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Affiliation(s)
- Aleksandar Sokolović
- Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, The Netherlands.
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Chaudhary S, Qian Q. Acute abdomen and ascites as presenting features of autosomal dominant polycystic kidney disease. World J Hepatol 2012; 4:394-8. [PMID: 23355918 PMCID: PMC3554804 DOI: 10.4254/wjh.v4.i12.394] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2011] [Revised: 09/02/2012] [Accepted: 11/17/2012] [Indexed: 02/06/2023] Open
Abstract
We describe a patient with sudden onset of abdominal pain and ascites, leading to the diagnosis of autosomal dominant polycystic kidney disease (ADPKD). Her presentation was consistent with acute liver cyst rupture as the cause of her acute illness. A review of literature on polycystic liver disease in patients with ADPKD and current management strategies are presented. This case alerts physicians that ADPKD could occasionally present as an acute abdomen; cyst rupture related to ADPKD may be considered in the differential diagnoses of acute abdomen.
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Affiliation(s)
- Sanjay Chaudhary
- Sanjay Chaudhary, Qi Qian, Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, United States
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Huang P, Zhou Z, Wang H, Wei Q, Zhang L, Zhou X, Hutz RJ, Shi F. Effect of the IGF-1/PTEN/Akt/FoxO signaling pathway on the development and healing of water immersion and restraint stress-induced gastric ulcers in rats. Int J Mol Med 2012; 30:650-8. [PMID: 22735908 DOI: 10.3892/ijmm.2012.1041] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2012] [Accepted: 05/24/2012] [Indexed: 12/23/2022] Open
Abstract
Insulin-like growth factor 1 (IGF-1) and Akt [also known as protein kinase B (PKB)] proteins have been reported to exhibit gastroprotective effects by reducing water immersion and restraint stress (WRS)-induced gastric mucosal cellular apoptosis. To confirm whether the IGF-1/PTEN/Akt/FoxO signaling pathway is effective in protecting against gastric ulcers, our current study was conducted to examine the expression and localization of IGF-1, phosphatase and tensin homologue deleted on chromosome 10 (PTEN), Akt and O subfamily of forkhead box (FoxO) proteins, caspase-3 activity and the number of apoptotic cells in gastric mucosa of rats subjected to WRS. Our results demonstrated that WRS induced gastric ulcers by enhancing cell apoptosis in rat gastric mucosa. In addition, in normal rat gastric mucosa, PTEN, total Akt and FoxO1 were found mainly in the cell cytoplasm of fundic glands in the lamina propria close to the muscularis mucosa. In addition, strong staining of IGF-1, FoxO3a and FoxO4 in the gastric mucosa was primarily concentrated in the cell cytoplasm of the fundic glands in whole lamina propria. However, in rat gastric ulcers, IGF-1, total Akt, FoxO3a and FoxO4 were localized in proximity to the base of the ulcer margin and were also present in the granulation tissues of the gastric ulcers. Moreover, in the rat gastric ulcers, the mRNA transcript levels of IGF-1, PTEN, Akt-1, Akt-2, FoxO3 and FoxO4 were upregulated in the gastric ulcer margin, with a peak between Days 4 and 8 following 7 h of WRS. In conclusion, our results imply that the IGF-1/PTEN/Akt/FoxO signaling pathway plays a certain role(s) in the protection against ulceration through the regulation of cellular apoptosis as observed in the development and healing of rat gastric ulcers.
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Affiliation(s)
- Pan Huang
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, P.R. China
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Jensen K, Marzioni M, Munshi K, Afroze S, Alpini G, Glaser S. Autocrine regulation of biliary pathology by activated cholangiocytes. Am J Physiol Gastrointest Liver Physiol 2012; 302:G473-83. [PMID: 22194419 PMCID: PMC3774492 DOI: 10.1152/ajpgi.00482.2011] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2011] [Accepted: 12/21/2011] [Indexed: 01/31/2023]
Abstract
The bile duct system of the liver is lined by epithelial cells (i.e., cholangiocytes) that respond to a large number of neuroendocrine factors through alterations in their proliferative activities and the subsequent modification of the microenvironment. As such, activation of biliary proliferation compensates for the loss of cholangiocytes due to apoptosis and slows the progression of toxic injury and cholestasis. Over the course of the last three decades, much progress has been made in identifying the factors that trigger the biliary epithelium to remodel and grow. Because a large number of autocrine factors have recently been identified as relevant clinical targets, a compiled review of their contributions and function in cholestatic liver diseases would be beneficial. In this context, it is important to define the specific processes triggered by autocrine factors that promote cholangiocytes to proliferate, activate neighboring cells, and ultimately lead to extracellular matrix deposition. In this review, we discuss the role of each of the known autocrine factors with particular emphasis on proliferation and fibrogenesis. Because many of these molecules interact with one another throughout the progression of liver fibrosis, a model speculating their involvement in the progression of cholestatic liver disease is also presented.
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Affiliation(s)
- Kendal Jensen
- Scott & White Digestive Disease Research Center, TX, USA
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25
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Munshi MK, Priester S, Gaudio E, Yang F, Alpini G, Mancinelli R, Wise C, Meng F, Franchitto A, Onori P, Glaser SS. Regulation of biliary proliferation by neuroendocrine factors: implications for the pathogenesis of cholestatic liver diseases. THE AMERICAN JOURNAL OF PATHOLOGY 2011; 178:472-84. [PMID: 21281779 DOI: 10.1016/j.ajpath.2010.09.043] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/15/2010] [Revised: 08/23/2010] [Accepted: 09/02/2010] [Indexed: 12/15/2022]
Abstract
The proliferation of cholangiocytes occurs during the progression of cholestatic liver diseases and is critical for the maintenance and/or restoration of biliary mass during bile duct damage. The ability of cholangiocytes to proliferate is important in many different human pathologic conditions. Recent studies have brought to light the concept that proliferating cholangiocytes serve as a unique neuroendocrine compartment in the liver. During extrahepatic cholestasis and other pathologic conditions that trigger ductular reaction, proliferating cholangiocytes acquire a neuroendocrine phenotype. Cholangiocytes have the capacity to secrete and respond to a variety of hormones, neuropeptides, and neurotransmitters, regulating their surrounding cell functions and proliferative activity. In this review, we discuss the regulation of cholangiocyte growth by neuroendocrine factors in animal models of cholestasis and liver injury, which includes a discussion of the acquisition of neuroendocrine phenotypes by proliferating cholangiocytes and how this relates to cholangiopathies. We also review what is currently known about the neuroendocrine phenotypes of cholangiocytes in human cholestatic liver diseases (ie, cholangiopathies) that are characterized by ductular reaction.
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Penz-Österreicher M, Österreicher CH, Trauner M. Fibrosis in autoimmune and cholestatic liver disease. Best Pract Res Clin Gastroenterol 2011; 25:245-58. [PMID: 21497742 PMCID: PMC3134112 DOI: 10.1016/j.bpg.2011.02.001] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2011] [Accepted: 02/18/2011] [Indexed: 01/31/2023]
Abstract
Autoimmune and cholestatic liver disease account for a significant part of end-stage liver disease and are leading indications for liver transplantation. Especially cholestatic liver diseases (primary biliary cirrhosis and primary sclerosing cholangitis) appear to be different from other chronic liver diseases with regards to pathogenesis. Portal fibroblasts located in the connective tissue surrounding bile ducts appear to be different from hepatic stellate cells with regards to expression of marker proteins and response the profibrogenic and mitogenic stimuli. In addition there is increasing evidence for a cross talk between activated cholangiocytes and portal myofibroblasts. Several animal models have improved our understanding of the mechanisms underlying these chronic liver diseases. In the present review, we discuss the current concepts and ideas with regards to myofibroblastic cell populations, mechanisms of fibrosis, summarize characteristic histological findings and currently employed animal models of autoimmune and cholestatic liver disease.
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Affiliation(s)
- Melitta Penz-Österreicher
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria
| | - Christoph H. Österreicher
- Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria,Corresponding author. Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 43 18-20, A-1090 Vienna, Austria. Tel.: +43 140 400 4741; fax: +43 140 400 4735.
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Pancreatic Duodenal Homeobox-1 de novo expression drives cholangiocyte neuroendocrine-like transdifferentiation. J Hepatol 2010; 53:663-70. [PMID: 20621380 DOI: 10.1016/j.jhep.2010.04.022] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2009] [Revised: 04/10/2010] [Accepted: 04/12/2010] [Indexed: 12/25/2022]
Abstract
BACKGROUND & AIMS Reactive cholangiocytes acquire a neuroendocrine-like phenotype, with synthesis and local release of neuropeptides and hormones. The mechanism that drives such phenotypical changes is still undefined. Pancreatic Duodenal Homeobox-1 (PDX-1) is a transcription factor required for pancreatic development, that sustains pancreatic beta-cell response to injury and insulin synthesis. PDX-1 induces neuroendocrine-like transition of pancreatic ductal cells. Cholangiocyte response to injury is modulated by Glucagon-Like Peptide-1 Receptor (GLP-1R), which, in the pancreas, activates PDX-1. We wanted to verify whether PDX-1 plays any role in cholangiocyte neuroendocrine-like transdifferentiation in response to injury. METHODS PDX-1 expression was assessed in cholangiocytes from normal and one week bile duct ligated (BDL) rats. Changes in PDX-1 expression and activation upon GLP-1R activation were then assayed. The effects of the lack of PDX-1 in cholangiocytes were studied in vitro by siRNA and in vivo by the employment of PDX-1-deficient (+/-) mice. RESULTS BDL but not normal cholangiocytes express PDX-1. GLP-1R activation elicits, in a PI3K-dependent fashion, PDX-1 expression, together with its nuclear translocation. In vitro, GLP-1R-induced increases in VEGF and IGF-1 mRNA expression were blunted in cells with PDX-1 siRNA. In vivo, the VEGF and IGF-1 mRNA expression in the liver after one week BDL was markedly reduced in PDX-1-deficient mice, together with reduced bile duct mass. CONCLUSIONS In response to injury, reactive cholangiocytes de novo express PDX-1, the activation of which allows cholangiocytes to synthesize IGF-1 and VEGF. These findings suggest that PDX-1 drives the acquisition of the neuroendocrine-like phenotype by cholangiocytes in response to cholestatic injury.
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Mancinelli R, Onori P, DeMorrow S, Francis H, Glaser S, Franchitto A, Carpino G, Alpini G, Gaudio E. Role of sex hormones in the modulation of cholangiocyte function. World J Gastrointest Pathophysiol 2010; 1:50-62. [PMID: 21607142 PMCID: PMC3097944 DOI: 10.4291/wjgp.v1.i2.50] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2010] [Revised: 05/28/2010] [Accepted: 06/04/2010] [Indexed: 02/06/2023] Open
Abstract
Over the last years, cholangiocytes, the cells that line the biliary tree, have been considered an important object of study for their biological properties which involves bile formation, proliferation, injury repair, fibrosis and angiogenesis. Cholangiocyte proliferation occurs in all pathologic conditions of liver injury where it is associated with inflammation and regeneration. During these processes, biliary cells start to secrete different cytokines, growth factors, neuropeptides and hormones which represent potential mechanisms for cross talk with other liver cells. Several studies suggest that hormones, and in particular, sex hormones, play a fundamental role in the modulation of the growth of this compartment in the injured liver which functionally conditions the progression of liver disease. Understanding the mechanisms of action and the intracellular pathways of these compounds on cholangiocyte pathophysiology will provide new potential strategies for the management of chronic liver diseases. The purpose of this review is to summarize the recent findings on the role of sex hormones in cholangiocyte proliferation and biology.
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Spirli C, Okolicsanyi S, Fiorotto R, Fabris L, Cadamuro M, Lecchi S, Tian X, Somlo S, Strazzabosco M. Mammalian target of rapamycin regulates vascular endothelial growth factor-dependent liver cyst growth in polycystin-2-defective mice. Hepatology 2010; 51:1778-88. [PMID: 20131403 PMCID: PMC2930014 DOI: 10.1002/hep.23511] [Citation(s) in RCA: 70] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
UNLABELLED Polycystic liver disease may complicate autosomal dominant polycystic kidney disease (ADPKD), a disease caused by mutations in polycystins, which are proteins that regulate signaling, morphogenesis, and differentiation in epithelial cells. The cystic biliary epithelium [liver cystic epithelium (LCE)] secretes vascular endothelial growth factor (VEGF), which promotes liver cyst growth via autocrine and paracrine mechanisms. The expression of insulin-like growth factor 1 (IGF1), insulin-like growth factor 1 receptor (IGF1R), and phosphorylated mammalian target of rapamycin (p-mTOR) and the protein kinase A (PKA)-dependent phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) are also up-regulated in LCE. We have hypothesized that mammalian target of rapamycin (mTOR) represents a common pathway for the regulation of hypoxia-inducible factor 1 alpha (HIF1alpha)-dependent VEGF secretion by IGF1 and ERK1/2. Conditional polycystin-2-knockout (Pkd2KO) mice were used for in vivo studies and to isolate cystic cholangiocytes [liver cystic epithelial cells (LCECs)]. The expression of p-mTOR, VEGF, cleaved caspase 3 (CC3), proliferating cell nuclear antigen (PCNA), IGF1, IGF1R, phosphorylated extracellular signal-regulated kinase, p-P70S6K, HIF1alpha, and VEGF in LCE, LCECs, and wild-type cholangiocytes was studied with immunohistochemistry, western blotting, or enzyme-linked immunosorbent assays. The cystic area was measured by computer-assisted morphometry of pancytokeratin-stained sections. Cell proliferation in vitro was studied with 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium and bromodeoxyuridine assays. The treatment of Pkd2KO mice with the mTOR inhibitor rapamycin significantly reduced the liver cyst area, liver/body weight ratio, pericystic microvascular density, and PCNA expression while increasing expression of CC3. Rapamycin inhibited IGF1-stimulated HIF1alpha accumulation and VEGF secretion in LCECs. IGF1-stimulated LCEC proliferation was inhibited by rapamycin and SU5416 (a vascular endothelial growth factor receptor 2 inhibitor). Phosphorylation of the mTOR-dependent kinase P70S6K was significantly reduced by PKA inhibitor 14-22 amide and by the mitogen signal-regulated kinase inhibitor U1026. CONCLUSION These data demonstrate that PKA-dependent up-regulation of mTOR has a central role in the proliferative, antiapoptotic, and pro-angiogenic effects of IGF1 and VEGF in polycystin-2-defective mice. This study also highlights a mechanistic link between PKA, ERK, mTOR, and HIF1alpha-mediated VEGF secretion and provides a proof of concept for the potential use of mTOR inhibitors in ADPKD and conditions with aberrant cholangiocyte proliferation.
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Affiliation(s)
- Carlo Spirli
- Dept. of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven Connecticut, USA.,Center for Liver Research (CeLiveR), Ospedali Riuniti di Bergamo, Bergamo, Italy
| | - Stefano Okolicsanyi
- Dept. of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven Connecticut, USA.,Center for Liver Research (CeLiveR), Ospedali Riuniti di Bergamo, Bergamo, Italy
| | - Romina Fiorotto
- Dept. of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven Connecticut, USA.,Center for Liver Research (CeLiveR), Ospedali Riuniti di Bergamo, Bergamo, Italy
| | - Luca Fabris
- Center for Liver Research (CeLiveR), Ospedali Riuniti di Bergamo, Bergamo, Italy
| | | | - Silvia Lecchi
- Dept. of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven Connecticut, USA.,Center for Liver Research (CeLiveR), Ospedali Riuniti di Bergamo, Bergamo, Italy
| | - Xin Tian
- Dept. of Internal Medicine, Section of Nephrology, Yale University, New Haven Connecticut, USA
| | - Stefan Somlo
- Dept. of Internal Medicine, Section of Nephrology, Yale University, New Haven Connecticut, USA
| | - Mario Strazzabosco
- Dept. of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven Connecticut, USA.,Center for Liver Research (CeLiveR), Ospedali Riuniti di Bergamo, Bergamo, Italy.,Dept. of Clinical Medicine and Prevention, University of Milano-Bicocca, Milan, Italy
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Torrice A, Cardinale V, Gatto M, Semeraro R, Napoli C, Onori P, Alpini G, Gaudio E, Alvaro D. Polycystins play a key role in the modulation of cholangiocyte proliferation. Dig Liver Dis 2010; 42:377-85. [PMID: 19897428 DOI: 10.1016/j.dld.2009.09.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2009] [Revised: 09/13/2009] [Accepted: 09/20/2009] [Indexed: 12/11/2022]
Abstract
BACKGROUND Polycystin-1 and -2 (PC-1 and PC-2) are critical components of primary cilia, which act as mechanosensors and drive cell response to injury. PC-1 activation involves the cleavage/processing of PC-1 cytoplasmic tail, driven by regulated intramembrane proteolysis or ubiquitine/proteasome, translocation in the nucleus and activation of transcription factors. Mutations of PC-1 or PC-2 occur in polycystic liver where cholangiocyte proliferation is enhanced. AIM We evaluated the involvement of PC-1 and PC-2 in modulating cholangiocyte proliferation. METHODS We investigated rat cholangiocytes induced to proliferate by 17beta-oestradiol. Proliferation was evaluated by PCNA immunoblotting or [(3)H]-thymidine incorporation into DNA. PC-1 silencing was performed by siRNA, while inhibition of regulated intramembrane proteolysis or proteasome by gamma-secretase inhibitor, leupeptin or MG115. RESULTS Cholangiocyte proliferation was associated with decreased PC-1 and PC-2 expression, which was inversely correlated with enhanced PCNA. The selective silencing of PC-1 induced activation of cholangiocyte proliferation in association with decreased PC-1 expression. Two different regulated intramembrane proteolysis inhibitors, gamma-secretase-inhibitor and leupeptin, and the proteasome inhibitor, MG115, abolished the 17beta-oestradiol proliferative effect. CONCLUSIONS PC-1 and PC-2 play a major role as modulators of cholangiocyte proliferation suggesting that primary cilia may act as sensors of cell injury driving, when activated, a proliferative cholangiocyte response to trigger the reparative processes.
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Affiliation(s)
- Alessia Torrice
- Division of Gastroenterology, University of Rome, Sapienza, Rome, Italy
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Clinical implications of novel aspects of biliary pathophysiology. Dig Liver Dis 2010; 42:238-44. [PMID: 20167547 DOI: 10.1016/j.dld.2010.01.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2009] [Revised: 01/11/2010] [Accepted: 01/11/2010] [Indexed: 12/11/2022]
Abstract
Cholangiocytes are the epithelial cells that line the biliary tree; they are the target of chronic diseases termed cholangiopathies, which represent a daily challenge for clinicians, since definitive medical treatments are not available yet. It is generally accepted that the progression of injury in the course of cholangiopathies, and promotion and progression of cholangiocarcinoma are at least in part due to the failure of the cholangiocytes' mechanisms of adaptation to injury. Recently, several studies on the pathophysiology of the biliary epithelium have shed some light on the mechanisms that govern cholangiocyte response to injury. These studies provide novel information to help interpret some of the clinical aspects of cholangiopathies and cholangiocarcinoma; the purpose of this review is thus to describe some of these novel findings, focusing on their significance from a clinical perspective.
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Onori P, Franchitto A, Mancinelli R, Carpino G, Alvaro D, Francis H, Alpini G, Gaudio E. Polycystic liver diseases. Dig Liver Dis 2010; 42:261-71. [PMID: 20138815 PMCID: PMC2894157 DOI: 10.1016/j.dld.2010.01.006] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2009] [Revised: 01/07/2010] [Accepted: 01/07/2010] [Indexed: 12/11/2022]
Abstract
Polycystic liver diseases (PCLDs) are genetic disorders with heterogeneous etiologies and a range of phenotypic presentations. PCLD exhibits both autosomal or recessive dominant pattern of inheritance and is characterized by the progressive development of multiple cysts, isolated or associated with polycystic kidney disease, that appear more extensive in women. Cholangiocytes have primary cilia, functionally important organelles (act as mechanosensors) that are involved in both normal developmental and pathological processes. The absence of polycystin-1, 2, and fibrocystin/polyductin, normally localized to primary cilia, represent a potential mechanism leading to cyst formation, associated with increased cell proliferation and apoptosis, enhanced fluid secretion, abnormal cell-matrix interactions, and alterations in cell polarity. Proliferative and secretive activities of cystic epithelium can be regulated by estrogens either directly or by synergizing growth factors including nerve growth factor, IGF1, FSH and VEGF. The abnormalities of primary cilia and the sensitivity to proliferative effects of estrogens and different growth factors in PCLD cystic epithelium provide the morpho-functional basis for future treatment targets, based on the possible modulation of the formation and progression of hepatic cysts.
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Affiliation(s)
- P. Onori
- Experimental Medicine, University of L'Aquila, L'Aquila, Italy
| | - A. Franchitto
- Dept Human Anatomy, University of Rome “La Sapienza”, Rome, Italy
| | - R. Mancinelli
- Dept Human Anatomy, University of Rome “La Sapienza”, Rome, Italy
| | - G. Carpino
- Dept Health Science, University of Rome “Foro Italico”, Italy
| | - D. Alvaro
- Gastroenterology, Polo Pontino, University of Rome “La Sapienza”, Rome, Italy
| | - H. Francis
- Research, Central Texas Veterans Health Care System, USA
| | - G. Alpini
- Research, Central Texas Veterans Health Care System, USA, Scott & White Digestive Disease Research Center, Texas A&M Health Science Center, College of Medicine, USA
| | - E. Gaudio
- Dept Human Anatomy, University of Rome “La Sapienza”, Rome, Italy, Corresponding author. Tel.: +39 0649918060; fax: +39 0649918062. (E. Gaudio)
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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] [Track Full Text] [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,* Corresponding author at: Digestive Disease Research Center, Texas A&M Health Science Center, 702 SW H.K. Dodgen Loop, Temple, TX 76504, United States. Tel.: +1 254 742 7058; fax: +1 254 724 5944. ** Corresponding author at: Department of Human Anatomy, University of Rome “La Sapienza”, Via Alfonso Borelli 50 00161 Rome, Rome 00161, Italy. Tel.: +39 06 4991 8060; fax: +39 06 4991 8062
| | - 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,* Corresponding author at: Digestive Disease Research Center, Texas A&M Health Science Center, 702 SW H.K. Dodgen Loop, Temple, TX 76504, United States. Tel.: +1 254 742 7058; fax: +1 254 724 5944. ** Corresponding author at: Department of Human Anatomy, University of Rome “La Sapienza”, Via Alfonso Borelli 50 00161 Rome, Rome 00161, Italy. Tel.: +39 06 4991 8060; fax: +39 06 4991 8062
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Wang Z, Zhou J, Lin J, Wang Y, Lin Y, Li X. RhGH attenuates ischemia injury of intrahepatic bile ducts relating to liver transplantation. J Surg Res 2010; 171:300-10. [PMID: 20462597 DOI: 10.1016/j.jss.2010.02.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2009] [Revised: 12/29/2009] [Accepted: 02/04/2010] [Indexed: 12/22/2022]
Abstract
BACKGROUND To study the effect of rhGH administration on intrahepatic cholangiocytes relating to liver transplantation with ischemia of hepatic artery, and ultimately, clarify pathologic mechanism of the injury. METHODS Rat orthotopic autologous liver transplantation was performed first. Three hours later, the rats were grouped as followed: HAL (hepatic artery ligation) group; HAL + rhGH (hepatic artery ligation followed by rhGH administration) group; CON (without hepatic artery ligation) group. Specimen was collected after 7 d. ALT and ALP of serum were measured. The pathologic changes of bile ducts of liver tissue were observed. The number of bile ducts and blood vessels in portal area were counted. Immunochemistry for VEGF, VEGFR-2, VEGFR-3, GHR, and IGF-1R of intrahepatic cholangiocytes was performed. Cholangiocytes apoptosis was evaluated by TUNEL analysis. Cholangiocytes proliferation was evaluated by PCNA immunolabeling. RESULTS ALT and ALP of HAL + rhGH group were significantly ameliorated compared with untreated animals (P < 0.05). ALT and ALP of HAL group were significantly higher compared with CON group (P < 0.05). In HAL group, the main injury of bile ducts was not reversible, whereas it was reversible in CON and rhGH groups. In HAL group, the number of bile ducts in portal area decreased, while the number of bile ducts not accompanying blood vessels increased (P < 0.05). In rhGH group, the number of bile ducts in portal area increased, while the number of bile ducts accompanying blood vessels increased compared with HAL group (P < 0.05). The expression of VEGF, VEGFR-2, VEGFR-3, GHR, and IGF-1R was significantly lower in HAL group than in CON group (P < 0.05). Following administration of rhGH to HAL rats, the expression of VEGF, VEGFR-2, VEGFR-3, IGF-1R, and GHR was significantly higher (P < 0.05). Administration of rhGH prevented increase in cholangiocytes apoptosis induced by HAL (P < 0.05). Administration of rhGH promoted increase in cholangiocytes proliferation held by HAL (P < 0.05). CONCLUSIONS Administration of rhGH appears to attenuate ischemia injury of intrahepatic bile ducts relating to liver transplantation. This function is partly related to the capacity that rhGH inhibits the apoptosis of intrahepatic cholangiocytes and prompts the proliferation and angiogenesis by increasing the expression of VEGF, VEGFR2, VEGFR3, GHR, and IGF1-R.
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Affiliation(s)
- Zheng Wang
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
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36
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Qian Q. Isolated polycystic liver disease. Adv Chronic Kidney Dis 2010; 17:181-9. [PMID: 20219621 DOI: 10.1053/j.ackd.2009.12.005] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2009] [Revised: 12/31/2009] [Accepted: 12/31/2009] [Indexed: 12/11/2022]
Abstract
Isolated polycystic liver disease (PCLD) is an autosomal dominant disease with genetic and clinical heterogeneity. Apart from liver cysts, it exhibits few extrahepatic manifestations, and the majority of patients with this condition are asymptomatic or subclinical. However, a small fraction of these patients develop acute liver cyst-related complications and/or massive cystic liver enlargement, causing morbidity and mortality. Currently, the management for symptomatic PCLD is centered on palliating symptoms and treating complications.
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Lemaigre FP. Molecular mechanisms of biliary development. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2010; 97:103-26. [PMID: 21074731 DOI: 10.1016/b978-0-12-385233-5.00004-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The biliary tree drains the bile produced by hepatocytes to the duodenum via a network of intrahepatic and extrahepatic ducts. In the embryo, the intrahepatic ducts are formed near the branches of the portal vein and derive from the liver precursor cells of the hepatic bud, whereas the extrahepatic ducts directly emerge from the primitive gut. Despite this dual origin, intrahepatic and extrahepatic ducts are lined by a common cell type, the cholangiocyte. In this chapter, we describe how bile ducts are formed and cholangiocytes differentiate, and focus on the regulation of these processes by intercellular signaling pathways and by transcriptional and posttranscriptional mechanisms.
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Cadoret A, Rey C, Wendum D, Elriz K, Tronche F, Holzenberger M, Housset C. IGF-1R contributes to stress-induced hepatocellular damage in experimental cholestasis. THE AMERICAN JOURNAL OF PATHOLOGY 2009; 175:627-35. [PMID: 19628767 PMCID: PMC2716962 DOI: 10.2353/ajpath.2009.081081] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 05/05/2009] [Indexed: 12/19/2022]
Abstract
The insulin-like growth factor type 1 receptor (IGF-1R) controls aging and cellular stress, both of which play major roles in liver disease. Stimulation of insulin-like growth factor signaling can generate cell death in vitro. Here, we tested whether IGF-1R contributes to stress insult in the liver. Cholestatic liver injury was induced by bile duct ligation in control and liver-specific IGF-1R knockout (LIGFREKO) mice. LIGFREKO mice displayed less bile duct ligation-induced hepatocyte damage than controls, while no differences in bile acid serum levels or better adaptation to cholestasis by efflux transporters were found. We therefore tested whether stress pathways contributed to this phenomenon; oxidative stress, ascertained by both malondialdehyde content and heme oxygenase-1 expression, was similar in knockout and control animals. However, together with a lower level of eukaryotic initiation factor-2 alpha phosphorylation, the endoplasmic reticulum stress protein CHOP and its downstream pro-apoptotic target Bax were induced to lesser extents in LIGFREKO mice than in controls. Expression levels of cytokeratin 19, transforming growth factor-beta1, alpha-smooth muscle actin, and collagen alpha1(I) in LIGFREKO mice were all lower than in controls, indicating reduced ductular and fibrogenic responses and increased cholestasis tolerance in these mutants. This stress resistance phenotype was also evidenced by longer post-bile duct ligation survival in mutants than controls. These results indicate that IGF-1R contributes to cholestatic liver injury, and suggests the involvement of both CHOP and Bax in this process.
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Affiliation(s)
- Axelle Cadoret
- Inserm UMR_S 938, CdR Saint-Antoine, Faculté de Médecine Pierre et Marie Curie, Site Saint-Antoine, 27 rue Chaligny, 75012 Paris, France
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Pereira FA, Facincani I, Jorgetti V, Ramalho LNZ, Volpon JB, Dos Reis LM, de Paula FJA. Etiopathogenesis of hepatic osteodystrophy in Wistar rats with cholestatic liver disease. Calcif Tissue Int 2009; 85:75-83. [PMID: 19424739 DOI: 10.1007/s00223-009-9249-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2009] [Accepted: 03/31/2009] [Indexed: 12/13/2022]
Abstract
The pathophysiology of hepatic osteodystrophy (HO) remains poorly understood. Our aim was to evaluate bone histomorphometry, biomechanical properties, and the role of the growth hormone (GH)/insulin-like growth factor-I (IGF-I) system in the onset of this disorder. Forty-six male Wistar rats were divided into two groups: sham-operated (SO, n = 23) and bile duct-ligated (BDL, n = 23). Rats were killed on day 30 postoperatively. Immunohistochemical expression of IGF-I and GH receptor was determined in liver tissue and in the proximal growth plate cartilage of the left tibia. Histomorphometric analysis was performed in the right tibia, and the right femur was used for biomechanical analysis. The maximal force at fracture and the stiffness of the mid-shaft femur were, respectively, 53% and 24% lower in BDL compared to SO. Histomorphometric measurements showed low cancellous bone volume and decreased cancellous bone connectivity in BDL, compatible with osteoporosis. This group also showed increased mineralization lag time, indicating disturbance in bone mineralization. Serum levels of IGF-I were lower in BDL (basal 1,816 +/- 336 vs. 30 days 1,062 +/- 191 ng/ml, P < 0.0001). BDL also showed higher IGF-I expression in the liver tissue but lower IGF-I and GH receptor expression in growth plate cartilage than SO. Osteoporosis is the most important feature of HO; BDL rats show striking signs of reduced bone volume and decreased bone strength, as early as after 1 month of cholestasis. The endocrine and autocrine-paracrine IGF-I systems are deeply affected by cholestasis. Further studies will be necessary to establish their role in the pathogenesis of HO.
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Affiliation(s)
- F A Pereira
- Department of Internal Medicine, School of Medicine of Ribeirão Preto, University of São Paulo, Av. Bandeirantes 3900, Ribeirão Preto, SP, Brazil
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Abstract
Cholangiocyte proliferation is triggered during extrahepatic bile duct obstruction induced by bile duct ligation, which is a common in vivo model used for the study of cholangiocyte proliferation and liver fibrosis. The proliferative response of cholangiocytes during cholestasis is regulated by the complex interaction of several factors, including gastrointestinal hormones, neuroendocrine hormones and autocrine or paracrine signalling mechanisms. Activation of biliary proliferation (ductular reaction) is thought to have a key role in the initiation and progression of liver fibrosis. The first part of this review provides an overview of the primary functions of cholangiocytes in terms of secretin-stimulated bicarbonate secretion--a functional index of cholangiocyte growth. In the second section, we explore the important regulators, both inhibitory and stimulatory, that regulate the cholangiocyte proliferative response during cholestasis. We discuss the role of proliferating cholangiocytes in the induction of fibrosis either directly via epithelial mesenchymal transition or indirectly via the activation of other liver cell types. The possibility of targeting cholangiocyte proliferation as potential therapy for reducing and/or preventing liver fibrosis, and future avenues for research into how cholangiocytes participate in the process of liver fibrogenesis are described.
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Marzioni M, Fava G, Alvaro D, Alpini G, Benedetti A. Control of cholangiocyte adaptive responses by visceral hormones and neuropeptides. Clin Rev Allergy Immunol 2009; 36:13-22. [PMID: 18548352 PMCID: PMC2628969 DOI: 10.1007/s12016-008-8090-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Cholangiocytes, the epithelial cells lining the biliary tree, are the target cells in several liver diseases, termed cholangiopathies. Cholangiopathies are a challenge for clinicians and an enigma for scientists, as the pathogenetic mechanisms by which they develop, and the therapeutic tools for these diseases are still undefined. Several studies demonstrate that many visceral hormones, neuropeptides, and neurotransmitters modulate the adaptive changes of cholangiocytes to chronic cholestatic injury. The aim of this review is to present the recent findings that contributed to clarify the role of visceral hormones and neuropeptides in the regulation of the pathophysiology of cholestasis. These studies helped to shed light on some aspects of cholangiocyte pathophysiology, revealing novel perspectives for the clinical managements of cholangiopathies.
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Affiliation(s)
- Marco Marzioni
- Department of Gastroenterology, Università Politecnica delle Miarche, Nuovo Polo Didattico, III piano, Via Tronto 10, 60020, Ancona, Italy.
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Repression of CFTR activity in human MMNK-1 cholangiocytes induces sulfotransferase 1E1 expression in co-cultured HepG2 hepatocytes. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2008; 1783:2391-7. [PMID: 18817817 DOI: 10.1016/j.bbamcr.2008.08.012] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/22/2008] [Revised: 08/22/2008] [Accepted: 08/25/2008] [Indexed: 11/22/2022]
Abstract
Mouse models of cystic fibrosis (CF) indicate that sulfotransferase (SULT) 1E1 is significantly induced in livers of many mice lacking cystic fibrosis transmembrane receptor (CFTR) activity. Increased SULT1E1 activity results in the alteration of estrogen-regulated protein expression in the livers of these mice. In this study, human MMNK-1 cholangiocytes with repressed CFTR function were used to induce SULT1E1 expression in human HepG2 hepatocytes to investigate whether SULT1E1 can be increased in human CF liver. CFTR expression was inhibited in MMNK-1 cholangiocytes using CFTR-siRNA, then the MMNK-1 and HepG2 cells were co-cultured in a membrane-separated Transwell system. Expression of SULT1E1 and selected estrogen-regulated proteins were then assayed in the HepG2 cells. Results demonstrate that inhibition of CFTR expression in MMNK-1 cells results in the induction of SULT1E1 message and activity in HepG2 cells in the Transwell system. The expression of estrogen-regulated proteins including insulin-like growth factor (IGF)-1, glutathione-S-transferase (GST) P1 and carbonic anhydrase (CA) II expression are repressed in the HepG2 cells cultured with the CFTR-siRNA-MMNK-1 cells apparently in response to the increased sulfation of beta-estradiol. Thus, we have shown that co-culture of HepG2 hepatocytes with MMNK-1 cholangiocytes with siRNA repressed CFTR expression results in the selective induction of SULT1E1 in the HepG2 cells. Loss of CFTR function in cholangiocytes may have a paracrine regulatory effect on hepatocytes via the induction of SULT1E1 and the increased sulfation of beta-estradiol. Experiments are presently underway in our laboratory to elucidate the identity of these paracrine regulatory factors.
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Svegliati-Baroni G, De Minicis S, Marzioni M. Hepatic fibrogenesis in response to chronic liver injury: novel insights on the role of cell-to-cell interaction and transition. Liver Int 2008; 28:1052-64. [PMID: 18783548 DOI: 10.1111/j.1478-3231.2008.01825.x] [Citation(s) in RCA: 84] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
Hepatic fibrosis represents the wound-healing response process of the liver to chronic injury, independently from aetiology. Advanced liver fibrosis results in cirrhosis that can lead to liver failure, portal hypertension and hepatocellular carcinoma. Currently, no effective therapies are available for hepatic fibrosis. After the definition of hepatic stellate cells (HSCs) as the main liver extracellular matrix-producing cells in the 1980s, the subsequent decade was dedicated to determine the role of specific cytokines and growth factors. Fibrotic progression of chronic liver diseases can be nowadays considered as a dynamic and highly integrated process of cellular response to chronic liver injury. The present review is dedicated to the novel mechanisms of cellular response to chronic liver injury leading to hepatic myofibroblasts' activation. The understanding of the cellular and molecular pathways regulating their function is crucial to counteract therapeutically the organ dysfunction caused by myofibroblasts' activation.
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Affiliation(s)
- Gianluca Svegliati-Baroni
- Department of Gastroenterology, Università Politecnica delle Marche and Ospedali Riuniti University Hospital, Ancona, Italy.
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Insulin-like growth factor-1 isoforms in rat hepatocytes and cholangiocytes and their involvement in protection against cholestatic injury. J Transl Med 2008; 88:986-94. [PMID: 18607346 PMCID: PMC2569860 DOI: 10.1038/labinvest.2008.63] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
A 'locally acting' IGF1 (insulin-like growth factor 1) isoform has been recently identified in the skeletal muscle and neural tissues where it accelerates injury repair. No information exist on the expression and function of IGF1 isoforms in the liver. We investigated IGF1 isoforms in rat hepatocytes and cholangiocytes and evaluated their involvement in cell proliferation or damage induced by experimental cholestasis (bile duct ligation, BDL) or hydrophobic bile salts. IGF1 isoforms were analyzed by real-time PCR by using beta-actin as internal reference. In both hepatocytes and cholangiocytes, the 'locally acting' IGF1 isoform (XO6108) and 'circulating' IGF1 isoform (NM_178866) represented respectively 44 and 52% of the total IGF1. Basal mRNAs for both 'locally acting' and 'circulating' IGF1 isoforms were higher (P<0.05) in hepatocytes than cholangiocytes. After BDL for 3 h, the 'locally acting' IGF1 isoform decreased threefold (P<0.05) in hepatocytes but remained stable in cholangiocytes with respect to sham-controls. After 1 week of BDL, hepatocytes displayed a further fivefold decrease of 'locally acting' IGF1 mRNA. In contrast, cholangiocytes showed an eightfold increase of the 'locally acting' IGF1 mRNA. The effect of 3 h of BDL on IGF1 isoforms was reproduced in vitro by incubation with glycochenodeoxycholate (GCDC). The cytotoxic effects (inhibition of proliferation and induction of apoptosis) of GCDC on isolated cholangiocytes were more pronounced after selective silencing (SiRNA) of 'locally acting' than 'circulating' IGF1 isoform. Rat hepatocytes and cholangiocytes express the 'locally acting' IGF1 isoform, which decreased during cell damage and increased during cell proliferation. The 'locally acting' IGF1 was more active than the 'circulating' isoform in protecting cholangiocytes from GCDC-induced cytotoxicity. These findings indicate that, besides muscle and neural tissues, also in liver cells the 'locally acting' IGF1 isoform is important in modulating response to damage.
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Wang M, Chen M, Zheng G, Dillard B, Tallarico M, Ortiz Z, Holterman AX. Transcriptional activation by growth hormone of HNF-6-regulated hepatic genes, a potential mechanism for improved liver repair during biliary injury in mice. Am J Physiol Gastrointest Liver Physiol 2008; 295:G357-66. [PMID: 18511741 PMCID: PMC2519853 DOI: 10.1152/ajpgi.00581.2007] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Growth hormone (GH) function is mediated through multiple endocrine pathways. In the liver, GH also transcriptionally activates hepatocyte nuclear factor-6 (HNF-6; OC-1), a liver-enriched transcription factor that regulates the expression of genes essential to hepatic function. We hypothesize that GH modulates hepatic function in the normal and injured liver through HNF-6 and HNF-6 target genes. CD1 mice received PBS or GH for the 1-, 7-, and 28-day course of Sham operation or bile duct ligation (BDL). Proliferation-, metabolic-, and profibrotic-specific hepatic functions were assessed with a focus on candidate HNF-6 transcriptional target genes. Confirmation of HNF-6 regulation was done by analysis of target gene expression in liver infected with recombinant adenovirus AdHNF-6 expression vectors. GH administration upregulated HNF-6 expression throughout the course of liver injury. This was associated with increased expression of HNF-6 proliferative target genes cyclin D1 and metabolic gene Cyp7A1 and downregulation of profibrogenic TGFb2R. Hepatic function improved such as enhanced hepatocyte proliferation, higher cholesterol clearance throughout the course of injury, and attenuated fibrogenic response at day 28 of BDL. GH treatment also transcriptionally increased albumin expression in an HNF-6-independent manner. This was associated with enhanced serum albumin levels. In conclusion, the GH/HNF-6 axis is a potential in vivo mechanism underlying GH diverse function in the liver to modulate the liver repair response to BDL.
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Affiliation(s)
- Minhua Wang
- Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago and Department of Surgery/Pediatric Surgery, Rush University Medical Center, Chicago, Illinois
| | - Michael Chen
- Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago and Department of Surgery/Pediatric Surgery, Rush University Medical Center, Chicago, Illinois
| | - Guoqiang Zheng
- Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago and Department of Surgery/Pediatric Surgery, Rush University Medical Center, Chicago, Illinois
| | - Barney Dillard
- Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago and Department of Surgery/Pediatric Surgery, Rush University Medical Center, Chicago, Illinois
| | - Mike Tallarico
- Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago and Department of Surgery/Pediatric Surgery, Rush University Medical Center, Chicago, Illinois
| | - Zorayda Ortiz
- Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago and Department of Surgery/Pediatric Surgery, Rush University Medical Center, Chicago, Illinois
| | - Ai-Xuan Holterman
- Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago and Department of Surgery/Pediatric Surgery, Rush University Medical Center, Chicago, Illinois
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Glaser S, DeMorrow S, Francis H, Ueno Y, Gaudio E, Vaculin S, Venter J, Franchitto A, Onori P, Vaculin B, Marzioni M, Wise C, Pilanthananond M, Savage J, Pierce L, Mancinelli R, Alpini G. Progesterone stimulates the proliferation of female and male cholangiocytes via autocrine/paracrine mechanisms. Am J Physiol Gastrointest Liver Physiol 2008; 295:G124-G136. [PMID: 18511743 PMCID: PMC2494724 DOI: 10.1152/ajpgi.00536.2007] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2007] [Accepted: 05/22/2008] [Indexed: 01/31/2023]
Abstract
During cholestatic liver diseases, cholangiocytes express neuroendocrine phenotypes and respond to a number of hormones and neuropeptides by paracrine and autocrine mechanisms. We examined whether the neuroendocrine hormone progesterone is produced by and targeted to cholangiocytes, thereby regulating biliary proliferation during cholestasis. Nuclear (PR-A and PR-B) and membrane (PRGMC1, PRGMC2, and mPRalpha) progesterone receptor expression was evaluated in liver sections and cholangiocytes from normal and bile duct ligation (BDL) rats, and NRC cells (normal rat cholangiocyte line). In vivo, normal rats were chronically treated with progesterone for 1 wk, or immediately after BDL, rats were treated with a neutralizing progesterone antibody for 1 wk. Cholangiocyte growth was measured by evaluating the number of bile ducts in liver sections. The expression of the progesterone synthesis pathway was evaluated in liver sections, cholangiocytes and NRC. Progesterone secretion was evaluated in supernatants from normal and BDL cholangiocytes and NRC. In vitro, NRC were stimulated with progesterone and cholangiocyte supernatants in the presence or absence of antiprogesterone antibody. Aminoglutethimide was used to block progesterone synthesis. Cholangiocytes and NRC express the PR-B nuclear receptor and PRGMC1, PRGMC2, and mPRalpha. In vivo, progesterone increased the number of bile ducts of normal rats, whereas antiprogesterone antibody inhibited cholangiocyte growth stimulated by BDL. Normal and BDL cholangiocytes expressed the biosynthetic pathway for and secrete progesterone. In vitro, 1) progesterone increased NRC proliferation; 2) cholangiocyte supernatants increased NRC proliferation, which was partially inhibited by preincubation with antiprogesterone; and 3) inhibition of progesterone steroidogenesis prevented NRC proliferation. In conclusion, progesterone may be an important autocrine/paracrine regulator of cholangiocyte proliferation.
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Affiliation(s)
- Shannon Glaser
- Department of Medicine, Scott & White Hospital and Texas A&M University System Health Science Center, College of Medicine, Temple, Texas 76504, USA.
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Alvaro D, Onori P, Alpini G, Franchitto A, Jefferson DM, Torrice A, Cardinale V, Stefanelli F, Mancino MG, Strazzabosco M, Angelico M, Attili A, Gaudio E. Morphological and functional features of hepatic cyst epithelium in autosomal dominant polycystic kidney disease. THE AMERICAN JOURNAL OF PATHOLOGY 2008; 172:321-32. [PMID: 18202196 DOI: 10.2353/ajpath.2008.070293] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
We evaluated the morphological and functional features of hepatic cyst epithelium in adult autosomal dominant polycystic kidney disease (ADPKD). In six ADPKD patients, we investigated the morphology of cyst epithelium apical surface by scanning electron microscopy and the expression of estrogen receptors (ERs), insulin-like growth factor 1 (IGF1), IGF1 receptors (IGF1-R), growth hormone receptor, the proliferation marker proliferating cell nuclear antigen, and pAKT by immunohistochemistry and immunofluorescence. Proliferation of liver cyst-derived epithelial cells was evaluated by both MTS proliferation assay and [(3)H]thymidine incorporation into DNA. The hepatic cyst epithelium displayed heterogeneous features, being normal in small cysts (<1 cm), characterized by rare or shortened cilia in 1- to 3-cm cysts, and exhibiting the absence of both primary cilia and microvilli in large cysts (>3 cm). Cyst epithelium showed marked immunohistochemical expression of ER, growth hormone receptor, IGF1, IGF1-R, proliferating cell nuclear antigen, and pAKT. IGF1 was 10-fold more enriched in the hepatic cyst fluid than in serum. Serum-deprived liver cyst-derived epithelial cells proliferated when exposed to 17beta-estradiol and IGF1 and when exposed to human cyst fluid. ER or IGF1-R antagonists inhibited the proliferative effect of serum readmission, cyst fluid, 17beta-estradiol, and IGF1. Our findings could explain the role of estrogens in accelerating the progression of ADPKD and may suggest a potential benefit of therapeutic strategies based on estrogen antagonism.
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Affiliation(s)
- Domenico Alvaro
- Department of Clinical Medicine, University of Rome Sapienza, via R. Rossellini 51, 00137 Rome, Italy. domenico.alvaro@uniroma1
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Smirnova OV, Ostroukhova TY, Bogorad RL. JAK-STAT pathway in carcinogenesis: Is it relevant to cholangiocarcinoma progression. World J Gastroenterol 2007; 13:6478-91. [PMID: 18161917 PMCID: PMC4611286 DOI: 10.3748/wjg.v13.i48.6478] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The features of JAK-STAT signaling in liver cells are discussed in the current review. The role of this signaling cascade in carcinogenesis is accentuated. The possible involvement of this pathway and alteration of its elements are compared for normal cholangiocytes, cholangiocarcinoma predisposition and development. Prolactin and interleukin-6 are described in detail as the best studied examples. In addition, the non-classical nuclear translocation of cytokine receptors is discussed in terms of its possible implication to cholangiocarcinoma development.
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Tanaka A, Tsuneyama K, Mikami M, Uegaki S, Aiso M, Takikawa H. Gene expression profiling in whole liver of bile duct ligated rats: VEGF-A expression is up-regulated in hepatocytes adjacent to the portal tracts. J Gastroenterol Hepatol 2007; 22:1993-2000. [PMID: 17914982 DOI: 10.1111/j.1440-1746.2006.04629.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
BACKGROUND AND AIM It would be of clinical importance to clarify molecular mechanisms of cholangiocytes proliferation for the treatment of intractable cholestatic diseases. The aim of this study was to elucidate gene expression profiling in the whole liver of bile duct ligated (BDL) rats using microarray analysis. In addition, the localization and time course of up-regulated expression of vascular endothelial growth factor (VEGF) was investigated. METHODS Male Sprague-Dawley rats were used. The whole liver was removed from BDL and sham-operated rats at day 2 after the procedure, and microarray analysis was performed using an array on which 3757 rat cDNA clones spotted. The up-regulation of VEGF expression was investigated by RT-PCR using livers at day 1, 2, 4 and 7, and immunoblotting and immunohistochemistry at day 2. RESULTS Marked proliferation of bile ducts was observed in livers of BDL rats. By microarray analysis, 38 up-regulated and 17 down-regulated transcripts were detected in whole liver of the BDL rat. The expression of VEGF-A was significantly elevated in the BDL rats at day 2; the VEGF-A/GAPDH ratio was 4.030 +/- 2.493 in BDL rats and 1.159 +/- 0.125 in sham-operated rats (P = 0.0330). The up-regulation of VEGF-A expression was maximal at day 2. Immunoblotting also demonstrated up-regulated expression of VEGF-A at the protein level. Immunostaining of VEGF revealed that the expression was evident in hepatocytes adjacent to the portal tracts, and scarcely observed in hepatocytes at the centrilobular area or cholangiocytes. CONCLUSION Gene expression profiling in the whole liver of the BDL rats revealed 38 up-regulated and 17 down-regulated transcripts. In addition, the up-regulated expression of VEGF was mainly observed in hepatocytes surrounding to the portal tracts.
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Affiliation(s)
- Atsushi Tanaka
- Department of Medicine, School of Medicine, Teikyo University, Tokyo, Japan.
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Alvaro D, Mancino MG. New insights on the molecular and cell biology of human cholangiopathies. Mol Aspects Med 2007; 29:50-7. [PMID: 18230407 DOI: 10.1016/j.mam.2007.09.007] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2007] [Accepted: 09/28/2007] [Indexed: 01/20/2023]
Abstract
Cholangiopathies are diseases of high social impact representing the main indication for liver transplantation in the infanthood and the third in adulthood. Despite the heterogeneous etiology and pathogenesis, cholangiopathies share many different common morphological features and, chronically progress toward a ductupenic condition clinically evidenced by the classical features of a cholestatic syndrome. The primary target of damage in the course of cholangiopathies are cholangiocytes, the epithelia cells lining the biliary tree. A bulk of researches performed in the last decade, highlighted the extraordinary biological properties of cholangiocytes involved in a number of important processes such as bile formation, proliferation, injury repair, fibrosis, angiogenesis and regulation of blood flow. Recent advances on the molecular and cell biology of human cholangiopathies are opening new potential therapeutic perspectives for these diseases.
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Affiliation(s)
- Domenico Alvaro
- Division of Gastroenterology, Department of Clinical Medicine, Rome, Italy
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