Human Nonalcoholic Steatohepatitis on a Chip.

Autor: Freag MS; Center for Engineered TherapeuticsDivision of Engineering in MedicineDepartment of MedicineBrigham and Women's HospitalHarvard Medical SchoolBostonMAUSA.; Division of Health Sciences and TechnologyHarvard-Massachusetts Institute of TechnologyMassachusetts Institute of TechnologyBostonMAUSA., Namgung B; Center for Engineered TherapeuticsDivision of Engineering in MedicineDepartment of MedicineBrigham and Women's HospitalHarvard Medical SchoolBostonMAUSA.; Division of Health Sciences and TechnologyHarvard-Massachusetts Institute of TechnologyMassachusetts Institute of TechnologyBostonMAUSA., Reyna Fernandez ME; Center for Engineered TherapeuticsDivision of Engineering in MedicineDepartment of MedicineBrigham and Women's HospitalHarvard Medical SchoolBostonMAUSA.; Division of Health Sciences and TechnologyHarvard-Massachusetts Institute of TechnologyMassachusetts Institute of TechnologyBostonMAUSA., Gherardi E; Unit of Immunology and General PathologyDepartment of Molecular MedicineUniversity of PaviaPaviaItaly., Sengupta S; Center for Engineered TherapeuticsDivision of Engineering in MedicineDepartment of MedicineBrigham and Women's HospitalHarvard Medical SchoolBostonMAUSA.; Division of Health Sciences and TechnologyHarvard-Massachusetts Institute of TechnologyMassachusetts Institute of TechnologyBostonMAUSA.; Dana Farber Cancer InstituteBostonMAUSA., Jang HL; Center for Engineered TherapeuticsDivision of Engineering in MedicineDepartment of MedicineBrigham and Women's HospitalHarvard Medical SchoolBostonMAUSA.
Jazyk: angličtina
Zdroj: Hepatology communications [Hepatol Commun] 2020 Nov 29; Vol. 5 (2), pp. 217-233. Date of Electronic Publication: 2020 Nov 29 (Print Publication: 2021).
DOI: 10.1002/hep4.1647
Abstrakt: Nonalcoholic steatohepatitis (NASH), an advanced stage of nonalcoholic fatty liver disease (NAFLD), is a rapidly growing and global health problem compounded by the current absence of specific treatments. A major limiting factor in the development of new NASH therapies is the absence of models that capture the unique cellular structure of the liver microenvironment and recapitulate the complexities of NAFLD progression to NASH. Organ-on-a-chip platforms have emerged as a powerful approach to dynamically model diseases and test drugs. Herein, we describe a NASH-on-a-chip platform. Four main types of human primary liver cells (hepatocytes [HCs], Kupffer cells, liver sinusoidal endothelial cells, and hepatic stellate cells [HSCs]) were cocultured under microfluidic dynamics. Our chip-based model successfully recapitulated a functional liver cellular microenvironment with stable albumin and urea secretion for at least 2 weeks. Exposing liver chips to a lipotoxic environment led to gradual development of NASH phenotypic characteristics, including intracellular lipid accumulation, hepatocellular ballooning, HSC activation, and elevation of inflammatory and profibrotic markers. Further, exposure of the chip to elafibranor, a drug under study for the therapy of NASH, inhibited the development of NASH-specific hallmarks, causing an ~8-fold decrease in intracellular lipids, a 3-fold reduction in number of ballooned HCs, a significant reduction in HSC activation, and a significant decrease in the levels of inflammatory and profibrotic markers compared with controls. Conclusion: We have successfully developed a microfluidic NASH-on-a-chip platform that recapitulates the main NASH histologic endpoints in a single chip and that can emerge as a powerful noninvasive, human-relevant, in vitro platform to study disease pathogenesis and develop novel anti-NASH drugs.
(© 2020 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of the American Association for the Study of Liver Diseases.)
Databáze: MEDLINE
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