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Adult human liver slice cultures:modelling of liver fibrosis and evaluation of new anti-fibrotic drugs

World Journal of Hepatology 2021年第2期13卷 187-217页

作者： Daria Kartasheva-Ebertz Jesintha Gaston loriane lair-m.hiri Pierre-Philippe massault Olivier Scatton Jean-Christophe Vaillant Vladimir Alexei morozov Stanislas Pol Sylvie Lagaye Institut Pasteur Immunobiologie des Cellules DendritiquesINSERM U1223Paris 75015France BioSPC Universitéde ParisParis 75005France Service de Chirurgie digestive Hépato-biliaire et EndocrinienneAPHPGroupe Hospitalier CochinParis 75014France Service de Chirurgie digestive et Hépato bilio pancréatique AP-HPGroupe Hospitalier La Pitié-SalpétrièreMedecine Sorbonne UniversitéParis 75013France Center for HIV and Retrovirology Department of Infectious DiseasesRobert Koch InstituteBerlin 13353Germany Département d'Hépatologie AP-HPGroupe Hospitalier CochinUniversitéde ParisParis 75014France

BACKGROUND Liver fibrosis can result in end-stage liver failure and *** To examine human liver fibrogenesis and anti-fibrotic therapies,we evaluated the three dimensional ex vivo liver slice(LS)*** Fibrotic liver samples(F0 to F4 fibrosis stage according to the mETAVIR score)were collected from patients after liver *** liver slices(HLS)were cultivated for up to 21 *** 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 *** 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 *** of the biomarkers of fibrosis and the triglyceride production were checked by quantitative reverse transcription polymerase chain reaction and/or enzymelinked immunosorbent *** The cultures were viable in vitro for 21 days allowing to study fibrosis inducers and to estimate the effect of anti-fibrotic *** 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 *** day 15 of the follow-up studies,a significant decrease of both transforming growth factorβ-1 and Procol1A1 expression and triglycerides production was observed when a combined anti-fibrotic treatment was applied on HCV infected F2-F4 LS *** 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.

关键词： Human liver fibrosis Hepatitis C virus Alcoholic liver disease Nonalcoholic steatohepatitis Ex vivo model Drugs

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