Recapitulating Cholangiopathy-Associated Necroptotic Cell Death In Vitro Using Human Cholangiocyte OrganoidsSummary
Background & Aims: Liver and bile duct diseases often are associated with extensive cell death of cholangiocytes. Necroptosis represents a common mode of programmed cell death in cholangiopathy, however, detailed mechanistic knowledge is limited owing to the lack of appropriate in vitro mode...
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| Format: | Article |
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Elsevier
2022-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X2100223X |
| _version_ | 1798021411801923584 |
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| author | Shaojun Shi Monique M.A. Verstegen Henk P. Roest Arif I. Ardisasmita Wanlu Cao Floris J.M. Roos Petra E. de Ruiter Marije Niemeijer Qiuwei Pan Jan N.M. IJzermans Luc J.W. van der Laan |
| author_facet | Shaojun Shi Monique M.A. Verstegen Henk P. Roest Arif I. Ardisasmita Wanlu Cao Floris J.M. Roos Petra E. de Ruiter Marije Niemeijer Qiuwei Pan Jan N.M. IJzermans Luc J.W. van der Laan |
| author_sort | Shaojun Shi |
| collection | DOAJ |
| description | Background & Aims: Liver and bile duct diseases often are associated with extensive cell death of cholangiocytes. Necroptosis represents a common mode of programmed cell death in cholangiopathy, however, detailed mechanistic knowledge is limited owing to the lack of appropriate in vitro models. To address this void, we investigated whether human intrahepatic cholangiocyte organoids (ICOs) can recapitulate cholangiopathy-associated necroptosis and whether this model can be used for drug screening. Methods: We evaluated the clinical relevance of necroptosis in end-stage liver diseases and liver transplantation by immunohistochemistry. Cholangiopathy-associated programmed cell death was evoked in ICOs derived from healthy donors or patients with primary sclerosing cholangitis or alcoholic liver diseases by the various stimuli. Results: The expression of key necroptosis mediators, receptor-interacting protein 3 and phosphorylated mixed lineage kinase domain-like, in cholangiocytes during end-stage liver diseases was confirmed. The phosphorylated mixed lineage kinase domain-like expression was etiology-dependent. Gene expression analysis confirmed that primary cholangiocytes are more prone to necroptosis compared with primary hepatocytes. Both apoptosis and necroptosis could be specifically evoked using tumor necrosis factor α and second mitochondrial-derived activator of caspases mimetic, with or without caspase inhibition in healthy and patient-derived ICOs. Necroptosis also was induced by ethanol metabolites or human bile in ICOs from donors and patients. The organoid cultures further uncovered interdonor variable and species-specific drug responses. Dabrafenib was identified as a potent necroptosis inhibitor and showed a protective effect against ethanol metabolite toxicity. Conclusions: Human ICOs recapitulate cholangiopathy-associated necroptosis and represent a useful in vitro platform for the study of biliary cytotoxicity and preclinical drug evaluation. |
| first_indexed | 2024-04-11T17:13:27Z |
| format | Article |
| id | doaj.art-2f4d610e4e7d4d40a0f49cbdf8749e04 |
| institution | Directory Open Access Journal |
| issn | 2352-345X |
| language | English |
| last_indexed | 2024-04-11T17:13:27Z |
| publishDate | 2022-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj.art-2f4d610e4e7d4d40a0f49cbdf8749e042022-12-22T04:12:48ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2022-01-01132541564Recapitulating Cholangiopathy-Associated Necroptotic Cell Death In Vitro Using Human Cholangiocyte OrganoidsSummaryShaojun Shi0Monique M.A. Verstegen1Henk P. Roest2Arif I. Ardisasmita3Wanlu Cao4Floris J.M. Roos5Petra E. de Ruiter6Marije Niemeijer7Qiuwei Pan8Jan N.M. IJzermans9Luc J.W. van der Laan10Department of Surgery, Erasmus MC Transplant Institute, Erasmus MC University Medical Center, Rotterdam, The NetherlandsDepartment of Surgery, Erasmus MC Transplant Institute, Erasmus MC University Medical Center, Rotterdam, The NetherlandsDepartment of Surgery, Erasmus MC Transplant Institute, Erasmus MC University Medical Center, Rotterdam, The NetherlandsDepartment of Metabolic Diseases, Wilhelmina Children’s Hospital, University Medical Centre Utrecht, Utrecht, The NetherlandsDepartment of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands; Department of Oncology, Shanghai East Hospital, Tongji University, Shanghai, P. R. ChinaDepartment of Surgery, Erasmus MC Transplant Institute, Erasmus MC University Medical Center, Rotterdam, The NetherlandsDepartment of Surgery, Erasmus MC Transplant Institute, Erasmus MC University Medical Center, Rotterdam, The NetherlandsDepartment of Surgery, Erasmus MC Transplant Institute, Erasmus MC University Medical Center, Rotterdam, The Netherlands; Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The NetherlandsDepartment of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The NetherlandsDepartment of Surgery, Erasmus MC Transplant Institute, Erasmus MC University Medical Center, Rotterdam, The NetherlandsDepartment of Surgery, Erasmus MC Transplant Institute, Erasmus MC University Medical Center, Rotterdam, The Netherlands; Correspondence Address correspondence to: Luc J. W. van der Laan, PhD, Department of Surgery, Erasmus MC Transplant Institute, Erasmus MC University Medical Center, ‘s-Gravendijkwal 230, Room Na-1008, 3015CE Rotterdam, The Netherlands. fax: (31)0107032793Background & Aims: Liver and bile duct diseases often are associated with extensive cell death of cholangiocytes. Necroptosis represents a common mode of programmed cell death in cholangiopathy, however, detailed mechanistic knowledge is limited owing to the lack of appropriate in vitro models. To address this void, we investigated whether human intrahepatic cholangiocyte organoids (ICOs) can recapitulate cholangiopathy-associated necroptosis and whether this model can be used for drug screening. Methods: We evaluated the clinical relevance of necroptosis in end-stage liver diseases and liver transplantation by immunohistochemistry. Cholangiopathy-associated programmed cell death was evoked in ICOs derived from healthy donors or patients with primary sclerosing cholangitis or alcoholic liver diseases by the various stimuli. Results: The expression of key necroptosis mediators, receptor-interacting protein 3 and phosphorylated mixed lineage kinase domain-like, in cholangiocytes during end-stage liver diseases was confirmed. The phosphorylated mixed lineage kinase domain-like expression was etiology-dependent. Gene expression analysis confirmed that primary cholangiocytes are more prone to necroptosis compared with primary hepatocytes. Both apoptosis and necroptosis could be specifically evoked using tumor necrosis factor α and second mitochondrial-derived activator of caspases mimetic, with or without caspase inhibition in healthy and patient-derived ICOs. Necroptosis also was induced by ethanol metabolites or human bile in ICOs from donors and patients. The organoid cultures further uncovered interdonor variable and species-specific drug responses. Dabrafenib was identified as a potent necroptosis inhibitor and showed a protective effect against ethanol metabolite toxicity. Conclusions: Human ICOs recapitulate cholangiopathy-associated necroptosis and represent a useful in vitro platform for the study of biliary cytotoxicity and preclinical drug evaluation.http://www.sciencedirect.com/science/article/pii/S2352345X2100223XNecroptosisApoptosisLiver DiseaseBiliary Injury |
| spellingShingle | Shaojun Shi Monique M.A. Verstegen Henk P. Roest Arif I. Ardisasmita Wanlu Cao Floris J.M. Roos Petra E. de Ruiter Marije Niemeijer Qiuwei Pan Jan N.M. IJzermans Luc J.W. van der Laan Recapitulating Cholangiopathy-Associated Necroptotic Cell Death In Vitro Using Human Cholangiocyte OrganoidsSummary Cellular and Molecular Gastroenterology and Hepatology Necroptosis Apoptosis Liver Disease Biliary Injury |
| title | Recapitulating Cholangiopathy-Associated Necroptotic Cell Death In Vitro Using Human Cholangiocyte OrganoidsSummary |
| title_full | Recapitulating Cholangiopathy-Associated Necroptotic Cell Death In Vitro Using Human Cholangiocyte OrganoidsSummary |
| title_fullStr | Recapitulating Cholangiopathy-Associated Necroptotic Cell Death In Vitro Using Human Cholangiocyte OrganoidsSummary |
| title_full_unstemmed | Recapitulating Cholangiopathy-Associated Necroptotic Cell Death In Vitro Using Human Cholangiocyte OrganoidsSummary |
| title_short | Recapitulating Cholangiopathy-Associated Necroptotic Cell Death In Vitro Using Human Cholangiocyte OrganoidsSummary |
| title_sort | recapitulating cholangiopathy associated necroptotic cell death in vitro using human cholangiocyte organoidssummary |
| topic | Necroptosis Apoptosis Liver Disease Biliary Injury |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X2100223X |
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