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de Génomique Fonctionnelle du Foie
A single procedure to generate functional hiPSCs-derived liver
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Abstract : a single procedure to generate functional hi ps cs-derived liver organoids - towards an innovative tools suitable for drug screening

  1. 1. VIII ème Colloque de Génomique Fonctionnelle du Foie A single procedure to generate functional hiPSCs-derived liver organoids - Towards an innovative tools suitable for drug screening Méryl Roudaut 1, 2, Amandine Caillaud 1, Aurélie Thédrez 1, Wieneke Dijk 1, Aurore Girardeau 1, Matthieu Pichelin 1, Lucie Arnaud 1, Mikaël Croyal 1, 3, Cédric Le May 1, Élodie Vandenhaute2, Zied Souguir 2, Nathalie Maubon 2, Bertrand Cariou 1, Karim Si-Tayeb 1 1°) Institut du thorax, INSERM U1087, CNRS 6291, IRS-UN, CHU-Nantes, Nantes, France 2°) HCS Pharma, Lille, France 3°) Plateforme de Spectrométrie de Masse, CRNHO, Inra UMR 1280, Nantes, France We previously showed that human pluripotent stem cells (hiPSCs) provide a suitable model to study metabolic diseases upon hepatocyte-like cell (HLC) differentiation. With a non-invasive approach, hiPSCs can be generated from urine samples of patients and HLCs have been used to model cholesterol metabolism regulation, by the study of LDLR- and PCSK9-mediated autosomal dominant hypercholesterolemia (ADH) as well as PCSK9- mediated familial hypobetalipoproteinemia (FHBL). This model provides promising advantages with a direct link to the patient and with an unlimited source of HLCs. But like all models, there are limitations, mainly by the neonatal characteristic of HLCs lead to difficulties for pharmacological investigations. Therefore, to overcome these burdens, we chose to 1. Differentiate hiPSCs into HLCs in an innovative 3D modified Hyaluronic Acid hydroscaffold, BIOMIMESYS® produces by HCS Pharma to enhance their maturation. 2. Adapt our 3D differentiation process to a 96-well format to make it compatible for drug screening. 3. Characterization of the 3D HLCs model by metabolism tests and compare to primary human hepatocyte (PHH). We gathered 3’ SRP data all along the differentiation process and RNAseq has been performed by comparing 2D and 3D differentiation conditions to characterize hiPSCs differentiation into liver organoïds. We observed an enhanced expression of most hepatic genes and genes expressed by non-parenchymal cells such as stellate cells. Immunofluorescence data confirmed the co-localization of albumin-positive hepatocytes, desmin-positive stellate cells and LYVE1-positive endothelial cells in liver organoïds. Finally, at a functional level, several CYP activities including CYP3A4 were detected at the basal level and successfully induced. Liver organoïds responded to pharmacological treatments as shown by their ability to accumulate lipids upon amiodarone treatment or uptake LDL-bodipy upon statin treatment. Altogether, our development gave rise to functional liver organoïds generated with a unique and common procedure, in a process of automating for future high throughput screening. E-mail correspondant/corresponding author : karim.si-tayeb@univ-nantes.fr

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Abstract for poster for the "VIIIème Colloque de Génomique Fonctionnelle du Foie" - Rennes (France) 2020


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