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Mo D, Lv M, Mao X. Using different zebrafish models to explore liver regeneration. Front Cell Dev Biol 2024; 12:1485773. [PMID: 39544362 PMCID: PMC11560876 DOI: 10.3389/fcell.2024.1485773] [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: 08/24/2024] [Accepted: 10/22/2024] [Indexed: 11/17/2024] Open
Abstract
The liver possesses an impressive capability to regenerate following various injuries. Given its profound implications for the treatment of liver diseases, which afflict millions globally, liver regeneration stands as a pivotal area of digestive organ research. Zebrafish (Danio rerio) has emerged as an ideal model organism in regenerative medicine, attributed to their remarkable ability to regenerate tissues and organs, including the liver. Many fantastic studies have been performed to explore the process of liver regeneration using zebrafish, especially the extreme hepatocyte injury model. Biliary-mediated liver regeneration was first discovered in the zebrafish model and then validated in mammalian models and human patients. Considering the notable expansion of biliary epithelial cells in many end-stage liver diseases, the promotion of biliary-mediated liver regeneration might be another way to treat these refractory liver diseases. To date, a comprehensive review discussing the current advancements in zebrafish liver regeneration models is lacking. Therefore, this review aims to investigate the utility of different zebrafish models in exploring liver regeneration, highlighting the genetic and cellular insights gained and discussing the potential translational impact on human health.
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Affiliation(s)
- Dashuang Mo
- Department of Immunology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, China
| | - Mengzhu Lv
- Department of Immunology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, China
| | - Xiaoyu Mao
- College of Language Intelligence, Sichuan International Studies University, Chongqing, China
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2
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Zhao J, Yue P, Mi N, Li M, Fu W, Zhang X, Gao L, Bai M, Tian L, Jiang N, Lu Y, Ma H, Dong C, Zhang Y, Zhang H, Zhang J, Ren Y, Suzuki A, Wong PF, Tanaka K, Rerknimitr R, Junger HH, Cheung TT, Melloul E, Demartines N, Leung JW, Yao J, Yuan J, Lin Y, Schlitt HJ, Meng W. Biliary fibrosis is an important but neglected pathological feature in hepatobiliary disorders: from molecular mechanisms to clinical implications. MEDICAL REVIEW (2021) 2024; 4:326-365. [PMID: 39135601 PMCID: PMC11317084 DOI: 10.1515/mr-2024-0029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Accepted: 06/06/2024] [Indexed: 08/15/2024]
Abstract
Fibrosis resulting from pathological repair secondary to recurrent or persistent tissue damage often leads to organ failure and mortality. Biliary fibrosis is a crucial but easily neglected pathological feature in hepatobiliary disorders, which may promote the development and progression of benign and malignant biliary diseases through pathological healing mechanisms secondary to biliary tract injuries. Elucidating the etiology and pathogenesis of biliary fibrosis is beneficial to the prevention and treatment of biliary diseases. In this review, we emphasized the importance of biliary fibrosis in cholangiopathies and summarized the clinical manifestations, epidemiology, and aberrant cellular composition involving the biliary ductules, cholangiocytes, immune system, fibroblasts, and the microbiome. We also focused on pivotal signaling pathways and offered insights into ongoing clinical trials and proposing a strategic approach for managing biliary fibrosis-related cholangiopathies. This review will offer a comprehensive perspective on biliary fibrosis and provide an important reference for future mechanism research and innovative therapy to prevent or reverse fibrosis.
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Affiliation(s)
- Jinyu Zhao
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Ping Yue
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Ningning Mi
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Matu Li
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Wenkang Fu
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Xianzhuo Zhang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Long Gao
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Mingzhen Bai
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Liang Tian
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Ningzu Jiang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Yawen Lu
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Haidong Ma
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Chunlu Dong
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Yong Zhang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Hengwei Zhang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Jinduo Zhang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Yanxian Ren
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Azumi Suzuki
- Department of Gastroenterology, Hamamatsu Medical Center, Hamamatsu, Japan
| | - Peng F. Wong
- Department of Vascular Surgery, The James Cook University Hospital, Middlesbrough, UK
| | - Kiyohito Tanaka
- Department of Gastroenterology, Kyoto Second Red Cross Hospital, Kyoto, Japan
| | - Rungsun Rerknimitr
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn, Bangkok, Thailand
- Excellence Center for Gastrointestinal Endoscopy, King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Henrik H. Junger
- Department of Surgery, University Medical Center Regensburg, Regensburg, Germany
| | - Tan T. Cheung
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Emmanuel Melloul
- Department of Visceral Surgery, Lausanne University Hospital CHUV, University of Lausanne (UNIL), Lausanne, Switzerland
| | - Nicolas Demartines
- Department of Visceral Surgery, Lausanne University Hospital CHUV, University of Lausanne (UNIL), Lausanne, Switzerland
| | - Joseph W. Leung
- Division of Gastroenterology and Hepatology, UC Davis Medical Center and Sacramento VA Medical Center, Sacramento, CA, USA
| | - Jia Yao
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, China
- Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, China
| | - Jinqiu Yuan
- Clinical Research Center, Big Data Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Yanyan Lin
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Hans J. Schlitt
- Department of Surgery, University Medical Center Regensburg, Regensburg, Germany
| | - Wenbo Meng
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
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3
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Dai Y, Peng Y, Lu Z, Mao T, Chen K, Lu X, Liu K, Zhou X, Hu W, Wang H. Prenatal prednisone exposure impacts liver development and function in fetal mice and its characteristics. Toxicol Sci 2024; 199:63-80. [PMID: 38439560 DOI: 10.1093/toxsci/kfae027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/06/2024] Open
Abstract
Prednisone, a widely used glucocorticoid drug in human and veterinary medicine, has been reported to cause developmental toxicity. However, systematic studies about the effect of prednisone on fetal liver development are still unclear. We investigated the potential effects of maternal exposure to clinically equivalent doses of prednisone during different gestational stages on cell proliferation and apoptosis, cell differentiation, glucose and lipid metabolism, and hematopoiesis in the liver of fetal mice, and explored the potential mechanisms. Results showed that prenatal prednisone exposure (PPE) could suppress cell proliferation, inhibit hepatocyte differentiation, and promote cholangiocyte differentiation in the fetal liver. Meanwhile, PPE could result in the enhancement of glyconeogenesis and bile acid synthesis and the inhibition of fatty acid β-oxidation and hematopoiesis in the fetal liver. Further analysis found that PPE-induced alterations in liver development had obvious stage and sex differences. Overall, the alteration in fetal liver development and function induced by PPE was most pronounced during the whole pregnancy (GD0-18), and the males were relatively more affected than the females. Additionally, fetal hepatic insulin-like growth factor 1 (IGF1) signaling pathway was inhibited by PPE. In conclusion, PPE could impact fetal liver development and multiple functions, and these alterations might be partially related to the inhibition of IGF1 signaling pathway.
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Affiliation(s)
- Yongguo Dai
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan, Hubei Province 430071, China
| | - Yu Peng
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan, Hubei Province 430071, China
| | - Zhengjie Lu
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan, Hubei Province 430071, China
- Department of Pharmacy, Zhongnan Hospital of Wuhan University, Wuhan, Hubei Province 430071, China
| | - Tongyun Mao
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan, Hubei Province 430071, China
| | - Kaiqi Chen
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan, Hubei Province 430071, China
| | - Xiaoqian Lu
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan, Hubei Province 430071, China
| | - Kexin Liu
- Department of Pharmacy, Zhongnan Hospital of Wuhan University, Wuhan, Hubei Province 430071, China
- Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan University School of Basic Medical Sciences, Wuhan, Hubei Province 430071, China
| | - Xinli Zhou
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan, Hubei Province 430071, China
| | - Wen Hu
- Department of Pharmacy, Zhongnan Hospital of Wuhan University, Wuhan, Hubei Province 430071, China
- Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan University School of Basic Medical Sciences, Wuhan, Hubei Province 430071, China
| | - Hui Wang
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan, Hubei Province 430071, China
- Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan University School of Basic Medical Sciences, Wuhan, Hubei Province 430071, China
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Crawford JM, Bioulac-Sage P, Hytiroglou P. Structure, Function and Responses to Injury. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:1-95. [DOI: 10.1016/b978-0-7020-8228-3.00001-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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5
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Hora S, Wuestefeld T. Liver Injury and Regeneration: Current Understanding, New Approaches, and Future Perspectives. Cells 2023; 12:2129. [PMID: 37681858 PMCID: PMC10486351 DOI: 10.3390/cells12172129] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 08/18/2023] [Accepted: 08/21/2023] [Indexed: 09/09/2023] Open
Abstract
The liver is a complex organ with the ability to regenerate itself in response to injury. However, several factors can contribute to liver damage beyond repair. Liver injury can be caused by viral infections, alcoholic liver disease, non-alcoholic steatohepatitis, and drug-induced liver injury. Understanding the cellular and molecular mechanisms involved in liver injury and regeneration is critical to developing effective therapies for liver diseases. Liver regeneration is a complex process that involves the interplay of various signaling pathways, cell types, and extracellular matrix components. The activation of quiescent hepatocytes that proliferate and restore the liver mass by upregulating genes involved in cell-cycle progression, DNA repair, and mitochondrial function; the proliferation and differentiation of progenitor cells, also known as oval cells, into hepatocytes that contribute to liver regeneration; and the recruitment of immune cells to release cytokines and angiogenic factors that promote or inhibit cell proliferation are some examples of the regenerative processes. Recent advances in the fields of gene editing, tissue engineering, stem cell differentiation, small interfering RNA-based therapies, and single-cell transcriptomics have paved a roadmap for future research into liver regeneration as well as for the identification of previously unknown cell types and gene expression patterns. In summary, liver injury and regeneration is a complex and dynamic process. A better understanding of the cellular and molecular mechanisms driving this phenomenon could lead to the development of new therapies for liver diseases and improve patient outcomes.
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Affiliation(s)
- Shainan Hora
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Genome, Singapore 138672, Singapore;
| | - Torsten Wuestefeld
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Genome, Singapore 138672, Singapore;
- National Cancer Centre Singapore, Singapore 168583, Singapore
- School of Biological Science, Nanyang Technological University, Singapore 637551, Singapore
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Lopez-Scarim J, Nambiar SM, Billerbeck E. Studying T Cell Responses to Hepatotropic Viruses in the Liver Microenvironment. Vaccines (Basel) 2023; 11:681. [PMID: 36992265 PMCID: PMC10056334 DOI: 10.3390/vaccines11030681] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 03/08/2023] [Accepted: 03/10/2023] [Indexed: 03/19/2023] Open
Abstract
T cells play an important role in the clearance of hepatotropic viruses but may also cause liver injury and contribute to disease progression in chronic hepatitis B and C virus infections which affect millions of people worldwide. The liver provides a unique microenvironment of immunological tolerance and hepatic immune regulation can modulate the functional properties of T cell subsets and influence the outcome of a virus infection. Extensive research over the last years has advanced our understanding of hepatic conventional CD4+ and CD8+ T cells and unconventional T cell subsets and their functions in the liver environment during acute and chronic viral infections. The recent development of new small animal models and technological advances should further increase our knowledge of hepatic immunological mechanisms. Here we provide an overview of the existing models to study hepatic T cells and review the current knowledge about the distinct roles of heterogeneous T cell populations during acute and chronic viral hepatitis.
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Affiliation(s)
| | | | - Eva Billerbeck
- Division of Hepatology, Department of Medicine and Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
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7
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Muntean A, Davenport M. Biliary atresia & choledochal malformation--Embryological and anatomical considerations. Semin Pediatr Surg 2022; 31:151235. [PMID: 36442454 DOI: 10.1016/j.sempedsurg.2022.151235] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The two main biliary pathologies in paediatric practice, biliary atresia and choledochal malformations (CM), have their origins within prenatal life. Nevertheless, the actual mechanisms remain elusive with many unanswered questions. The extrahepatic bile duct develops as a funnel-like structure emerging from the foregut from about 3-4 weeks of gestation into the mesenchyme of the septum transversum. The cranial elements of this contain hepatoblasts - the precursors to the two key cell lines that will become hepatocytes and biliary epithelial cells. The intrahepatic bile ducts develop separately and emerge from a complex process involving the ductal plate surrounding the in-growing portal venous system from about the 7-8th week of gestation. A developmental defect at some point(s) in this process may be the cause of at least some variants of BA - the Biliary Atresia Splenic Malformation syndrome particularly - though evidence in the more common isolated BA is much more circumstantial. Similarly, some types of choledochal malformation, specifically the cystic type of CM, are invariably present during prenatal life although again an actual aetiological mechanism remains elusive.
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Affiliation(s)
- Ancuta Muntean
- Deptartment of Paediatric Surgery, Kings College Hospital, London
| | - Mark Davenport
- Deptartment of Paediatric Surgery, Kings College Hospital, London.
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8
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He J, Cui H, Shi X, Jin Q, Han X, Han T, Peng J, Guo S, Zhang L, Zhao Y, Zhou B, Chen L, Chen L, Arial Zeng Y, Wang H, Jin G, Gao D. Functional hepatobiliary organoids recapitulate liver development and reveal essential drivers of hepatobiliary cell fate determination. LIFE MEDICINE 2022; 1:345-358. [PMID: 39872746 PMCID: PMC11749142 DOI: 10.1093/lifemedi/lnac055] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 11/25/2022] [Indexed: 01/30/2025]
Abstract
During liver development, hepatocytes, and cholangiocytes are concurrently differentiated from common liver progenitor cells and are assembled into hepatobiliary architecture to perform proper hepatic function. However, the generation of functional hepatobiliary architecture from hepatocytes in vitro is still challenging, and the exact molecular drivers of hepatobiliary cell lineage determination is largely unknown. In this study, functional hepatobiliary organoids (HBOs) are generated from hepatocytes. These HBOs contain a bile duct network surrounded by mature hepatocytes and stably maintain hepatic characteristics and function in vitro and upon transplantation in vivo. Morphological transition and expression profile of hepatocyte-derived organoids recapitulate the process of liver development. Gene regulation landscape of hepatocyte-derived organoids reveal that Tead4 and Ddit3 promote the cell fate commitment of liver progenitors to functional cholangiocytes and hepatocytes, respectively. Liver cell fate determination is reversed by inhibiting Tead4 or increasing Ddit3 expression both in vitro and upon transplantation in vivo. Collectively, hepatocyte-derived HBOs reveal the essential transcription drivers of liver hepatobiliary cell lineage determination and represent powerful models for liver development and regeneration.
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Affiliation(s)
- Juan He
- State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Haoyue Cui
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
| | - Xiaohan Shi
- Department of Hepatobiliary Pancreatic Surgery, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - Qiqi Jin
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
| | - Ximeng Han
- State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China
| | - Tiantian Han
- State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China
| | - Jiayin Peng
- State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China
| | - Shiwei Guo
- Department of Hepatobiliary Pancreatic Surgery, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - Lei Zhang
- State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China
| | - Yun Zhao
- State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China
| | - Bin Zhou
- State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China
| | - Luonan Chen
- State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China
| | - Lei Chen
- The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
- National Center for Liver Cancer, Shanghai 200441, China
| | - Yi Arial Zeng
- State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China
| | - Hongyang Wang
- The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
- National Center for Liver Cancer, Shanghai 200441, China
| | - Gang Jin
- Department of Hepatobiliary Pancreatic Surgery, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - Dong Gao
- State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China
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Ellis JL, Evason KJ, Zhang C, Fourman MN, Liu J, Ninov N, Delous M, Vanhollebeke B, Fiddes I, Otis JP, Houvras Y, Farber SA, Xu X, Lin X, Stainier DYR, Yin C. A missense mutation in the proprotein convertase gene furinb causes hepatic cystogenesis during liver development in zebrafish. Hepatol Commun 2022; 6:3083-3097. [PMID: 36017776 PMCID: PMC9592797 DOI: 10.1002/hep4.2038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 05/28/2022] [Accepted: 06/17/2022] [Indexed: 12/14/2022] Open
Abstract
Hepatic cysts are fluid-filled lesions in the liver that are estimated to occur in 5% of the population. They may cause hepatomegaly and abdominal pain. Progression to secondary fibrosis, cirrhosis, or cholangiocarcinoma can lead to morbidity and mortality. Previous studies of patients and rodent models have associated hepatic cyst formation with increased proliferation and fluid secretion in cholangiocytes, which are partially due to impaired primary cilia. Congenital hepatic cysts are thought to originate from faulty bile duct development, but the underlying mechanisms are not fully understood. In a forward genetic screen, we identified a zebrafish mutant that developed hepatic cysts during larval stages. The cyst formation was not due to changes in biliary cell proliferation, bile secretion, or impairment of primary cilia. Instead, time-lapse live imaging data showed that the mutant biliary cells failed to form interconnecting bile ducts because of defects in motility and protrusive activity. Accordingly, immunostaining revealed a disorganized actin and microtubule cytoskeleton in the mutant biliary cells. By whole-genome sequencing, we determined that the cystic phenotype in the mutant was caused by a missense mutation in the furinb gene, which encodes a proprotein convertase. The mutation altered Furinb localization and caused endoplasmic reticulum (ER) stress. The cystic phenotype could be suppressed by treatment with the ER stress inhibitor 4-phenylbutyric acid and exacerbated by treatment with the ER stress inducer tunicamycin. The mutant liver also exhibited increased mammalian target of rapamycin (mTOR) signaling. Treatment with mTOR inhibitors halted cyst formation at least partially through reducing ER stress. Conclusion: Our study has established a vertebrate model for studying hepatic cystogenesis and illustrated the contribution of ER stress in the disease pathogenesis.
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Affiliation(s)
- Jillian L. Ellis
- Division of Gastroenterology, Hepatology, and NutritionCincinnati Children's Hospital Medical CenterCincinnatiOhioUSA
| | - Kimberley J. Evason
- Department of Biochemistry and BiophysicsProgram in Developmental and Stem Cell BiologyLiver Center and Diabetes CenterUniversity of California, San FranciscoSan FranciscoCaliforniaUSA
- Huntsman Cancer Institute and Department of PathologyUniversity of UtahSalt Lake CityUtahUSA
| | - Changwen Zhang
- Division of Gastroenterology, Hepatology, and NutritionCincinnati Children's Hospital Medical CenterCincinnatiOhioUSA
| | - Makenzie N. Fourman
- Division of Gastroenterology, Hepatology, and NutritionCincinnati Children's Hospital Medical CenterCincinnatiOhioUSA
| | - Jiandong Liu
- Department of Biochemistry and BiophysicsProgram in Developmental and Stem Cell BiologyLiver Center and Diabetes CenterUniversity of California, San FranciscoSan FranciscoCaliforniaUSA
- McAllister Heart InstituteDepartment of Pathology and Laboratory MedicineSchool of MedicineThe University of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
| | - Nikolay Ninov
- Department of Biochemistry and BiophysicsProgram in Developmental and Stem Cell BiologyLiver Center and Diabetes CenterUniversity of California, San FranciscoSan FranciscoCaliforniaUSA
- Center for Regenerative Therapies TU DresdenDresdenGermany
- Paul Langerhans Institute Dresden of the Helmholtz Center Munich at the University Hospital Carl Gustav Carus of TU DresdenGerman Center for Diabetes ResearchDresdenGermany
| | - Marion Delous
- Department of Biochemistry and BiophysicsProgram in Developmental and Stem Cell BiologyLiver Center and Diabetes CenterUniversity of California, San FranciscoSan FranciscoCaliforniaUSA
- Equipe GENDEVCentre de Recherche en Neurosciences de LyonInserm U1028CNRS UMR5292Universite Lyon 1Universite St EtienneLyonFrance
| | - Benoit Vanhollebeke
- Department of Biochemistry and BiophysicsProgram in Developmental and Stem Cell BiologyLiver Center and Diabetes CenterUniversity of California, San FranciscoSan FranciscoCaliforniaUSA
- Laboratory of Neurovascular SignalingDepartment of Molecular BiologyULB Neuroscience InstituteUniversite Libre de BruxellesGosseliesBelgium
| | - Ian Fiddes
- Department of Biochemistry and BiophysicsProgram in Developmental and Stem Cell BiologyLiver Center and Diabetes CenterUniversity of California, San FranciscoSan FranciscoCaliforniaUSA
| | - Jessica P. Otis
- Department of EmbryologyCarnegie Institution for ScienceBaltimoreMarylandUSA
- Department of BiologyJohns Hopkins UniversityBaltimoreMarylandUSA
- Department of Molecular and Cellular Biology and BiochemistryBrown UniversityProvidenceRhode IslandUSA
| | - Yariv Houvras
- Weill Cornell Medical College and New York Presbyterian HospitalNew YorkNew YorkUSA
| | - Steven A. Farber
- Department of EmbryologyCarnegie Institution for ScienceBaltimoreMarylandUSA
- Department of BiologyJohns Hopkins UniversityBaltimoreMarylandUSA
| | - Xiaolei Xu
- Department of Biochemistry and Molecular BiologyDepartment of Cardiovascular MedicineMayo ClinicRochesterMinnesotaUSA
| | - Xueying Lin
- Department of Biochemistry and Molecular BiologyDepartment of Cardiovascular MedicineMayo ClinicRochesterMinnesotaUSA
| | - Didier Y. R. Stainier
- Department of Biochemistry and BiophysicsProgram in Developmental and Stem Cell BiologyLiver Center and Diabetes CenterUniversity of California, San FranciscoSan FranciscoCaliforniaUSA
- Department of Developmental GeneticsMax Planck Institute for Heart and Lung ResearchBad NauheimGermany
| | - Chunyue Yin
- Division of Gastroenterology, Hepatology, and NutritionCincinnati Children's Hospital Medical CenterCincinnatiOhioUSA
- Department of Biochemistry and BiophysicsProgram in Developmental and Stem Cell BiologyLiver Center and Diabetes CenterUniversity of California, San FranciscoSan FranciscoCaliforniaUSA
- Division of Developmental BiologyCincinnati Children's Hospital Medical CenterCincinnatiOhioUSA
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10
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Jain I, Berg IC, Acharya A, Blaauw M, Gosstola N, Perez-Pinera P, Underhill GH. Delineating cooperative effects of Notch and biomechanical signals on patterned liver differentiation. Commun Biol 2022; 5:1073. [PMID: 36207581 PMCID: PMC9546876 DOI: 10.1038/s42003-022-03840-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 08/12/2022] [Indexed: 11/22/2022] Open
Abstract
Controlled in vitro multicellular culture systems with defined biophysical microenvironment have been used to elucidate the role of Notch signaling in the spatiotemporal regulation of stem and progenitor cell differentiation. In addition, computational models incorporating features of Notch ligand-receptor interactions have provided important insights into Notch pathway signaling dynamics. However, the mechanistic relationship between Notch-mediated intercellular signaling and cooperative microenvironmental cues is less clear. Here, liver progenitor cell differentiation patterning was used as a model to systematically evaluate the complex interplay of cellular mechanics and Notch signaling along with identifying combinatorial mechanisms guiding progenitor fate. We present an integrated approach that pairs a computational intercellular signaling model with defined microscale culture configurations provided within a cell microarray platform. Specifically, the cell microarray-based experiments were used to validate and optimize parameters of the intercellular Notch signaling model. This model incorporated the experimentally established multicellular dimensions of the cellular microarray domains, mechanical stress-related activation parameters, and distinct Notch receptor-ligand interactions based on the roles of the Notch ligands Jagged-1 and Delta-like-1. Overall, these studies demonstrate the spatial control of mechanotransduction-associated components, key growth factor and Notch signaling interactions, and point towards a possible role of E-Cadherin in translating intercellular mechanical gradients to downstream Notch signaling.
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Affiliation(s)
- Ishita Jain
- Department of Bioengineering, University of Illinois at Urbana Champaign, Urbana, USA
| | - Ian C Berg
- Department of Bioengineering, University of Illinois at Urbana Champaign, Urbana, USA
| | - Ayusha Acharya
- Department of Bioengineering, University of Illinois at Urbana Champaign, Urbana, USA
| | - Maddie Blaauw
- Department of Bioengineering, University of Illinois at Urbana Champaign, Urbana, USA
| | - Nicholas Gosstola
- Department of Bioengineering, University of Illinois at Urbana Champaign, Urbana, USA
| | - Pablo Perez-Pinera
- Department of Bioengineering, University of Illinois at Urbana Champaign, Urbana, USA
| | - Gregory H Underhill
- Department of Bioengineering, University of Illinois at Urbana Champaign, Urbana, USA.
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11
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Uemoto Y, Taura K, Nakamura D, Xuefeng L, Nam NH, Kimura Y, Yoshino K, Fuji H, Yoh T, Nishio T, Yamamoto G, Koyama Y, Seo S, Tsuruyama T, Iwaisako K, Uemoto S, Tabata Y, Hatano E. Bile duct regeneration with an artificial bile duct made of gelatin hydrogel non-woven fabrics. Tissue Eng Part A 2022; 28:737-748. [PMID: 35383474 DOI: 10.1089/ten.tea.2021.0209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Although choledochojejunostomy is the standard technique for biliary reconstruction, there are various associated problems that need to be solved such as reflux cholangitis. Interposition with an artificial bile duct (ABD) to replace the resected bile duct maintains a physiological conduit for bile and may solve this problem. This study investigated the usefulness of an ABD made of gelatin hydrogel non-woven fabric (GHNF). GHNF was prepared by the solution blow spinning method. The migration and activity of murine fibroblast L929 cells were examined in GHNF sheets. L929 cells migrated into GHNF sheets, where they proliferated and synthesized collagen, suggesting GHNF is a promising scaffold for bile duct regeneration. ABDs made of GHNF were implanted in place of resected bile duct segments in rats. The rats were sacrificed at 2, 6, and 12 weeks post-implantation. The implantation site was histologically evaluated for bile duct regeneration. At postoperative 2 weeks, migrating cells were observed in the ABD pores. The implanted ABD was mostly degraded and replaced by collagen fibers at 6 weeks. Ki67-positive bile duct epithelial cells appeared within the implanted ABD. These were most abundant within the central part of the ABD after 6 weeks. The percentages of Ki67-positive cells were 31.7%±9.1% in the experimental group and 0.8%±0.6% in the sham operation group at 6 weeks (p<0.05), indicating that mature biliary epithelial cells at the stump proliferated to regenerate the biliary epithelium. Biliary epithelial cells had almost completely covered the bile duct lumen at 12 weeks (epithelialization ratios: 10.4%±6.9% at 2 weeks, 93.1%±5.1% at 6 weeks, 99.2%±1.6% at 12 weeks). The regenerated epithelium was positive for the bile duct epithelium marker cytokeratin 19. Bile duct regeneration was accompanied by angiogenesis, as evidenced by the appearance of CD31-positive vascular structures. Capillaries were induced 2 weeks after implantation. The number of capillaries reached a maximum at 6 weeks and decreased to the same level as that of normal bile ducts at 12 weeks. These results showed that an ABD of GHNF contributed to successful bile duct regeneration in rats by facilitating the cell migration required for extracellular matrix synthesis, angiogenesis, and epithelialization.
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Affiliation(s)
- Yusuke Uemoto
- Kyoto University, 12918, Surgery, Kyoto, Japan.,Kyoto University Institute for Frontier Life and Medical Sciences, 84090, Regeneration Science and Engineering, Kyoto, Kyoto, Japan;
| | | | | | - Li Xuefeng
- Kyoto University, 12918, Surgery, Kyoto, Japan;
| | | | | | - Kenji Yoshino
- Kyoto University, 12918, Surgery, Kyoto, Japan.,Nagahama City Hospital, 37078, Surgery, Nagahama, Shiga, Japan;
| | | | - Tomoaki Yoh
- Kyoto University, 12918, Surgery, Kyoto, Japan;
| | | | | | | | - Satoru Seo
- Kyoto University, 12918, Surgery, Kyoto, Japan;
| | - Tatsuaki Tsuruyama
- Kyoto University Hospital Clinical Bio Resource Center, 593766, Kyoto, Kyoto, Japan;
| | - Keiko Iwaisako
- Doshisha University - Kyotanabe Campus, 358002, Medical Life Systems, Kyotanabe, Kyoto, Japan;
| | - Shinji Uemoto
- Shiga University of Medical Science, 13051, Otsu, Shiga, Japan;
| | - Yasuhiko Tabata
- Kyoto University Institute for Frontier Life and Medical Sciences, 84090, Regeneration Science and Engineering, Kyoto, Kyoto, Japan;
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12
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Kanno M, Suzuki M, Tanikawa K, Numakura C, Matsuzawa SI, Niihori T, Aoki Y, Matsubara Y, Makino S, Tamiya G, Nakano S, Funayama R, Shirota M, Nakayama K, Mitsui T, Hayasaka K. Heterozygous calcyclin-binding protein/Siah1-interacting protein (CACYBP/SIP) gene pathogenic variant linked to a dominant family with paucity of interlobular bile duct. J Hum Genet 2022; 67:393-397. [PMID: 35087201 DOI: 10.1038/s10038-022-01017-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 01/11/2022] [Accepted: 01/13/2022] [Indexed: 11/09/2022]
Abstract
Paucity of interlobular bile ducts (PILBD) is a heterogeneous disorder classified into two categories, syndromic and non-syndromic bile duct paucity. Syndromic PILBD is characterized by the presence of clinical manifestations of Alagille syndrome. Non-syndromic PILBD is caused by multiple diseases, such as metabolic and genetic disorders, infectious diseases, and inflammatory and immune disorders. We evaluated a family with a dominantly inherited PILBD, who presented with cholestasis at 1-2 months of age but spontaneously improved by 1 year of age. Next-generation sequencing analysis revealed a heterozygous CACYBP/SIP p.E177Q pathogenic variant. Calcyclin-binding protein and Siah1 interacting protein (CACYBP/SIP) form a ubiquitin ligase complex and induce proteasomal degradation of non-phosphorylated β-catenin. Immunohistochemical analysis revealed a slight decrease in CACYBP and β-catenin levels in the liver of patients in early infancy, which almost normalized by 13 months of age. The CACYBP/SIP p.E177Q pathogenic variant may form a more active or stable ubiquitin ligase complex that enhances the degradation of β-catenin and delays the maturation of intrahepatic bile ducts. Our findings indicate that accurate regulation of the β-catenin concentration is essential for the development of intrahepatic bile ducts and CACYBP/SIP pathogenic variant is a novel cause of PILDB.
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Affiliation(s)
- Miyako Kanno
- Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan
| | - Mitsuyoshi Suzuki
- Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Ken Tanikawa
- Departments of Pathology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Chikahiko Numakura
- Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan
| | - Shu-Ichi Matsuzawa
- Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Tetsuya Niihori
- Department of Medical Genetics, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yoko Aoki
- Department of Medical Genetics, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yoichi Matsubara
- National Center for Child Health and Development, Setagaya, Tokyo, Japan
| | - Satoshi Makino
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
| | - Gen Tamiya
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.,Statistical Genetics Team, RIKEN Center for Advanced Intelligence Project, Tokyo, Japan
| | - Satoshi Nakano
- Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Ryo Funayama
- Division of Cell Proliferation, ART, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Matsuyuki Shirota
- Division of Interdisciplinary Medical Sciences, ART, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Keiko Nakayama
- Division of Cell Proliferation, ART, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tetsuo Mitsui
- Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan
| | - Kiyoshi Hayasaka
- Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan. .,Department of Pediatrics, Miyukikai Hospital, Social Medical Corporation Miyuki, Kaminoyama, Japan.
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13
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Hadjittofi C, Feretis M, Martin J, Harper S, Huguet E. Liver regeneration biology: Implications for liver tumour therapies. World J Clin Oncol 2021; 12:1101-1156. [PMID: 35070734 PMCID: PMC8716989 DOI: 10.5306/wjco.v12.i12.1101] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 06/22/2021] [Accepted: 11/28/2021] [Indexed: 02/06/2023] Open
Abstract
The liver has remarkable regenerative potential, with the capacity to regenerate after 75% hepatectomy in humans and up to 90% hepatectomy in some rodent models, enabling it to meet the challenge of diverse injury types, including physical trauma, infection, inflammatory processes, direct toxicity, and immunological insults. Current understanding of liver regeneration is based largely on animal research, historically in large animals, and more recently in rodents and zebrafish, which provide powerful genetic manipulation experimental tools. Whilst immensely valuable, these models have limitations in extrapolation to the human situation. In vitro models have evolved from 2-dimensional culture to complex 3 dimensional organoids, but also have shortcomings in replicating the complex hepatic micro-anatomical and physiological milieu. The process of liver regeneration is only partially understood and characterized by layers of complexity. Liver regeneration is triggered and controlled by a multitude of mitogens acting in autocrine, paracrine, and endocrine ways, with much redundancy and cross-talk between biochemical pathways. The regenerative response is variable, involving both hypertrophy and true proliferative hyperplasia, which is itself variable, including both cellular phenotypic fidelity and cellular trans-differentiation, according to the type of injury. Complex interactions occur between parenchymal and non-parenchymal cells, and regeneration is affected by the status of the liver parenchyma, with differences between healthy and diseased liver. Finally, the process of termination of liver regeneration is even less well understood than its triggers. The complexity of liver regeneration biology combined with limited understanding has restricted specific clinical interventions to enhance liver regeneration. Moreover, manipulating the fundamental biochemical pathways involved would require cautious assessment, for fear of unintended consequences. Nevertheless, current knowledge provides guiding principles for strategies to optimise liver regeneration potential.
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Affiliation(s)
- Christopher Hadjittofi
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Michael Feretis
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Jack Martin
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Simon Harper
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Emmanuel Huguet
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
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14
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Sun Q, Shen Z, Liang X, He Y, Kong D, Midgley AC, Wang K. Progress and Current Limitations of Materials for Artificial Bile Duct Engineering. MATERIALS 2021; 14:ma14237468. [PMID: 34885623 PMCID: PMC8658964 DOI: 10.3390/ma14237468] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 10/19/2021] [Accepted: 10/25/2021] [Indexed: 01/30/2023]
Abstract
Bile duct injury (BDI) and bile tract diseases are regarded as prominent challenges in hepatobiliary surgery due to the risk of severe complications. Hepatobiliary, pancreatic, and gastrointestinal surgery can inadvertently cause iatrogenic BDI. The commonly utilized clinical treatment of BDI is biliary-enteric anastomosis. However, removal of the Oddi sphincter, which serves as a valve control over the unidirectional flow of bile to the intestine, can result in complications such as reflux cholangitis, restenosis of the bile duct, and cholangiocarcinoma. Tissue engineering and biomaterials offer alternative approaches for BDI treatment. Reconstruction of mechanically functional and biomimetic structures to replace bile ducts aims to promote the ingrowth of bile duct cells and realize tissue regeneration of bile ducts. Current research on artificial bile ducts has remained within preclinical animal model experiments. As more research shows artificial bile duct replacements achieving effective mechanical and functional prevention of biliary peritonitis caused by bile leakage or obstructive jaundice after bile duct reconstruction, clinical translation of tissue-engineered bile ducts has become a theoretical possibility. This literature review provides a comprehensive collection of published works in relation to three tissue engineering approaches for biomimetic bile duct construction: mechanical support from scaffold materials, cell seeding methods, and the incorporation of biologically active factors to identify the advancements and current limitations of materials and methods for the development of effective artificial bile ducts that promote tissue regeneration.
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Affiliation(s)
- Qiqi Sun
- Key Laboratory of Bioactive Materials for the Ministry of Education, College of Life Sciences, Nankai University, Tianjin 300071, China; (Q.S.); (D.K.)
| | - Zefeng Shen
- Department of General Surgery, Sir Run-Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China; (Z.S.); (X.L.)
| | - Xiao Liang
- Department of General Surgery, Sir Run-Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China; (Z.S.); (X.L.)
| | - Yingxu He
- School of Computing, National University of Singapore, Singapore 119077, Singapore;
| | - Deling Kong
- Key Laboratory of Bioactive Materials for the Ministry of Education, College of Life Sciences, Nankai University, Tianjin 300071, China; (Q.S.); (D.K.)
| | - Adam C. Midgley
- Key Laboratory of Bioactive Materials for the Ministry of Education, College of Life Sciences, Nankai University, Tianjin 300071, China; (Q.S.); (D.K.)
- Correspondence: (A.C.M.); (K.W.)
| | - Kai Wang
- Key Laboratory of Bioactive Materials for the Ministry of Education, College of Life Sciences, Nankai University, Tianjin 300071, China; (Q.S.); (D.K.)
- Correspondence: (A.C.M.); (K.W.)
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15
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Wang X, Lei J, Li Z, Yan L. Potential Effects of Coronaviruses on the Liver: An Update. Front Med (Lausanne) 2021; 8:651658. [PMID: 34646834 PMCID: PMC8502894 DOI: 10.3389/fmed.2021.651658] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Accepted: 07/22/2021] [Indexed: 02/06/2023] Open
Abstract
The coronaviruses that cause notable diseases, namely, severe acute respiratory syndrome (SARS), middle east respiratory syndrome (MERS) and coronavirus disease 2019 (COVID-19), exhibit remarkable similarities in genomic components and pathogenetic mechanisms. Although coronaviruses have widely been studied as respiratory tract pathogens, their effects on the hepatobiliary system have seldom been reported. Overall, the manifestations of liver injury caused by coronaviruses typically involve decreased albumin and elevated aminotransferase and bilirubin levels. Several pathophysiological hypotheses have been proposed, including direct damage, immune-mediated injury, ischemia and hypoxia, thrombosis and drug hepatotoxicity. The interaction between pre-existing liver disease and coronavirus infection has been illustrated, whereby coronaviruses influence the occurrence, severity, prognosis and treatment of liver diseases. Drugs and vaccines used for treating and preventing coronavirus infection also have hepatotoxicity. Currently, the establishment of optimized therapy for coronavirus infection and liver disease comorbidity is of significance, warranting further safety tests, animal trials and clinical trials.
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Affiliation(s)
- Xinyi Wang
- Thyroid and Parathyroid Surgery Center, West China Hospital of Sichuan University, Chengdu, China
- Liver Surgery Center, West China Hospital of Sichuan University, Chengdu, China
| | - Jianyong Lei
- Thyroid and Parathyroid Surgery Center, West China Hospital of Sichuan University, Chengdu, China
- Liver Surgery Center, West China Hospital of Sichuan University, Chengdu, China
| | - Zhihui Li
- Thyroid and Parathyroid Surgery Center, West China Hospital of Sichuan University, Chengdu, China
- Liver Surgery Center, West China Hospital of Sichuan University, Chengdu, China
| | - Lunan Yan
- Liver Surgery Center, West China Hospital of Sichuan University, Chengdu, China
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16
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Dong C, Zhang BP, Ying YQ, Hou L, Wu W, Wei H, Luo XP. Oestradiol promotes the intrahepatic bile duct development of C57BL/6CrSlc mice during embryonic period via Notch signalling pathway. J Cell Mol Med 2021; 25:9447-9459. [PMID: 34498380 PMCID: PMC8500961 DOI: 10.1111/jcmm.16888] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 07/28/2021] [Accepted: 08/12/2021] [Indexed: 01/23/2023] Open
Abstract
Oestradiol (E2) is a critical factor for multiple systems' development during the embryonic period. Here, we aimed to investigate the effects of oestradiol on intrahepatic bile duct development, which may allow a better understanding of congenital bile duct dysplasia. DLK+ hepatoblasts were extracted from the C57BL/6CrSlc foetal mice and randomly divided into control group, oestradiol groups (1, 10, 100 nM) and oestradiol (10 nM) + DAPT (inhibitor of Notch signalling; 40 µM) group for in vitro experiments. For in vivo analysis, pregnant mice were divided into control group, oestradiol (intraperitoneal injection of 0.6 mg/kg/day) ± DAPT (subcutaneous injection of 10 mg/kg/day) groups and tamoxifen (gavage administration of 0.4 mg/kg/day) group. The results showed that oestradiol promoted hepatoblast differentiation into cholangiocytes and intrahepatic bile duct development during the embryonic period. Tamoxifen, an antioestrogenic drug, inhibited the above processes. Moreover, oestradiol promoted the expression of Notch signalling pathway‐associated proteins and genes both in vitro and in vivo. Notably, DAPT addition inhibited the oestradiol‐mediated effects. In conclusion, oestradiol can promote hepatoblast differentiation into cholangiocytes and intrahepatic bile duct development of C57BL/6CrSlc mice during embryonic period via the Notch signalling pathway.
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Affiliation(s)
- Chen Dong
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ben-Ping Zhang
- Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yan-Qin Ying
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ling Hou
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wei Wu
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hong Wei
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiao-Ping Luo
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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17
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Merrell AJ, Peng T, Li J, Sun K, Li B, Katsuda T, Grompe M, Tan K, Stanger BZ. Dynamic Transcriptional and Epigenetic Changes Drive Cellular Plasticity in the Liver. Hepatology 2021; 74:444-457. [PMID: 33423324 PMCID: PMC8271088 DOI: 10.1002/hep.31704] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 11/05/2020] [Accepted: 12/03/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Following liver injury, a fraction of hepatocytes adopt features of biliary epithelial cells (BECs) in a process known as biliary reprogramming. The aim of this study was to elucidate the molecular events accompanying this dramatic shift in cellular identity. APPROACH AND RESULTS We applied the techniques of bulk RNA-sequencing (RNA-seq), single-cell RNA-seq, and assay for transposase-accessible chromatin with high-throughput sequencing to define the epigenetic and transcriptional changes associated with biliary reprogramming. In addition, we examined the role of TGF-β signaling by profiling cells undergoing reprogramming in mice with hepatocyte-specific deletion in the downstream TGF-β signaling component mothers against decapentaplegic homolog 4 (Smad4). Biliary reprogramming followed a stereotyped pattern of altered gene expression consisting of robust induction of biliary genes and weaker repression of hepatocyte genes. These changes in gene expression were accompanied by corresponding modifications at the chromatin level. Although some reprogrammed cells had molecular features of "fully differentiated" BECs, most lacked some biliary characteristics and retained some hepatocyte characteristics. Surprisingly, single-cell analysis of Smad4 mutant mice revealed a dramatic increase in reprogramming. CONCLUSION Hepatocytes undergo widespread chromatin and transcriptional changes during biliary reprogramming, resulting in epigenetic and gene expression profiles that are similar to, but distinct from, native BECs. Reprogramming involves a progressive accumulation of biliary molecular features without discrete intermediates. Paradoxically, canonical TGF-β signaling through Smad4 appears to constrain biliary reprogramming, indicating that TGF-β can either promote or inhibit biliary differentiation depending on which downstream components of the pathway are engaged. This work has implications for the formation of BECs and bile ducts in the adult liver.
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Affiliation(s)
- Allyson J Merrell
- Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
- These authors contributed equally to this work
| | - Tao Peng
- Department of Biomedical and Health Informatics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
- These authors contributed equally to this work
| | - Jinyang Li
- Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Kathryn Sun
- Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
- Institute for Biomedical Informatics, Perelman School of Medicine at the University of Pennsylvania, PA 19104, USA
| | - Bin Li
- Papé Family Pediatric Research Center, Oregon Health and Science University, Portland, OR 97239, USA
| | - Takeshi Katsuda
- Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Markus Grompe
- Papé Family Pediatric Research Center, Oregon Health and Science University, Portland, OR 97239, USA
| | - Kai Tan
- Department of Biomedical and Health Informatics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
- Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Ben Z. Stanger
- Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
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18
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Zhu C, Ho YJ, Salomao MA, Dapito DH, Bartolome A, Schwabe RF, Lee JS, Lowe SW, Pajvani UB. Notch activity characterizes a common hepatocellular carcinoma subtype with unique molecular and clinicopathologic features. J Hepatol 2021; 74:613-626. [PMID: 33038431 PMCID: PMC7897246 DOI: 10.1016/j.jhep.2020.09.032] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 09/27/2020] [Accepted: 09/29/2020] [Indexed: 12/21/2022]
Abstract
BACKGROUND & AIMS The hepatocyte Notch pathway is a pathogenic factor in non-alcoholic steatohepatitis (NASH)-associated fibrosis, but its role in hepatocellular carcinoma (HCC) is less well defined. Herein, we aimed to characterize the molecular and clinical features of Notch-active human HCC, and to investigate the mechanisms by which Notch affects NASH-driven HCC. METHODS Using a 14-gene Notch score, we stratified human HCCs from multiple comprehensively profiled datasets. We performed gene set enrichment analyses to compare Notch-active HCCs with published HCC subtype signatures. Next, we sorted Notch-active hepatocytes from Notch reporter mice for RNA sequencing and characterized Notch-active tumors in an HCC model combining a carcinogen and a NASH-inducing diet. We used genetic mouse models to manipulate hepatocyte Notch to investigate the sufficiency and necessity of Notch in NASH-driven tumorigenesis. RESULTS Notch-active signatures were found in ~30% of human HCCs that transcriptionally resemble cholangiocarcinoma-like HCC, exhibiting a lack of activating CTNNB1 (β-catenin) mutations and a generally poor prognosis. Endogenous Notch activation in hepatocytes is associated with repressed β-catenin signaling and hepatic metabolic functions, in lieu of increased interactions with the extracellular matrix in NASH. Constitutive hepatocyte Notch activation is sufficient to induce β-catenin-inactive HCC in mice with NASH. Notch and β-catenin show a pattern of mutual exclusivity in carcinogen-induced HCC; in this mouse model, chronic blockade of Notch led to β-catenin-dependent tumor development. CONCLUSIONS Notch activity characterizes a distinct HCC molecular subtype with unique histology and prognosis. Sustained Notch signaling in chronic liver diseases can drive tumor formation without acquiring specific genomic driver mutations. LAY SUMMARY The Notch signaling pathway is known to be involved in the pathogenesis of liver fibrosis. However, its role in liver cancer has not been well defined. Herein, we show that Notch activity is increased in a subset of liver cancers and is associated with poor outcomes. We also used a mouse model to show that aberrant Notch activity can drive cancer progression in obese mice.
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Affiliation(s)
- Changyu Zhu
- Department of Medicine, Columbia University, New York, NY, USA;,Department of Cancer Biology and Genetics, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Yu-Jui Ho
- Department of Cancer Biology and Genetics, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Marcela A. Salomao
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, AZ, USA
| | | | | | | | - Ju-Seog Lee
- Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Scott W. Lowe
- Department of Cancer Biology and Genetics, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA;,Howard Hughes Medical Institute, Chevy Chase, MD, USA
| | - Utpal B. Pajvani
- Department of Medicine, Columbia University, New York, NY, USA;,Corresponding author: Utpal B. Pajvani, Department of Medicine, Columbia University, Russ Berrie Medical Science Pavilion, 1150 St Nicholas Ave, New York, NY, 10032. ; fax: (212) 851-5493
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19
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Maladaptive regeneration - the reawakening of developmental pathways in NASH and fibrosis. Nat Rev Gastroenterol Hepatol 2021; 18:131-142. [PMID: 33051603 PMCID: PMC7854502 DOI: 10.1038/s41575-020-00365-6] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/28/2020] [Indexed: 02/06/2023]
Abstract
With the rapid expansion of the obesity epidemic, nonalcoholic fatty liver disease is now the most common chronic liver disease, with almost 25% global prevalence. Nonalcoholic fatty liver disease ranges in severity from simple steatosis, a benign 'pre-disease' state, to the liver injury and inflammation that characterize nonalcoholic steatohepatitis (NASH), which in turn predisposes individuals to liver fibrosis. Fibrosis is the major determinant of clinical outcomes in patients with NASH and is associated with increased risks of cirrhosis and hepatocellular carcinoma. NASH has no approved therapies, and liver fibrosis shows poor response to existing pharmacotherapy, in part due to an incomplete understanding of the underlying pathophysiology. Patient and mouse data have shown that NASH is associated with the activation of developmental pathways: Notch, Hedgehog and Hippo-YAP-TAZ. Although these evolutionarily conserved fundamental signals are known to determine liver morphogenesis during development, new data have shown a coordinated and causal role for these pathways in the liver injury response, which becomes maladaptive during obesity-associated chronic liver disease. In this Review, we discuss the aetiology of this reactivation of developmental pathways and review the cell-autonomous and cell-non-autonomous mechanisms by which developmental pathways influence disease progression. Finally, we discuss the potential prognostic and therapeutic implications of these data for NASH and liver fibrosis.
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20
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Tulasi DY, Castaneda DM, Wager K, Hogan CB, Alcedo KP, Raab JR, Gracz AD. Sox9 EGFP Defines Biliary Epithelial Heterogeneity Downstream of Yap Activity. Cell Mol Gastroenterol Hepatol 2021; 11:1437-1462. [PMID: 33497866 PMCID: PMC8024983 DOI: 10.1016/j.jcmgh.2021.01.009] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 01/12/2021] [Accepted: 01/13/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Defining the genetic heterogeneity of intrahepatic biliary epithelial cells (BECs) is challenging, and tools for identifying BEC subpopulations are limited. Here, we characterize the expression of a Sox9EGFP transgene in the liver and demonstrate that green fluorescent protein (GFP) expression levels are associated with distinct cell types. METHODS Sox9EGFP BAC transgenic mice were assayed by immunofluorescence, flow cytometry, and gene expression profiling to characterize in vivo characteristics of GFP populations. Single BECs from distinct GFP populations were isolated by fluorescence-activated cell sorting, and functional analysis was conducted in organoid forming assays. Intrahepatic ductal epithelium was grown as organoids and treated with a Yes-associated protein (Yap) inhibitor or bile acids to determine upstream regulation of Sox9 in BECs. Sox9EGFP mice were subjected to bile duct ligation, and GFP expression was assessed by immunofluorescence. RESULTS BECs express low or high levels of GFP, whereas periportal hepatocytes express sublow GFP. Sox9EGFP+ BECs are differentially distributed by duct size and demonstrate distinct gene expression signatures, with enrichment of Cyr61 and Hes1 in GFPhigh BECs. Single Sox9EGFP+ cells form organoids that exhibit heterogeneous survival, growth, and HNF4A activation dependent on culture conditions, suggesting that exogenous signaling impacts BEC heterogeneity. Yap is required to maintain Sox9 expression in biliary organoids, but bile acids are insufficient to induce BEC Yap activity or Sox9 in vivo and in vitro. Sox9EGFP remains restricted to BECs and periportal hepatocytes after bile duct ligation. CONCLUSIONS Our data demonstrate that Sox9EGFP levels provide readout of Yap activity and delineate BEC heterogeneity, providing a tool for assaying subpopulation-specific cellular function in the liver.
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Affiliation(s)
- Deepthi Y. Tulasi
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Diego Martinez Castaneda
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Kortney Wager
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Connor B. Hogan
- Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia
| | - Karel P. Alcedo
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Jesse R. Raab
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina,Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Adam D. Gracz
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina,Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina,Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia,Correspondence Address correspondence to: Adam D. Gracz, PhD, 615 Michael Street NE, Suite 201A, Atlanta, Georgia 30322.fax: (404) 727-5767.
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21
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Gao C, Peng J. All routes lead to Rome: multifaceted origin of hepatocytes during liver regeneration. CELL REGENERATION 2021; 10:2. [PMID: 33403526 PMCID: PMC7785766 DOI: 10.1186/s13619-020-00063-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Accepted: 09/09/2020] [Indexed: 12/19/2022]
Abstract
Liver is the largest internal organ that serves as the key site for various metabolic activities and maintenance of homeostasis. Liver diseases are great threats to human health. The capability of liver to regain its mass after partial hepatectomy has widely been applied in treating liver diseases either by removing the damaged part of a diseased liver in a patient or transplanting a part of healthy liver into a patient. Vast efforts have been made to study the biology of liver regeneration in different liver-damage models. Regarding the sources of hepatocytes during liver regeneration, convincing evidences have demonstrated that different liver-damage models mobilized different subtype hepatocytes in contributing to liver regeneration. Under extreme hepatocyte ablation, biliary epithelial cells can undergo dedifferentiation to liver progenitor cells (LPCs) and then LPCs differentiate to produce hepatocytes. Here we will focus on summarizing the progresses made in identifying cell types contributing to producing new hepatocytes during liver regeneration in mice and zebrafish.
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Affiliation(s)
- Ce Gao
- MOE Key Laboratory for Molecular Animal Nutrition, College of Animal Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Jinrong Peng
- MOE Key Laboratory for Molecular Animal Nutrition, College of Animal Sciences, Zhejiang University, Hangzhou, 310058, China.
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22
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Kuchay MS, Choudhary NS, Mishra SK. Pathophysiological mechanisms underlying MAFLD. Diabetes Metab Syndr 2020; 14:1875-1887. [PMID: 32998095 DOI: 10.1016/j.dsx.2020.09.026] [Citation(s) in RCA: 94] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Revised: 09/21/2020] [Accepted: 09/23/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS The pathophysiology underlying metabolic associated fatty liver disease (MAFLD) involves a multitude of interlinked processes, including insulin resistance (IR) underlying the metabolic syndrome, lipotoxicity attributable to the accumulation of toxic lipid species, infiltration of proinflammatory cells causing hepatic injury and ultimately leading to hepatic stellate cell (HSC) activation and fibrogenesis. The proximal processes, such as IR, lipid overload and lipotoxicity are relatively well established, but the downstream molecular mechanisms, such as inflammatory processes, hepatocyte lipoapoptosis, and fibrogenesis are incompletely understood. METHODS A literature search was performed with Medline (PubMed), Scopus and Google Scholar electronic databases till June 2020, using relevant keywords (nonalcoholic fatty liver disease; metabolic associated fatty liver disease; nonalcoholic steatohepatitis; NASH pathogenesis) to extract relevant studies describing pathogenesis of MAFLD/MASH. RESULTS Several studies have reported new concepts underlying pathophysiology of MAFLD. Activation of HSCs is the common final pathway for diverse signals from damaged hepatocytes and proinflammatory cells. Activated HSCs then secrete excess extracellular matrix (ECM) which accumulates and impairs structure and function of the liver. TAZ (a transcriptional regulator), hedgehog (HH) ligands, transforming growth factor-β (TGF-β), bone morphogenetic protein 8B (BMP8B) and osteopontin play important roles in activating these HSCs. Dysfunctional gut microbiome, dysregulated bile acid metabolism, endogenous alcohol production, and intestinal fructose handling, modify individual susceptibility to MASH. CONCLUSIONS Newer concepts of pathophysiology underlying MASH, such as TAZ/Ihh pathway, extracellular vesicles, microRNA, dysfunctional gut microbiome and intestinal fructose handling present promising targets for the development of therapeutic agents.
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Affiliation(s)
- Mohammad Shafi Kuchay
- Division of Endocrinology and Metabolism, Medanta the Medicity Hospital, Gurugram, 122001, Haryana, India.
| | - Narendra Singh Choudhary
- Institute of Digestive and Hepatobiliary Sciences, Medanta-The Medicity Hospital, Gurugram, 122001, Haryana, India
| | - Sunil Kumar Mishra
- Division of Endocrinology and Metabolism, Medanta the Medicity Hospital, Gurugram, 122001, Haryana, India
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23
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The synthetic toxin biliatresone causes biliary atresia in mice. J Transl Med 2020; 100:1425-1435. [PMID: 32681026 DOI: 10.1038/s41374-020-0467-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Revised: 06/24/2020] [Accepted: 06/24/2020] [Indexed: 11/08/2022] Open
Abstract
Exposure to environmental toxins may be responsible for biliary atresia. The focus of this study was to investigate the effect of biliatresone on the development of the hepatobiliary system in mice. We successfully synthesized biliatresone with a purity of 98% and confirmed its biliary toxicity. Exposure to high doses of biliatresone caused abortion or death in pregnant mice. Neonatal mice injected with biliatresone developed clinical signs of biliary obstruction, and dysplasia or the absence of extrahepatic biliary tract lumen, which confirmed the occurrence of biliary atresia. In the portal tract of biliary atresia mice, signs of infiltration of inflammatory cells and liver fibrosis were observed. The signature of extrahepatic biliary gene expression in these mice mainly involved the cell adhesion process, and hepatic RNA-seq was highly linked to transcriptional evidence of oxidative stress. When compared with the control group, hepatic glutathione levels were markedly reduced after biliatresone injection. Taken together, these data confirm that biliatresone causes severe developmental abnormalities of the hepatobiliary system in mice. Furthermore, decreased levels of glutathione may play a mechanistic role in the pathogenesis of liver fibrosis in biliatresone-induced experimental biliary atresia.
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24
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Chaturantabut S, Shwartz A, Garnaas MK, LaBella K, Li CC, Carroll KJ, Cutting CC, Budrow N, Palaria A, Gorelick DA, Tremblay KD, North TE, Goessling W. Estrogen Acts Through Estrogen Receptor 2b to Regulate Hepatobiliary Fate During Vertebrate Development. Hepatology 2020; 72:1786-1799. [PMID: 32060934 PMCID: PMC8290048 DOI: 10.1002/hep.31184] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Accepted: 01/22/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS During liver development, bipotent progenitor cells differentiate into hepatocytes and biliary epithelial cells to ensure a functional liver required to maintain organismal homeostasis. The developmental cues controlling the differentiation of committed progenitors into these cell types, however, are incompletely understood. Here, we discover an essential role for estrogenic regulation in vertebrate liver development to affect hepatobiliary fate decisions. APPROACH AND RESULTS Exposure of zebrafish embryos to 17β-estradiol (E2) during liver development significantly decreased hepatocyte-specific gene expression, liver size, and hepatocyte number. In contrast, pharmacological blockade of estrogen synthesis or nuclear estrogen receptor (ESR) signaling enhanced liver size and hepatocyte marker expression. Transgenic reporter fish demonstrated nuclear ESR activity in the developing liver. Chemical inhibition and morpholino knockdown of nuclear estrogen receptor 2b (esr2b) increased hepatocyte gene expression and blocked the effects of E2 exposure. esr2b-/- mutant zebrafish exhibited significantly increased expression of hepatocyte markers with no impact on liver progenitors, other endodermal lineages, or vasculature. Significantly, E2-stimulated Esr2b activity promoted biliary epithelial differentiation at the expense of hepatocyte fate, whereas loss of esr2b impaired biliary lineage commitment. Chemical and genetic epistasis studies identified bone morphogenetic protein (BMP) signaling as a mediator of the estrogen effects. The divergent impact of estrogen on hepatobiliary fate was confirmed in a human hepatoblast cell line, indicating the relevance of this pathway for human liver development. CONCLUSIONS Our studies identify E2, esr2b, and downstream BMP activity as important regulators of hepatobiliary fate decisions during vertebrate liver development. These results have significant clinical implications for liver development in infants exposed to abnormal estrogen levels or estrogenic compounds during pregnancy.
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Affiliation(s)
| | - Arkadi Shwartz
- Genetics Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Maija K. Garnaas
- Genetics Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Kyle LaBella
- Genetics Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Chia-Cheng Li
- Genetics Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Kelli J. Carroll
- Stem Cell Program, Division of Hematology-Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Claire C. Cutting
- Genetics Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Nadine Budrow
- Stem Cell Program, Division of Hematology-Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Amrita Palaria
- Department of Animal and Veterinary Sciences, University of Massachusetts, Amherst, MA, USA
| | - Daniel A. Gorelick
- Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX, USA
| | - Kimberly D. Tremblay
- Department of Animal and Veterinary Sciences, University of Massachusetts, Amherst, MA, USA
| | - Trista E. North
- Stem Cell Program, Division of Hematology-Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA.,Harvard Stem Cell Institute, Cambridge, MA, USA
| | - Wolfram Goessling
- Genetics Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.,Harvard Stem Cell Institute, Cambridge, MA, USA.,Broad Institute of MIT and Harvard, Cambridge, MA, USA.,Dana-Farber Cancer Institute, Boston, MA, USA.,Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA, USA.,Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA
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25
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Repair of acute liver damage with immune evasive hESC derived hepato-blasts. Stem Cell Res 2020; 49:102010. [PMID: 33011360 DOI: 10.1016/j.scr.2020.102010] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Revised: 08/23/2020] [Accepted: 09/21/2020] [Indexed: 01/20/2023] Open
Abstract
Human embryonic stem cells (hESCs) can undergo unlimited self-renewal and differentiate into hepatic cells, including expandable hepato-blasts (HBs) and hepatocyte-like cells (HLCs) in vitro. Therefore, hESC-derived HBs have the potential to become a renewable cell source for cell therapy of serious liver damage. However, one of the key challenges for such cell therapy is the allogeneic immune rejection of hESC-derived HBs. To overcome this challenge, we developed a strategy to protect the hESC-derived HBs from allogeneic immune rejection by ectopically expressing immune suppressive molecules CTLA4-Ig and PD-L1, denoted CP HBs. Like HBs derived from normal hESCs, CP HBs are capable of repairing liver damage in animal models. Using humanized mice (Hu-mice) reconstituted with human immune system, we showed that CP HBs are protected from allogeneic immune system and can survive long-term in Hu-mice. These data support the feasibility to develop CP HBs into a cell therapy to treat serious liver damage.
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26
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Rauff B, Malik A, Bhatti YA, Chudhary SA, Qadri I, Rafiq S. Notch signalling pathway in development of cholangiocarcinoma. World J Gastrointest Oncol 2020; 12:957-974. [PMID: 33005291 PMCID: PMC7509998 DOI: 10.4251/wjgo.v12.i9.957] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 08/03/2020] [Accepted: 08/25/2020] [Indexed: 02/06/2023] Open
Abstract
Cholangiocarcinoma (CCA) comprises of extra-hepatic cholangiocarcinoma and intrahepatic cholangiocarcinoma cancers as a result of inflammation of epithelium cell lining of the bile duct. The incidence rate is increasing dramatically worldwide with highest rates in Eastern and South Asian regions. Major risk factors involve chronic damage and inflammation of bile duct epithelium from primary sclerosing cholangitis, chronic hepatitis virus infection, gallstones and liver fluke infection. Various genetic variants have also been identified and as CCA develops on the background of biliary inflammation, diverse range of molecular mechanisms are involved in its progression. Among these, the Notch signalling pathway acts as a major driver of cholangiocarcinogenesis and its components (receptors, ligands and downstream signalling molecules) represent a promising therapeutic targets. Gamma-Secretase Inhibitors have been recognized in inhibiting the Notch pathway efficiently. A comprehensive knowledge of the molecular pathways activated by the Notch signalling cascade as well as its functional crosstalk with other signalling pathways provide better approach in developing innovative therapies against CCA.
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Affiliation(s)
- Bisma Rauff
- Institute of Molecular Biology and Biotechnology, University of Lahore, Lahore 54000, Pakistan
| | - Arif Malik
- Institute of Molecular Biology and Biotechnology, University of Lahore, Lahore 54000, Pakistan
| | - Yasir Ali Bhatti
- Institute of Molecular Biology and Biotechnology, University of Lahore, Lahore 54000, Pakistan
| | - Shafiq Ahmad Chudhary
- Institute of Biomedical and Allied Health Sciences, University of Health Sciences, Lahore 54000, Pakistan
| | - Ishtiaq Qadri
- Department of Biology, Faculty of Science, King Abdulaziz University Jeddah Kingdom of Saudi Arabia
| | - Shafquat Rafiq
- Department of Gastrointestinal medicine, Croydon University Hospital, Croydon CR7 7YE, United Kingdom
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27
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Afshari A, Shamdani S, Uzan G, Naserian S, Azarpira N. Different approaches for transformation of mesenchymal stem cells into hepatocyte-like cells. Stem Cell Res Ther 2020; 11:54. [PMID: 32033595 PMCID: PMC7007672 DOI: 10.1186/s13287-020-1555-8] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Revised: 12/21/2019] [Accepted: 01/07/2020] [Indexed: 01/09/2023] Open
Abstract
Due to the prominent role of the liver in the body and detoxification, its functionality can be affected in an irreversible manner by diseases. This phenomenon renders the liver to stop working, leading to morbidity and mortality. Therefore, liver transplantation is the only way to tackle this issue.In order to compensate for the lack of adequate healthy liver tissue for transplantation, therapeutic approaches such as hepatocyte transplantation have been proposed as an alternative. Recognizing the fact that mesenchymal stem cells are adult stem cells with the capacity to differentiate into several cell types, different methods have been invented to produce hepatocyte-like cells from mesenchymal stem cells. They can be divided into three main categories, such as addition of cytokines and growth factors, genetic modifications, and adjustment of microenvironment as well as physical parameters.In this review, we attempted to introduce diverse efficient methods for differentiating mesenchymal stem cells and their capability for transformation into hepatocyte-like cells.
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Affiliation(s)
- Afsoon Afshari
- Transplant Research Center, Shiraz University of Medical Sciences, Khalili street, Shiraz, Iran
| | - Sara Shamdani
- INSERM UMR-S-MD 1197/Ministry of the Armed Forces, Biomedical Research Institute of the Armed Forces (IRBA), Paul-Brousse Hospital Villejuif and CTSA Clamart, 94807, Villejuif, France.,SivanCell, Tehran, Iran.,CellMedEx, Saint Maur Des Fossés, France
| | - Georges Uzan
- INSERM UMR-S-MD 1197/Ministry of the Armed Forces, Biomedical Research Institute of the Armed Forces (IRBA), Paul-Brousse Hospital Villejuif and CTSA Clamart, 94807, Villejuif, France
| | - Sina Naserian
- INSERM UMR-S-MD 1197/Ministry of the Armed Forces, Biomedical Research Institute of the Armed Forces (IRBA), Paul-Brousse Hospital Villejuif and CTSA Clamart, 94807, Villejuif, France.,SivanCell, Tehran, Iran.,CellMedEx, Saint Maur Des Fossés, France
| | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Khalili street, Shiraz, Iran.
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28
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Generation of qualified clinical-grade functional hepatocytes from human embryonic stem cells in chemically defined conditions. Cell Death Dis 2019; 10:763. [PMID: 31601782 PMCID: PMC6787193 DOI: 10.1038/s41419-019-1967-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Revised: 08/10/2019] [Accepted: 09/09/2019] [Indexed: 12/12/2022]
Abstract
Hepatocytes have been successfully generated from human pluripotent stem cells (hPSCs). However, the cost-effective and clinical-grade generation of hepatocytes from hPSCs still need to be improved. In this study, we reported the production of functional hepatocytes from clinical-grade human embryonic stem cells (hESCs) under good manufacturing practice (GMP) requirements. We sequentially generated primitive streak (PS), definitive endoderm (DE), hepatoblasts and hepatocyte-like cells (HLCs) from hESCs in the different stages with completely defined reagents. During hepatoblast differentiation, dimethyl sulfoxide (DMSO), transferrin, L-ascorbic acid 2-phosphate sesquimagnesium salt hydrate (Vc-Mg), insulin, and sodium selenite were used instead of cytokines and FBS/KOSR. Then, hepatoblasts were differentiated into HLCs that had a typical hepatocyte morphology and possessed characteristics of mature hepatocytes, such as metabolic-related gene expression, albumin secretion, fat accumulation, glycogen storage, and inducible cytochrome P450 activity in vitro. HLCs integrated into the livers of Tet-uPA Rag2–/– Il2rg–/– (URG) mice, which partially recovered after transplantation. Furthermore, a series of biosafety-related experiments were performed to ensure future clinical applications. In conclusion, we developed a chemically defined system to generate qualified clinical-grade HLCs from hESCs under GMP conditions. HLCs have been proven to be safe and effective for treating liver failure. This efficient platform could facilitate the treatment of liver diseases using hESC-derived HLCs transplantation.
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29
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Buisson EM, Jeong J, Kim HJ, Choi D. Regenerative Medicine of the Bile Duct: Beyond the Myth. Int J Stem Cells 2019; 12:183-194. [PMID: 31022996 PMCID: PMC6657949 DOI: 10.15283/ijsc18055] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Revised: 08/31/2018] [Accepted: 09/03/2018] [Indexed: 12/12/2022] Open
Abstract
Cholangiopathies are rare diseases of the bile duct with high mortality rates. The current treatment for cholangiopathies is liver transplantation, but there are significant obstacles including a shortage of donors and a high risk of complications. Currently, there is only one available medicine on the market targeting cholangiopathies, and the results have been inadequate in clinical therapy. To overcome these obstacles, many researchers have used human induced pluripotent stem cells (hPSC) as a source for cholangiocyte-like cell generation and have incorporated advances in bioprinting to create artificial bile ducts for implantation and transplantation. This has allowed the field to move dramatically forward in studies of biliary regenerative medicine. In this review, the authors provide an overview of cholangiocytes, the organogenesis of the bile duct, cholangiopathies, and the current treatment and advances that have been made that are opening new doors to the study of cholangiopathies.
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Affiliation(s)
- Elina Maria Buisson
- Department of Translational Medicine, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea.,Department of Surgery, Hanyang University College of Medicine, Hanyang University, Seoul, Korea.,HY Indang Center of Regenerative Medicine and Stem Cell Research, Hanyang University, Hanyang University, Seoul, Korea
| | - Jaemin Jeong
- Department of Surgery, Hanyang University College of Medicine, Hanyang University, Seoul, Korea.,HY Indang Center of Regenerative Medicine and Stem Cell Research, Hanyang University, Hanyang University, Seoul, Korea
| | - Han Joon Kim
- Department of Surgery, Hanyang University College of Medicine, Hanyang University, Seoul, Korea
| | - Dongho Choi
- Department of Translational Medicine, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea.,Department of Surgery, Hanyang University College of Medicine, Hanyang University, Seoul, Korea.,HY Indang Center of Regenerative Medicine and Stem Cell Research, Hanyang University, Hanyang University, Seoul, Korea
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30
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Abstract
Cholangiocytes, the epithelial cells lining the intrahepatic and extrahepatic bile ducts, are highly specialized cells residing in a complex anatomic niche where they participate in bile production and homeostasis. Cholangiocytes are damaged in a variety of human diseases termed cholangiopathies, often causing advanced liver failure. The regulation of cholangiocyte transport properties is increasingly understood, as is their anatomical and functional heterogeneity along the biliary tract. Furthermore, cholangiocytes are pivotal in liver regeneration, especially when hepatocyte regeneration is compromised. The role of cholangiocytes in innate and adaptive immune responses, a critical subject relevant to immune-mediated cholangiopathies, is also emerging. Finally, reactive ductular cells are present in many cholestatic and other liver diseases. In chronic disease states, this repair response contributes to liver inflammation, fibrosis and carcinogenesis and is a subject of intense investigation. This Review highlights advances in cholangiocyte research, especially their role in development and liver regeneration, their functional and biochemical heterogeneity, their activation and involvement in inflammation and fibrosis and their engagement with the immune system. We aim to focus further attention on cholangiocyte pathobiology and the search for new disease-modifying therapies targeting the cholangiopathies.
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31
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Affiliation(s)
- Stefano Romeo
- From the Department of Molecular and Clinical Medicine, University of Gothenburg, and the Cardiology Department, Sahlgrenska University Hospital, Gothenburg, Sweden; and the Clinical Nutrition Unit, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
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32
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Zhu C, Kim K, Wang X, Bartolome A, Salomao M, Dongiovanni P, Meroni M, Graham MJ, Yates KP, Diehl AM, Schwabe RF, Tabas I, Valenti L, Lavine JE, Pajvani UB. Hepatocyte Notch activation induces liver fibrosis in nonalcoholic steatohepatitis. Sci Transl Med 2018; 10:10/468/eaat0344. [PMID: 30463916 PMCID: PMC6822168 DOI: 10.1126/scitranslmed.aat0344] [Citation(s) in RCA: 176] [Impact Index Per Article: 25.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Revised: 06/03/2018] [Accepted: 10/31/2018] [Indexed: 01/07/2023]
Abstract
Fibrosis is the major determinant of morbidity and mortality in patients with nonalcoholic steatohepatitis (NASH) but has no approved pharmacotherapy in part because of incomplete understanding of its pathogenic mechanisms. Here, we report that hepatocyte Notch activity tracks with disease severity and treatment response in patients with NASH and is similarly increased in a mouse model of diet-induced NASH and liver fibrosis. Hepatocyte-specific Notch loss-of-function mouse models showed attenuated NASH-associated liver fibrosis, demonstrating causality to obesity-induced liver pathology. Conversely, forced activation of hepatocyte Notch induced fibrosis in both chow- and NASH diet-fed mice by increasing Sox9-dependent Osteopontin (Opn) expression and secretion from hepatocytes, which activate resident hepatic stellate cells. In a cross-sectional study, we found that OPN explains the positive correlation between liver Notch activity and fibrosis stage in patients. Further, we developed a Notch inhibitor [Nicastrin antisense oligonucleotide (Ncst ASO)] that reduced fibrosis in NASH diet-fed mice. In summary, these studies demonstrate the pathological role and therapeutic accessibility of the maladaptive hepatocyte Notch response in NASH-associated liver fibrosis.
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Affiliation(s)
- Changyu Zhu
- Department of Medicine, Columbia University, New York, NY 10032, USA
| | - KyeongJin Kim
- Department of Medicine, Columbia University, New York, NY 10032, USA
| | - Xiaobo Wang
- Department of Medicine, Columbia University, New York, NY 10032, USA
| | - Alberto Bartolome
- Department of Medicine, Columbia University, New York, NY 10032, USA
| | - Marcela Salomao
- Department of Pathology, Mayo Clinic, Phoenix, AZ 85054, USA
| | - Paola Dongiovanni
- Department of Pathophysiology and Transplantation, Università degli Studi Milano, and Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Policlinico, Milan 20122, Italy
| | - Marica Meroni
- Department of Pathophysiology and Transplantation, Università degli Studi Milano, and Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Policlinico, Milan 20122, Italy
| | | | - Katherine P. Yates
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
| | - Anna Mae Diehl
- Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA
| | - Robert F. Schwabe
- Department of Medicine, Columbia University, New York, NY 10032, USA
| | - Ira Tabas
- Department of Medicine, Columbia University, New York, NY 10032, USA
| | - Luca Valenti
- Department of Pathophysiology and Transplantation, Università degli Studi Milano, and Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Policlinico, Milan 20122, Italy
| | - Joel E. Lavine
- Department of Pediatrics, Columbia University, New York, NY 10032, USA
| | - Utpal B. Pajvani
- Department of Medicine, Columbia University, New York, NY 10032, USA.,Corresponding author.
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33
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Ober EA, Lemaigre FP. Development of the liver: Insights into organ and tissue morphogenesis. J Hepatol 2018; 68:1049-1062. [PMID: 29339113 DOI: 10.1016/j.jhep.2018.01.005] [Citation(s) in RCA: 146] [Impact Index Per Article: 20.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Revised: 12/29/2017] [Accepted: 01/06/2018] [Indexed: 02/08/2023]
Abstract
Recent development of improved tools and methods to analyse tissues at the three-dimensional level has expanded our capacity to investigate morphogenesis of foetal liver. Here, we review the key morphogenetic steps during liver development, from the prehepatic endoderm stage to the postnatal period, and consider several model organisms while focussing on the mammalian liver. We first discuss how the liver buds out of the endoderm and gives rise to an asymmetric liver. We next outline the mechanisms driving liver and lobe growth, and review morphogenesis of the intra- and extrahepatic bile ducts; morphogenetic responses of the biliary tract to liver injury are discussed. Finally, we describe the mechanisms driving formation of the vasculature, namely venous and arterial vessels, as well as sinusoids.
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Affiliation(s)
- Elke A Ober
- Novo Nordisk Center for Stem Cell Biology (DanStem), University of Copenhagen, Copenhagen, Denmark
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Ogawa T, Li Y, Lua I, Hartner A, Asahina K. Isolation of a unique hepatic stellate cell population expressing integrin α8 from embryonic mouse livers. Dev Dyn 2018; 247:867-881. [PMID: 29665133 DOI: 10.1002/dvdy.24634] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Revised: 03/16/2018] [Accepted: 04/10/2018] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Hepatic stellate cells (HSCs) play an important role in liver fibrogenesis. However, little is known about their phenotype and role in liver development. The aim of this study is to identify specific markers for embryonic HSCs. RESULTS Using antibodies against ALCAM and PDPN, we separated mesothelial cells (MCs) and HSCs from developing livers and identified integrin α8 (ITGA8) as a marker for embryonic desmin+ HSCs that are preferentially localized near the developing liver surface and α-smooth muscle actin+ perivascular mesenchymal cells around the vein. A cell lineage-tracing study revealed that upon differentiation, MC-derived HSCs or perivascular mesenchymal cells express ITGA8 during liver development. Using anti-ITGA8 antibodies, we succeeded in isolating MC-derived HSCs and perivascular mesenchymal cells from embryonic livers. In direct co-culture, ITGA8+ mesenchymal cells promoted the expression of hepatocyte and cholangiocyte markers in hepatoblasts. In the normal adult liver, expression of ITGA8 was restricted to portal fibroblasts in the portal triad. Upon liver injury, myofibroblasts increased the expression of ITGA8. CONCLUSIONS ITGA8 is a specific cell surface marker of MC-derived HSCs and perivascular mesenchymal cells in the developing liver. Our data suggest that ITGA8+ mesenchymal cells maintain the phenotype of hepatoblast in liver development. Developmental Dynamics 247:867-881, 2018. © 2018 Wiley Periodicals, Inc.
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Affiliation(s)
- Tomohiro Ogawa
- Southern California Research Center for ALPD and Cirrhosis and Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, California.,Center for the Advancement of Higher Education, Faculty of Engineering, Kindai University, Hiroshima, Japan
| | - Yuchang Li
- Southern California Research Center for ALPD and Cirrhosis and Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, California
| | - Ingrid Lua
- Southern California Research Center for ALPD and Cirrhosis and Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, California
| | - Andrea Hartner
- Department of Pediatrics and Adolescent Medicine, University Hospital of Erlangen, Erlangen, Germany
| | - Kinji Asahina
- Southern California Research Center for ALPD and Cirrhosis and Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, California
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Crawford JM, Bioulac-Sage P, Hytiroglou P. Structure, Function, and Responses to Injury. MACSWEEN'S PATHOLOGY OF THE LIVER 2018:1-87. [DOI: 10.1016/b978-0-7020-6697-9.00001-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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36
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The Hippo signaling functions through the Notch signaling to regulate intrahepatic bile duct development in mammals. J Transl Med 2017; 97:843-853. [PMID: 28581486 PMCID: PMC5901959 DOI: 10.1038/labinvest.2017.29] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Revised: 12/22/2016] [Accepted: 02/06/2017] [Indexed: 12/24/2022] Open
Abstract
The Hippo signaling pathway and the Notch signaling pathway are evolutionary conserved signaling cascades that have important roles in embryonic development of many organs. In murine liver, disruption of either pathway impairs intrahepatic bile duct development. Recent studies suggested that the Notch signaling receptor Notch2 is a direct transcriptional target of the Hippo signaling pathway effector YAP, and the Notch signaling is a major mediator of the Hippo signaling in maintaining biliary cell characteristics in adult mice. However, it remains to be determined whether the Hippo signaling pathway functions through the Notch signaling in intrahepatic bile duct development. We found that loss of the Hippo signaling pathway tumor suppressor Nf2 resulted in increased expression levels of the Notch signaling pathway receptor Notch2 in cholangiocytes but not in hepatocytes. When knocking down Notch2 on the background of Nf2 deficiency in mouse livers, the excessive bile duct development induced by Nf2 deficiency was suppressed by heterozygous and homozygous deletion of Notch2 in a dose-dependent manner. These results implicated that Notch signaling is one of the downstream effectors of the Hippo signaling pathway in regulating intrahepatic bile duct development.
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Abstract
Despite decades of basic research, biliary diseases remain prevalent, highly morbid, and notoriously difficult to treat. We have, however, dramatically increased our understanding of biliary developmental biology, cholangiocyte pathophysiology, and the endogenous mechanisms of biliary regeneration and repair. All of this complex and rapidly evolving knowledge coincides with an explosion of new technological advances in the area of regenerative medicine. New breakthroughs such as induced pluripotent stem cells and organoid culture are increasingly being applied to the biliary system; it is only a matter of time until new regenerative therapeutics for the cholangiopathies are unveiled. In this review, the authors integrate what is known about biliary development, regeneration, and repair, and link these conceptual advances to the technological breakthroughs that are collectively driving the emergence of a new global field in biliary regenerative medicine.
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Affiliation(s)
- Thiago M. De Assuncao
- Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, MN,Gastroenterology Research Unit, Mayo Clinic and Foundation, Rochester, MN
| | - Nidhi Jalan-Sakrikar
- Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, MN,Gastroenterology Research Unit, Mayo Clinic and Foundation, Rochester, MN
| | - Robert C. Huebert
- Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, MN,Gastroenterology Research Unit, Mayo Clinic and Foundation, Rochester, MN,Center for Cell Signaling in Gastroenterology; Mayo Clinic and Foundation, Rochester, MN
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38
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Awad A, Gassama-Diagne A. PI3K/SHIP2/PTEN pathway in cell polarity and hepatitis C virus pathogenesis. World J Hepatol 2017; 9:18-29. [PMID: 28105255 PMCID: PMC5220268 DOI: 10.4254/wjh.v9.i1.18] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Revised: 09/10/2016] [Accepted: 11/02/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infects hepatocytes, polarized cells in the liver. Chronic HCV infection often leads to steatosis, fibrosis, cirrhosis and hepatocellular carcinoma, and it has been identified as the leading cause of liver transplantation worldwide. The HCV replication cycle is dependent on lipid metabolism and particularly an accumulation of lipid droplets in host cells. Phosphoinositides (PIs) are minor phospholipids enriched in different membranes and their levels are tightly regulated by specific PI kinases and phosphatases. PIs are implicated in a vast array of cellular responses that are central to morphogenesis, such as cytoskeletal changes, cytokinesis and the recruitment of downstream effectors to govern mechanisms involved in polarization and lumen formation. Important reviews of the literature identified phosphatidylinositol (PtdIns) 4-kinases, and their lipid products PtdIns(4)P, as critical regulators of the HCV life cycle. SH2-containing inositol polyphosphate 5-phosphatase (SHIP2), phosphoinositide 3-kinase (PI3K) and their lipid products PtdIns(3,4)P2 and PtdIns(3,4,5)P3, respectively, play an important role in the cell membrane and are key to the establishment of apicobasal polarity and lumen formation. In this review, we will focus on these new functions of PI3K and SHIP2, and their deregulation by HCV, causing a disruption of apicobasal polarity, actin organization and extracellular matrix assembly. Finally we will highlight the involvement of this pathway in the event of insulin resistance and nonalcoholic fatty liver disease related to HCV infection.
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Che L, Fan B, Pilo MG, Xu Z, Liu Y, Cigliano A, Cossu A, Palmieri G, Pascale RM, Porcu A, Vidili G, Serra M, Dombrowski F, Ribback S, Calvisi DF, Chen X. Jagged 1 is a major Notch ligand along cholangiocarcinoma development in mice and humans. Oncogenesis 2016; 5:e274. [PMID: 27918553 PMCID: PMC5177771 DOI: 10.1038/oncsis.2016.73] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Revised: 09/26/2016] [Accepted: 10/10/2016] [Indexed: 02/07/2023] Open
Abstract
Intrahepatic cholangiocarcinoma (ICC) is a rare yet deadly malignancy with limited treatment options. Activation of the Notch signalling cascade has been implicated in cholangiocarcinogenesis. However, while several studies focused on the Notch receptors required for ICC development, little is known about the upstream inducers responsible for their activation. Here, we show that the Jagged 1 (Jag1) ligand is almost ubiquitously upregulated in human ICC samples when compared with corresponding non-tumorous counterparts. Furthermore, we found that while overexpression of Jag1 alone does not lead to liver tumour development, overexpression of Jag1 synergizes with activated AKT signalling to promote liver carcinogenesis in AKT/Jag1 mice. Histologically, tumours consisted exclusively of ICC, with hepatocellular tumours not occurring in AKT/Jag1 mice. Furthermore, tumours from AKT/Jag1 mice exhibited extensive desmoplastic reaction, an important feature of human ICC. At the molecular level, we found that both AKT/mTOR and Notch cascades are activated in AKT/Jag1 ICC tissues, and that the Notch signalling is necessary for ICC development in AKT/Jag1 mice. In human ICC cell lines, silencing of Jag1 via specific small interfering RNA reduces proliferation and increases apoptosis. Finally, combined inhibition of AKT and Notch pathways is highly detrimental for the in vitro growth of ICC cell lines. In summary, our study demonstrates that Jag1 is an important upstream inducer of the Notch signalling in human and mouse ICC. Targeting Jag1 might represent a novel therapeutic strategy for the treatment of this deadly disease.
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Affiliation(s)
- L Che
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China.,Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA
| | - B Fan
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China.,Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA
| | - M G Pilo
- Institute of Pathology, University of Greifswald, Greifswald, Germany
| | - Z Xu
- Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA.,Department of Gastroenterology, Guizhou Provincial People's Hospital, The Affiliated People's Hospital of Guizhou Medical University, Guiyang, China
| | - Y Liu
- Department of Gastroenterology, 307 Hospital of PLA, Beijing, China
| | - A Cigliano
- Institute of Pathology, University of Greifswald, Greifswald, Germany
| | - A Cossu
- Unit of Pathology, Azienda Ospedaliero Universitaria Sassari, Sassari, Italy
| | - G Palmieri
- Institute of Biomolecular Chemistry, National Research Council, Sassari, Italy
| | - R M Pascale
- Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy
| | - A Porcu
- Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy
| | - G Vidili
- Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy
| | - M Serra
- Institute of Pathology, University of Greifswald, Greifswald, Germany
| | - F Dombrowski
- Institute of Pathology, University of Greifswald, Greifswald, Germany
| | - S Ribback
- Institute of Pathology, University of Greifswald, Greifswald, Germany
| | - D F Calvisi
- Institute of Pathology, University of Greifswald, Greifswald, Germany.,Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy
| | - X Chen
- Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA
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Abstract
OBJECTIVES Biliary atresia (BA) is an idiopathic neonatal liver disease, characterized by inflammatory and fibrotic obliteration of extrahepatic bile ducts. Therefore, reliable methods for noninvasive diagnosis are needed. The present study aimed to analyze circulating microRNAs (miRNAs) in patients with BA using next-generation sequencing for identifying novel diagnostic biomarkers. METHODS An initial screening of miRNAs in plasma from patients with BA and healthy controls (HCs) was performed on an Illumina next-generation sequencing platform. Differential miRNAs were validated by quantitative real-time polymerase chain reaction (qPCR). Target genes and related signal transduction pathways of differential miRNAs were predicted by online software. RESULTS In total, 146 differential miRNAs were identified by deep sequencing. Fifteen miRNAs with read counts >1000, that included 7 upregulated and 8 downregulated miRNAs, were predicted to be associated with liver fibrosis, biliary differentiation, and bile duct development. Of these, 6 miRNAs with read counts >5000 were analyzed by qPCR on an independent sample set comprising 44 patients with BA, 20 cholestatic disease controls, and 20 HCs. Two upregulated miRNAs (miR-122-5p, miR-100-5p) and 2 downregulated miRNAs (miR-140-3p, miR-126-3p) were confirmed by individual qPCR. Only miR-140-3p was significantly different from controls (P < 0.05), yielding an area under receiver operating characteristic curve of 0.75 with sensitivity of 66.7% and specificity of 79.1% at optimal threshold. CONCLUSIONS Our findings indicate that patients with BA exhibit a distinct profile of circulating miRNAs and that plasma miR-140-3p may be a promising diagnostic biomarker for this disease.
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41
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Shan Y, Shen N, Han L, Chen Q, Zhang J, Long X, Xia Q. MicroRNA-499 Rs3746444 polymorphism and biliary atresia. Dig Liver Dis 2016; 48:423-8. [PMID: 26795543 DOI: 10.1016/j.dld.2015.11.014] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2015] [Revised: 11/11/2015] [Accepted: 11/16/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND Single nucleotide polymorphisms within microRNAs are known to affect the risk in development and prognosis of many diseases. This study was designed to investigate whether polymorphism of microRNA-499 (miR-499, rs3746444 A>G) is associated with risk to biliary atresia (BA). METHODS A hospital-based cases-control study was performed on a total of 507 Han Chinese (207 BA cases and 300 ethnically-matched healthy controls without any evidence of liver diseases) so as to analyze the association between miR-499 rs3746444 polymorphism and BA risk as well as liver function remission (LFR) after liver transplantation. RESULTS A significant higher frequency of the rs3746444 G alleles was found in the BA cases than the control group (odd ratio, 1.55, 95% confidence intervals [CIs], 1.15-2.10). This polymorphism was also observed to correlate with some clinic-pathological features of BA cases such as liver inflammatory. Further research found both higher levels of IL-6 (P<0.05) and TNF-α (P<0.05) in removed liver as well as in serum. What is more, the miR-499 rs3746444 polymorphism significantly affected the status of LFR (hazard ratio, 1.37; 95% CI, 1.08-1.83). CONCLUSIONS MiR-499 (rs3746444) gene polymorphisms may be genetic determinants for increased risk of BA and prolonged recovery of BA patients after liver transplantation in Han Chinese.
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Affiliation(s)
- Yuhua Shan
- Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, China.
| | - Nan Shen
- Joint Molecular Rheumatology Laboratory of the Institute of Health Sciences and Shanghai Renji Hospital, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Longzhi Han
- Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, China.
| | - Qimin Chen
- Department of Surgery, Shanghai Children's Medical Centre, School of Medicine, Shanghai Jiao Tong University, China.
| | - Jianjun Zhang
- Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, China.
| | - Xidai Long
- Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, China.
| | - Qiang Xia
- Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, China.
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Baiting for Cancer: Using the Zebrafish as a Model in Liver and Pancreatic Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 916:391-410. [DOI: 10.1007/978-3-319-30654-4_17] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Berasain C, Avila MA. Regulation of hepatocyte identity and quiescence. Cell Mol Life Sci 2015; 72:3831-51. [PMID: 26089250 PMCID: PMC11114060 DOI: 10.1007/s00018-015-1970-7] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2015] [Revised: 05/23/2015] [Accepted: 06/12/2015] [Indexed: 12/11/2022]
Abstract
The liver is a highly differentiated organ with a central role in metabolism, detoxification and systemic homeostasis. To perform its multiple tasks, liver parenchymal cells, the hepatocytes, express a large complement of enabling genes defining their complex phenotype. This phenotype is progressively acquired during fetal development and needs to be maintained in adulthood to guarantee the individual's survival. Upon injury or loss of functional mass, the liver displays an extraordinary regenerative response, mainly based on the proliferation of hepatocytes which otherwise are long-lived quiescent cells. Increasing observations suggest that loss of hepatocellular differentiation and quiescence underlie liver malfunction in chronic liver disease and pave the way for hepatocellular carcinoma development. Here, we briefly review the essential mechanisms leading to the acquisition of liver maturity. We also identify the key molecular factors involved in the preservation of hepatocellular homeostasis and finally discuss potential strategies to preserve liver identity and function.
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Affiliation(s)
- Carmen Berasain
- Division of Hepatology, CIMA, University of Navarra, CIBEREHD, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Avda. Pio XII, n55, 31008, Pamplona, Spain.
| | - Matías A Avila
- Division of Hepatology, CIMA, University of Navarra, CIBEREHD, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Avda. Pio XII, n55, 31008, Pamplona, Spain.
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Nguyen Q, Anders RA, Alpini G, Bai H. Yes-associated protein in the liver: Regulation of hepatic development, repair, cell fate determination and tumorigenesis. Dig Liver Dis 2015; 47:826-35. [PMID: 26093945 DOI: 10.1016/j.dld.2015.05.011] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Revised: 04/30/2015] [Accepted: 05/14/2015] [Indexed: 12/11/2022]
Abstract
The liver is a vital organ that plays a major role in many bodily functions from protein production and blood clotting to cholesterol, glucose and iron metabolism and nutrition storage. Maintenance of liver homeostasis is critical for these essential bodily functions and disruption of liver homeostasis causes various kinds of liver diseases, some of which have high mortality rate. Recent research advances of the Hippo signalling pathway have revealed its nuclear effector, Yes-associated protein, as an important regulator of liver development, repair, cell fate determination and tumorigenesis. Therefore, a precise control of Yes-associated protein activity is critical for the maintenance of liver homeostasis. This review is going to summarize the discoveries on how the manipulation of Yes-associated protein activity affects liver homeostasis and induces liver diseases and the regulatory mechanisms that determine the Yes-associated protein activity in the liver. Finally, we will discuss the potential of targeting Yes-associated protein as therapeutic strategies in liver diseases.
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Affiliation(s)
- Quy Nguyen
- Research, Central Texas Veterans Health Care System, Temple, TX, United States
| | - Robert A Anders
- Department of Pathology, Johns Hopkins University, Baltimore, MD, United States
| | - Gianfranco Alpini
- Research, Central Texas Veterans Health Care System, Temple, TX, United States; Digestive Diseases Research Center, BaylorScott&White Healthcare, Temple, TX, United States; Department of Internal Medicine and Medical Physiology, Texas A&M Health Science Center, Temple, TX, United States
| | - Haibo Bai
- Research, Central Texas Veterans Health Care System, Temple, TX, United States; Digestive Diseases Research Center, BaylorScott&White Healthcare, Temple, TX, United States; Department of Internal Medicine and Medical Physiology, Texas A&M Health Science Center, Temple, TX, United States.
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45
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De Assuncao TM, Sun Y, Jalan-Sakrikar N, Drinane M, Huang BQ, Li Y, Davila JI, Wang R, O’Hara SP, Lomberk GA, Urrutia RA, Ikeda Y, Huebert RC. Development and characterization of human-induced pluripotent stem cell-derived cholangiocytes. J Transl Med 2015; 95:684-96. [PMID: 25867762 PMCID: PMC4447567 DOI: 10.1038/labinvest.2015.51] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2014] [Revised: 01/26/2015] [Accepted: 02/04/2015] [Indexed: 12/25/2022] Open
Abstract
Cholangiocytes are the target of a heterogeneous group of liver diseases known as the cholangiopathies. An evolving understanding of the mechanisms driving biliary development provides the theoretical underpinnings for rational development of induced pluripotent stem cell (iPSC)-derived cholangiocytes (iDCs). Therefore, the aims of this study were to develop an approach to generate iDCs and to fully characterize the cells in vitro and in vivo. Human iPSC lines were generated by forced expression of the Yamanaka pluripotency factors. We then pursued a stepwise differentiation strategy toward iDCs, using precise temporal exposure to key biliary morphogens, and we characterized the cells, using a variety of morphologic, molecular, cell biologic, functional, and in vivo approaches. Morphology shows a stepwise phenotypic change toward an epithelial monolayer. Molecular analysis during differentiation shows appropriate enrichment in markers of iPSC, definitive endoderm, hepatic specification, hepatic progenitors, and ultimately cholangiocytes. Immunostaining, western blotting, and flow cytometry demonstrate enrichment of multiple functionally relevant biliary proteins. RNA sequencing reveals that the transcriptome moves progressively toward that of human cholangiocytes. iDCs generate intracellular calcium signaling in response to ATP, form intact primary cilia, and self-assemble into duct-like structures in three-dimensional culture. In vivo, the cells engraft within mouse liver, following retrograde intrabiliary infusion. In summary, we have developed a novel approach to generate mature cholangiocytes from iPSCs. In addition to providing a model of biliary differentiation, iDCs represent a platform for in vitro disease modeling, pharmacologic testing, and individualized, cell-based, regenerative therapies for the cholangiopathies.
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Affiliation(s)
- Thiago M. De Assuncao
- Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, MN,Gastroenterology Research Unit, Mayo Clinic and Foundation, Rochester, MN
| | - Yan Sun
- Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, MN,Gastroenterology Research Unit, Mayo Clinic and Foundation, Rochester, MN
| | - Nidhi Jalan-Sakrikar
- Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, MN,Gastroenterology Research Unit, Mayo Clinic and Foundation, Rochester, MN
| | - Mary Drinane
- Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, MN,Gastroenterology Research Unit, Mayo Clinic and Foundation, Rochester, MN
| | - Bing Q. Huang
- Center for Basic Research in Digestive Diseases, Mayo Clinic and Foundation, Rochester, MN
| | - Ying Li
- Division of Biomedical Statistics and Informatics, Mayo Clinic and Foundation, Rochester, MN
| | - Jaime I. Davila
- Division of Biomedical Statistics and Informatics, Mayo Clinic and Foundation, Rochester, MN
| | - Ruisi Wang
- Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, MN,Gastroenterology Research Unit, Mayo Clinic and Foundation, Rochester, MN
| | - Steven P. O’Hara
- Center for Basic Research in Digestive Diseases, Mayo Clinic and Foundation, Rochester, MN
| | - Gwen A. Lomberk
- Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, MN,Gastroenterology Research Unit, Mayo Clinic and Foundation, Rochester, MN,Center for Cell Signaling in Gastroenterology, Mayo Clinic and Foundation, Rochester, MN
| | - Raul A. Urrutia
- Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, MN,Gastroenterology Research Unit, Mayo Clinic and Foundation, Rochester, MN,Center for Cell Signaling in Gastroenterology, Mayo Clinic and Foundation, Rochester, MN
| | - Yasuhiro Ikeda
- Department of Molecular Medicine; Mayo Clinic and Foundation, Rochester, MN
| | - Robert C. Huebert
- Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, MN,Gastroenterology Research Unit, Mayo Clinic and Foundation, Rochester, MN,Center for Cell Signaling in Gastroenterology, Mayo Clinic and Foundation, Rochester, MN
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Raggi C, Invernizzi P, Andersen JB. Impact of microenvironment and stem-like plasticity in cholangiocarcinoma: molecular networks and biological concepts. J Hepatol 2015; 62:198-207. [PMID: 25220250 DOI: 10.1016/j.jhep.2014.09.007] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2014] [Revised: 08/30/2014] [Accepted: 09/03/2014] [Indexed: 12/13/2022]
Abstract
Clinical complexity, anatomic diversity and molecular heterogeneity of cholangiocarcinoma (CCA) represent a major challenge in the assessment of effective targeted therapies. Molecular and cellular mechanisms underlying the diversity of CCA growth patterns remain a key issue of clinical concern. Crucial questions comprise the nature of the CCA-origin, the initial target for cellular transformation as well as the relationship with the cancer stem cells (CSC) concept. Additionally, since CCA often develops in the context of an inflammatory milieu (cirrhosis and cholangitis), the stromal compartment or tumour microenvironment (TME) likely promotes initiation and progression of this malignancy, contributing to its heterogeneity. This review will emphasize the dynamic interplay between stem-like intrinsic and TME-extrinsic pathways, which may represent novel options for multi-targeted therapies in CCA.
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Affiliation(s)
- Chiara Raggi
- Liver Unit and Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano, Italy.
| | - Pietro Invernizzi
- Liver Unit and Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano, Italy
| | - Jesper B Andersen
- Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.
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47
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Geisler F, Strazzabosco M. Emerging roles of Notch signaling in liver disease. Hepatology 2015; 61:382-92. [PMID: 24930574 PMCID: PMC4268103 DOI: 10.1002/hep.27268] [Citation(s) in RCA: 193] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2014] [Revised: 06/11/2014] [Accepted: 06/12/2014] [Indexed: 12/13/2022]
Abstract
This review critically discusses the most recent advances in the role of Notch signaling in liver development, homeostasis, and disease. It is now clear that the significance of Notch in determining mammalian cell fates and functions extends beyond development, and Notch is a major regular of organ homeostasis. Moreover, Notch signaling is reactivated upon injury and regulates the complex interactions between the distinct liver cell types involved in the repair process. Notch is also involved in the regulation of liver metabolism, inflammation, and cancer. The net effects of Notch signaling are highly variable and finely regulated at multiple levels, but also depend on the specific cellular context in which Notch is activated. Persistent activation of Notch signaling is associated with liver malignancies, such as hepatocellular carcinoma with stem cell features and intrahepatic cholangiocarcinoma. The complexity of the pathway provides several possible targets for agents able to inhibit Notch. However, further cell- and context-specific in-depth understanding of Notch signaling in liver homeostasis and disease will be essential to translate these concepts into clinical practice and be able to predict benefits and risks of evolving therapies.
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Affiliation(s)
- Fabian Geisler
- 2nd Department of Internal Medicine, Klinikum rechts der Isar, Technical University of Munich, 81675 Munich, Germany
| | - Mario Strazzabosco
- Liver Center & Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA,Department of Surgery and Interdisciplinary Medicine, University of Milano-Bicocca, Milan, Italy
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48
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Abstract
During chronic injury a population of bipotent hepatic progenitor cells (HPCs) become activated to regenerate both cholangiocytes and hepatocytes. Here we show in human diseased liver and mouse models of the ductular reaction that Notch and Wnt signaling direct specification of HPCs via their interactions with activated myofibroblasts or macrophages. In particular, we found that during biliary regeneration, expression of Jagged 1 (a Notch ligand) by myofibroblasts promoted Notch signaling in HPCs and thus their biliary specification to cholangiocytes. Alternatively, during hepatocyte regeneration, macrophage engulfment of hepatocyte debris induced Wnt3a expression. This resulted in canonical Wnt signaling in nearby HPCs, thus maintaining expression of Numb (a cell fate determinant) within these cells and the promotion of their specification to hepatocytes. By these two pathways adult parenchymal regeneration during acute liver injury is promoted.
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Affiliation(s)
- Ben Z. Stanger
- Departments of Medicine and Cell and Developmental Biology Perelman
School of Medicine University of Pennsylvania, Philadelphia, PA
| | - Linda Greenbaum
- Departments of Cancer Biology and Medicine Thomas Jefferson
University School of Medicine Philadelphia, PA
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