A Microphysiological System for Studying Nonalcoholic Steatohepatitis
| العنوان: | A Microphysiological System for Studying Nonalcoholic Steatohepatitis |
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| المؤلفون: | Alina Miedzik, David Hughes, Krista Rombouts, Tomasz Kostrzewski, Sophie Snow, Ana Levi, Paloma Maraver, Larissa Ouro-Gnao |
| المصدر: | Hepatology Communications Hepatology Communications, Vol 4, Iss 1, Pp 77-91 (2020) |
| بيانات النشر: | John Wiley and Sons Inc., 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Lipopolysaccharide, Biology, medicine.disease_cause, digestive system, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, In vivo, Nonalcoholic fatty liver disease, medicine, lcsh:RC799-869, 030304 developmental biology, 0303 health sciences, Mutation, Hepatology, Obeticholic acid, nutritional and metabolic diseases, Original Articles, medicine.disease, Phenotype, In vitro, digestive system diseases, 3. Good health, chemistry, Cancer research, Hepatic stellate cell, 030211 gastroenterology & hepatology, lcsh:Diseases of the digestive system. Gastroenterology, Original Article |
| الوصف: | Nonalcoholic steatohepatitis (NASH) is the most severe form of nonalcoholic fatty liver disease (NAFLD), which to date has no approved drug treatments. There is an urgent need for better understanding of the genetic and molecular pathways that underlie NAFLD/NASH, and currently available preclinical models, be they in vivo or in vitro, do not fully represent key aspects of the human disease state. We have developed a human in vitro co‐culture NASH model using primary human hepatocytes, Kupffer cells and hepatic stellate cells, which are cultured together as microtissues in a perfused three‐dimensional microphysiological system (MPS). The microtissues were cultured in medium containing free fatty acids for at least 2 weeks, to induce a NASH‐like phenotype. The co‐culture microtissues within the MPS display a NASH‐like phenotype, showing key features of the disease including hepatic fat accumulation, the production of an inflammatory milieu, and the expression of profibrotic markers. Addition of lipopolysaccharide resulted in a more pro‐inflammatory milieu. In the model, obeticholic acid ameliorated the NASH phenotype. Microtissues were formed from both wild‐type and patatin‐like phospholipase domain containing 3 (PNPLA3) I148M mutant hepatic stellate cells. Stellate cells carrying the mutation enhanced the overall disease state of the model and in particular produced a more pro‐inflammatory milieu. Conclusion: The MPS model displays a phenotype akin to advanced NAFLD or NASH and has utility as a tool for exploring mechanisms underlying the disease. Furthermore, we demonstrate that in co‐culture the PNPLA3 I148M mutation alone can cause hepatic stellate cells to enhance the overall NASH disease phenotype. We have developed an advanced human in vitro co‐culture model of nonalcoholic steatohepatitis. The model was used to explore effects of genetic mutations in the PNPLA3 gene on hepatic stellate cell function and disease progression. |
| اللغة: | English |
| تدمد: | 2471-254X |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::55ed9498252abdf44f8c8ac1c854b39c http://europepmc.org/articles/PMC6939502 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....55ed9498252abdf44f8c8ac1c854b39c |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 2471254X |
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