A 3D Human Liver Model of Nonalcoholic Steatohepatitis.

Autor:	Duriez M; Translational Sciences, Sanofi, 1 Avenue Pierre Brossolette, Chilly-Mazarin, France., Jacquet A; Translational Sciences, Sanofi, 1 Avenue Pierre Brossolette, Chilly-Mazarin, France., Hoet L; Translational Sciences, Sanofi, 1 Avenue Pierre Brossolette, Chilly-Mazarin, France., Roche S; Translational Sciences, Sanofi, 1 Avenue Pierre Brossolette, Chilly-Mazarin, France., Bock MD; Translational Sciences, Sanofi, 1 Avenue Pierre Brossolette, Chilly-Mazarin, France., Rocher C; Translational Sciences, Sanofi, 1 Avenue Pierre Brossolette, Chilly-Mazarin, France., Haussy G; Translational Sciences, Sanofi, 1 Avenue Pierre Brossolette, Chilly-Mazarin, France., Vigé X; Translational Sciences, Sanofi, 1 Avenue Pierre Brossolette, Chilly-Mazarin, France., Bocskei Z; Translational Sciences, Sanofi, 1 Avenue Pierre Brossolette, Chilly-Mazarin, France., Slavnic T; IT&M STATS, Groupe IT&M, Neuilly-sur-Seine, France., Martin V; Non Clinical Biostatistics, Sanofi, Vitry sur Seine, France., Guillemot JC; Translational Sciences, Sanofi, 1 Avenue Pierre Brossolette, Chilly-Mazarin, France., Didier M; Translational Sciences, Sanofi, 1 Avenue Pierre Brossolette, Chilly-Mazarin, France., Kannt A; Diabetes and Cardiovascular Research, Sanofi, Industriepark Höchst, Frankfurt, Germany.; Present address: Institute of Experimental Pharmacology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany., Orsini C; Translational Sciences, Sanofi, 1 Avenue Pierre Brossolette, Chilly-Mazarin, France., Mikol V; Translational Sciences, Sanofi, 1 Avenue Pierre Brossolette, Chilly-Mazarin, France., Fèvre AL; Translational Sciences, Sanofi, 1 Avenue Pierre Brossolette, Chilly-Mazarin, France.
Jazyk:	angličtina
Zdroj:	Journal of clinical and translational hepatology [J Clin Transl Hepatol] 2020 Dec 28; Vol. 8 (4), pp. 359-370. Date of Electronic Publication: 2020 Dec 15.
DOI:	10.14218/JCTH.2020.00015
Abstrakt:	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. Competing Interests: All of the authors except TS were employees of Sanofi during the course of the study, and all are or have been shareholders of Sanofi. (© 2020 Authors.)
Databáze:	MEDLINE
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