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Modèle de fibrogenèse hépatique humaine : analyses immunopathologiques

Abstract : Major progress has been made in understanding the pathophysiology of fibrosis, but despite a wide range of therapeutic targets, the gap between basic and clinical research persists due to limitations in the duration of clinical studies and invasive evaluation methods. The ex vivo culture model of human liver slices with a duration of up to 21 days was used to study variations in fibrogenesis in the human liver at different stages of F0 to F4 fibrosis, in particular the early stages of molecular liver fibrogenesis due to ethanol, HCV, or steatosis, which are the main factors in clinical liver injury. The expression of several molecules involved in the fibrosis process, such as TGF-β1, procolA1, MMP-2, MMP-9, α-SMA, HSP47, VEGF and the production of triglycerides increased significantly throughout the kinetics. As ongoing randomized clinical trials have certain limitations (based on serial liver biopsies, long duration (3 years) to generate speculative positive results, placebo-controlled studies with a single drug), our study provided proof of concept that the ex vivo model of human liver slice culture allows the rapid evaluation of the potency of new anti-fibrotic therapies alone or in combination.The human liver slice culture model can allow studies of immune components of liver disease. Basic research suggests that the development of fibrosis is subject to type 3 inflammation, guided by IL-17A and IL-22. Type 3 inflammation can be regulated by active metabolites of vitamin A, of which the liver is a storage site. In human liver samples available to us, we have shown that the concentration of IL-17A and IL-22 in liver tissue does not follow the severity of fibrosis as opposed to TGF-β1. The immune profile of the liver differs from that of circulating blood, with the preponderance of non-canonical immune populations, such as Mucosal-Associated Invariant T cells (MAIT), LTγδ, NKT cells. IL-17A secretion is mainly carried out by the Th17 population in the blood, while in the liver, the sources of IL-17A diversify, giving way to LTh17, MAIT and LTc17 cells. Stimulation of human liver slices with IL-17A revealed the fibrotic potential of IL-17A but did not reveal the dialogue with the retinoic acid (the active metabolite of vitamin A). On the other hand, the study on the energetic potential of the Huh7.5.1 hepatocarcinoma cell line using SeaHorse, revealed the effect of RA in compensating for IL-17A-induced disturbances in mitochondrial respiration. This compensation was translated by the activation of autophagy in the cells of the lineage, which was not the case in the human liver slice model.This work shows the significant need for human tissue-based models to better understand, describe and resolve existing problems in Hepatology.
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Submitted on : Saturday, September 11, 2021 - 1:01:42 AM
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  • HAL Id : tel-03341551, version 1



Daria Kartasheva-Ebertz. Modèle de fibrogenèse hépatique humaine : analyses immunopathologiques. Médecine humaine et pathologie. Université Paris Cité, 2020. Français. ⟨NNT : 2020UNIP7124⟩. ⟨tel-03341551⟩



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