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©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
Adult human liver slice cultures: Modelling of liver fibrosis and evaluation of new anti-fibrotic drugs
Daria Kartasheva-Ebertz, Jesintha Gaston, Loriane Lair-Mehiri, Pierre-Philippe Massault, Olivier Scatton, Jean-Christophe Vaillant, Vladimir Alexei Morozov, Stanislas Pol, Sylvie Lagaye
Daria Kartasheva-Ebertz, Jesintha Gaston, Loriane Lair-Mehiri, Stanislas Pol, Sylvie Lagaye, Institut Pasteur, Immunobiologie des Cellules Dendritiques, INSERM U1223, Paris 75015, France
Daria Kartasheva-Ebertz, Jesintha Gaston, Loriane Lair-Mehiri, BioSPC, Université de Paris, Paris 75005, France
Pierre-Philippe Massault, Service de Chirurgie digestive, Hépato-biliaire et Endocrinienne, AP-HP, Groupe Hospitalier Cochin, Paris 75014, France
Olivier Scatton, Jean-Christophe Vaillant, Service de Chirurgie digestive et Hépato bilio pancréatique, AP-HP, Groupe Hospitalier La Pitié-Salpétrière, Medecine Sorbonne Université, Paris 75013, France
Vladimir Alexei Morozov, Center for HIV and Retrovirology, Department of Infectious Diseases, Robert Koch Institute, Berlin 13353, Germany
Stanislas Pol, Département d'Hépatologie, AP-HP, Groupe Hospitalier Cochin, Université de Paris, Paris 75014, France
Author contributions: Kartasheva-Ebertz D, Gaston J, Lair-Mehiri L, Morozov VA, Pol S, and Lagaye S were responsible for the overall study design; Massault PP, Scatton O, Vaillant JC, and Pol S selected and contributed patients’ samples; Kartasheva-Ebertz D, Gaston J, Lair-Mehiri L, and Lagaye S performed experiments; Kartasheva-Ebertz D, Morozov VA, Pol S, and Lagaye S analyzed and interpreted the data; Kartasheva-Ebertz D, Morozov VA, Pol S, and Lagaye S contributed to the writing of the manuscript, discussed and refined the manuscript.
Supported by the Institut National de la Santé et de la Recherche Médicale (INSERM, France) and by Institut Pasteur (Paris, France); Daria Kartasheva-Ebertz received a PhD Fellowship from Assistance Publique-Hôpitaux de Paris (AP-HP, France).
Institutional review board statement: An institutional review board statement is not required for manuscript submission in our Institution.
Conflict-of-interest statement: No conflict of interest to declare indicated in the manuscript.
Data sharing statement: No data sharing.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
http://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Sylvie Lagaye, DSc, PhD, Senior Scientist, Institut Pasteur, Immunobiologie des Cellules Dendritiques, INSERM U1223, 25-28 rue du Dr Roux, Paris 75015, France. sylvie.lagaye@inserm.fr
Received: August 27, 2020
Peer-review started: August 26, 2020
First decision: October 21, 2020
Revised: November 4, 2020
Accepted: December 30, 2020
Article in press: December 30, 2020
Published online: February 27, 2021
BACKGROUND
Liver fibrosis can result in end-stage liver failure and death.
AIM
To examine human liver fibrogenesis and anti-fibrotic therapies, we evaluated the three dimensional ex vivo liver slice (LS) model.
METHODS
Fibrotic liver samples (F0 to F4 fibrosis stage according to the METAVIR score) were collected from patients after liver resection. Human liver slices (HLS) were cultivated for up to 21 days. Hepatitis C virus (HCV) infection, alcohol (ethanol stimulation) and steatosis (palmitate stimulation) were examined in fibrotic (F2 to F4) liver slices infected (or not) with HCV. F0-F1 HLS were used as controls. At day 0, either ursodeoxycholic acid (choleretic and hepatoprotective properties) and/or α-tocopherol (antioxidant properties) were added to standard of care on HLS and fibrotic liver slices, infected (or not) with HCV. Expression of the biomarkers of fibrosis and the triglyceride production were checked by quantitative reverse transcription polymerase chain reaction and/or enzyme-linked immunosorbent assay.
RESULTS
The cultures were viable in vitro for 21 days allowing to study fibrosis inducers and to estimate the effect of anti-fibrotic drugs. Expression of the biomarkers of fibrosis and the progression to steatosis (estimated by triglycerides production) was increased with the addition of HCV and /or ethanol or palmitate. From day 15 of the follow-up studies, a significant decrease of both transforming growth factor β-1 and Procol1A1 expression and triglycerides production was observed when a combined anti-fibrotic treatment was applied on HCV infected F2-F4 LS cultures.
CONCLUSION
These results show that the human three dimensional ex vivo model effectively reflects the in vivo processes in damaged human liver (viral, alcoholic, nonalcoholic steatohepatitis liver diseases) and provides the proof of concept that the LS examined model permits a rapid evaluation of new anti-fibrotic therapies when used alone or in combination.
Core Tip: In the developed world, about 45% of deaths are due to fibroproliferative diseases. Liver fibrosis is frequently associated with viral infection (Hepatitis C virus and Hepatitis B virus infection), chronic inflammation and excessive alcohol consumption. Despite the availability of effective antiviral drugs, morbidity, and mortality related to viral hepatitis are still increasing. Moreover, the number of non-viral liver diseases such as nonalcoholic steatohepatitis, and alcoholic liver disease is steadily growing. Our studies provide the proof of concept that the three-dimensional ex vivo model of human liver slice culture can be used for the molecular investigation of fibrosis as well as to perform follow-up studies of new anti-fibrotic drugs and therapies for a 21-days period.
