Journal of Clinical and Translational Hepatology

Journal of Clinical and Translational Hepatology

Tuesday, 03 / 09 / 2021

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ORIGINAL ARTICLE

A 3D Human Liver Model of Nonalcoholic Steatohepatitis

Marion Duriez1, Agnes Jacquet1Lucile Hoet1Sandrine Roche1Marie-Dominique Bock1Corinne Rocher1Gilles Haussy1Xavier Vigé1Zsolt Bocskei1 Tamara Slavnic2 Valérie Martin3Jean-Claude Guillemot1Michel Didier1Aimo Kannt4,5Cécile Orsini, Vincent Mikol1 and Anne-Céline Le Fèvre*,1

1  Translational Sciences, Sanofi, 1 Avenue Pierre Brossolette, Chilly-Mazarin, France
2  IT&M STATS, Groupe IT&M, Neuilly-sur-Seine, France
3  Non Clinical Biostatistics, Sanofi, Vitry sur Seine, France
4  Diabetes and Cardiovascular Research, Sanofi, Industriepark Höchst, Frankfurt, Germany
5  Present address: Institute of Experimental Pharmacology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
*Correspondence to: Anne-Céline Le Fèvre, Translational Sciences, Sanofi, 1 Avenue Pierre Brossolette, 91385 Chilly-Mazarin, France. Tel: +33-160495815, E-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.

Journal of Clinical and Translational Hepatology 2020;8(4):359-370 DOI: 10.14218/JCTH.2020.00015
Received: March 2, 2020 Accepted: June 1, 2020 Published online: December 15, 2020

Abstract

Background and Aims: To better understand nonalcoholic steatohepatitis (NASH) disease progression and to evaluate drug targets and compound activity, we undertook the development of an in vitro 3D model to mimic liver architecture and the NASH environment.

Methods: We have developed an in vitro preclinical 3D NASH model by coculturing primary human hepatocytes, human stellate cells, liver endothelial cells and Kupffer cells embedded in a hydrogel of rat collagen on a 96-well plate. A NASH-like environment was induced by addition of medium containing free fatty acids and tumor necrosis factor-α. This model was then characterized by biochemical, imaging and transcriptomics analyses.

Results: We succeeded in defining suitable culture conditions to maintain the 3D coculture for up to 10 days in vitro, with the lowest level of steatosis and reproducible low level of inflammation and fibrosis. NASH disease was induced with a custom medium mimicking NASH features. The cell model exhibited the key NASH disease phenotypes of hepatocyte injury, steatosis, inflammation, and fibrosis. Hepatocyte injury was highlighted by a decrease of CYP3A4 expression and activity, without loss of viability up to day 10. Moreover, the model was able to stimulate a stable inflammatory and early fibrotic environment, with expression and secretion of several cytokines. A global gene expression analysis confirmed the NASH induction.

Conclusions: This is a new in vitro model of NASH disease consisting of four human primary cell-types that exhibits most features of the disease. The 10-day cell viability and cost effectiveness of the model make it suitable for medium throughput drug screening and provide attractive avenues to better understand disease physiology and to identify and characterize new drug targets.

Keywords

3D liver model, Human primary cells, Key features of NASH

Journal of Clinical and Translational Hepatology 2020 vol. 8, 359-370  [ Html  ] [ PDF Full-text ]

© The Authors 2020. This article is published under the terms of the Creative Commons Attribution-Noncommercial License (CC BY-NC 4.0), which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license.

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