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Prix Poster - Les Jeudi 8 et Vendredi 9 Octobre 2020

Résumé N° : PP_006

Hepatic stellate cell hypertrophy is associated with metabolic liver fibrosis

Céline Hoffmann* (Paris), Céline Hoffmann* (Paris), Nour El Houda Djerir* (Paris), Anne Danckaert (Paris), Julien Fernandes (Paris), Anne-Marie Lachagès (Paris), Charlotte Frédéric (Paris), Karine Clément (Paris), Judith Aron-Wisnewsky (Paris), Fabienne Foufelle (Paris), Honoré Ratziu (Paris), Bernard Hainque (Paris), Dominique Bonnefont-Rousselot (Paris), Pascal Bigey (Paris), Virginie Escriou (Paris)

Introduction : Hepatic fibrosis is a major consequence of chronic liver disease such as non-alcoholic steatohepatitis which is undergoing a dramatic evolution given the obesity progression worldwide. Hepatic stellate cells (HSC) play a key role in the fibrosis process as upon liver injury they transdifferentiate from a quiescent to an activated phenotype responsible for most the collagen deposition in liver tissue. Here we characterized a new phenotype of HSC and highlighted its association with liver fibrosis

Patients et méthodes / ou matériel et méthodes : C57BL/6J mice were submitted to a choline-deficient amino acid-defined and high fat diet (CDAHFD) for 3 to 22 weeks; to a methionine and choline deficient diet (MCD) for 9 weeks or to a High Fat and High Carbohydrate diet (HFHC) for 16 weeks. Surgical liver biopsy samples were obtained from 27 severely obese patients (FIBROTA cohort) presenting several fibrosis stages F0 (n=4), F1 (n=5), F2 (n=9), F3 (n=5) and F4 (n=4). 16 human liver biopsies were obtained from patients (Hepatogastroenterology Department of the Pitié-Salpêtrière Hospital, Paris France) who underwent liver biopsy for suspicion of NASH (n=4) or Viral Hepatitis C (n=7) and alcoholism (n=5) with known stage of fibrosis, from F0 to F4. Immunocytochemistry study of HSC specific markers (desmin, cRBP1, α-SMA) and spatio-temporal analysis of both retinoid fluorescence and collagen fibers by multiphoton microscopy were performed

Résultats : Using a diet-induced liver fibrosis murine model (CDAHFD), we characterized a specific population of HSCs organized as clusters presenting simultaneously hypertrophy of retinoid droplets, quiescent and activated HSC markers. We showed that hypertrophied HSCs co-localized with fibrosis areas in space and time. Importantly, we reported the existence of this phenotype and its association with collagen deposition in three other mouse fibrosis models, including CCl4-induced fibrosis model. Moreover, we have also shown its relevance in human liver fibrosis associated with different etiologies (obesity, non-alcoholic steatohepatitis, viral hepatitis C and alcoholism). In particular, we have demonstrated a significant positive correlation between the stage of liver fibrosis and HSC hypertrophy in a cohort of obese patients with hepatic fibrosis.

Conclusion : Hypertrophied HSCs are closely related to liver fibrosis and further characterization of these cells would shed light on the mechanisms of HSC activation during liver fibrogenesis. This may allow the identification of potential targets for a therapeutic strategy of liver fibrosis.

Remerciements : We are grateful to the Animal Platform and Virginie Mignon from Imaging Platform, UMS 3612 CNRS – US25 Inserm – Faculté de Pharmacie de Paris, Université Paris Descartes, Paris, France. We are also grateful to Nicolas Sorhaindo, Plateforme de Biochimie, CRI, Faculté de Médecine Site Bichat, Paris. This work was supported by the Agence Nationale de la Recherche (ANR, ANR Fibrother ANR-18-CE18-0005-01 to C.H.). The UtechS PBI (A.D., J.F.) is part of the France BioImaging infrastructure supported by the French National Research Agency (ANR-10-INSB-04-01, “Investments for the future”). Funding for patient’s recruitment (K.C.) was obtained by the Clinical Research Contrat (CRC-Fibrota).

Références : Hoffmann, C., Djerir, N.E.H., Danckaert, A. et al. Hepatic stellate cell hypertrophy is associated with metabolic liver fibrosis. Sci Rep 10, 3850 (2020). https://doi.org/10.1038/s41598-020-60615-0

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