A 3D primary human cell-based in vitro model of non-alcoholic steatohepatitis for efficacy testing of clinical drug candidates

Abstract Non-alcoholic steatohepatitis (NASH) is a progressive and severe liver disease, characterized by lipid accumulation, inflammation, and downstream fibrosis. Despite its increasing prevalence, there is no approved treatment yet available for patients. This has been at least partially due to t...

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Autores principales:	Simon Ströbel, Radina Kostadinova, Katia Fiaschetti-Egli, Jana Rupp, Manuela Bieri, Agnieszka Pawlowska, Donna Busler, Thomas Hofstetter, Katarzyna Sanchez, Sue Grepper, Eva Thoma
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f68ec732dd9c4e5cbe369ca6c1215b3e
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spelling	oai:doaj.org-article:f68ec732dd9c4e5cbe369ca6c1215b3e2021-11-28T12:18:48ZA 3D primary human cell-based in vitro model of non-alcoholic steatohepatitis for efficacy testing of clinical drug candidates10.1038/s41598-021-01951-72045-2322https://doaj.org/article/f68ec732dd9c4e5cbe369ca6c1215b3e2021-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-01951-7https://doaj.org/toc/2045-2322Abstract Non-alcoholic steatohepatitis (NASH) is a progressive and severe liver disease, characterized by lipid accumulation, inflammation, and downstream fibrosis. Despite its increasing prevalence, there is no approved treatment yet available for patients. This has been at least partially due to the lack of predictive preclinical models for studying this complex disease. Here, we present a 3D in vitro microtissue model that uses spheroidal, scaffold free co-culture of primary human hepatocytes, Kupffer cells, liver endothelial cells and hepatic stellate cells. Upon exposure to defined and clinically relevant lipotoxic and inflammatory stimuli, these microtissues develop key pathophysiological features of NASH within 10 days, including an increase of intracellular triglyceride content and lipids, and release of pro-inflammatory cytokines. Furthermore, fibrosis was evident through release of procollagen type I, and increased deposition of extracellular collagen fibers. Whole transcriptome analysis revealed changes in the regulation of pathways associated with NASH, such as lipid metabolism, inflammation and collagen processing. Importantly, treatment with anti-NASH drug candidates (Selonsertib and Firsocostat) decreased the measured specific disease parameter, in accordance with clinical observations. These drug treatments also significantly changed the gene expression patterns of the microtissues, thus providing mechanisms of action and revealing therapeutic potential. In summary, this human NASH model represents a promising drug discovery tool for understanding the underlying complex mechanisms in NASH, evaluating efficacy of anti-NASH drug candidates and identifying new approaches for therapeutic interventions.Simon StröbelRadina KostadinovaKatia Fiaschetti-EgliJana RuppManuela BieriAgnieszka PawlowskaDonna BuslerThomas HofstetterKatarzyna SanchezSue GrepperEva ThomaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-18 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Simon Ströbel Radina Kostadinova Katia Fiaschetti-Egli Jana Rupp Manuela Bieri Agnieszka Pawlowska Donna Busler Thomas Hofstetter Katarzyna Sanchez Sue Grepper Eva Thoma A 3D primary human cell-based in vitro model of non-alcoholic steatohepatitis for efficacy testing of clinical drug candidates
description	Abstract Non-alcoholic steatohepatitis (NASH) is a progressive and severe liver disease, characterized by lipid accumulation, inflammation, and downstream fibrosis. Despite its increasing prevalence, there is no approved treatment yet available for patients. This has been at least partially due to the lack of predictive preclinical models for studying this complex disease. Here, we present a 3D in vitro microtissue model that uses spheroidal, scaffold free co-culture of primary human hepatocytes, Kupffer cells, liver endothelial cells and hepatic stellate cells. Upon exposure to defined and clinically relevant lipotoxic and inflammatory stimuli, these microtissues develop key pathophysiological features of NASH within 10 days, including an increase of intracellular triglyceride content and lipids, and release of pro-inflammatory cytokines. Furthermore, fibrosis was evident through release of procollagen type I, and increased deposition of extracellular collagen fibers. Whole transcriptome analysis revealed changes in the regulation of pathways associated with NASH, such as lipid metabolism, inflammation and collagen processing. Importantly, treatment with anti-NASH drug candidates (Selonsertib and Firsocostat) decreased the measured specific disease parameter, in accordance with clinical observations. These drug treatments also significantly changed the gene expression patterns of the microtissues, thus providing mechanisms of action and revealing therapeutic potential. In summary, this human NASH model represents a promising drug discovery tool for understanding the underlying complex mechanisms in NASH, evaluating efficacy of anti-NASH drug candidates and identifying new approaches for therapeutic interventions.
format	article
author	Simon Ströbel Radina Kostadinova Katia Fiaschetti-Egli Jana Rupp Manuela Bieri Agnieszka Pawlowska Donna Busler Thomas Hofstetter Katarzyna Sanchez Sue Grepper Eva Thoma
author_facet	Simon Ströbel Radina Kostadinova Katia Fiaschetti-Egli Jana Rupp Manuela Bieri Agnieszka Pawlowska Donna Busler Thomas Hofstetter Katarzyna Sanchez Sue Grepper Eva Thoma
author_sort	Simon Ströbel
title	A 3D primary human cell-based in vitro model of non-alcoholic steatohepatitis for efficacy testing of clinical drug candidates
title_short	A 3D primary human cell-based in vitro model of non-alcoholic steatohepatitis for efficacy testing of clinical drug candidates
title_full	A 3D primary human cell-based in vitro model of non-alcoholic steatohepatitis for efficacy testing of clinical drug candidates
title_fullStr	A 3D primary human cell-based in vitro model of non-alcoholic steatohepatitis for efficacy testing of clinical drug candidates
title_full_unstemmed	A 3D primary human cell-based in vitro model of non-alcoholic steatohepatitis for efficacy testing of clinical drug candidates
title_sort	3d primary human cell-based in vitro model of non-alcoholic steatohepatitis for efficacy testing of clinical drug candidates
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/f68ec732dd9c4e5cbe369ca6c1215b3e
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A 3D primary human cell-based in vitro model of non-alcoholic steatohepatitis for efficacy testing of clinical drug candidates

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