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3D innovative hiPSC-based models including the microenvironment for phenotypic screening - Application on metabolic diseases
This document summarizes research from the Thorax Institute on using induced pluripotent stem cells (iPSCs) to model metabolic diseases like familial hypercholesterolemia (FH). Researchers generated iPSCs from a FH patient and differentiated them into hepatocyte-like cells. These cells reproduced the patient's phenotype of impaired LDL cholesterol uptake and responded to pharmacological treatment. The researchers propose that 3D culture systems could further mature the cells to enable phenotypic screening of diseases like non-alcoholic steatohepatitis and fibrosis.
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3D innovative hiPSC-based models including the microenvironment for phenotypic screening - Application on metabolic diseases
- 1. BANDEAU TUTELLES L’unité de recherche de l’institut du thorax Inserm UMR 1087 / CNRS UMR 6291 Nantes, France 3D innovative hiPSC-basedmodels including the microenvironment for phenotypic screening - Application on metabolic diseases Karim Si-Tayeb ELRIGfr Conference 23/24 mai 2018 Le Bischenberg, Bischoffsheim, France
- 2. 2 Familial hypercholesterolemia (FH) Facteurs de risque génétique Récepteur LDL Inconnus APOB PCSK9 Hypercholesterolemia: Impaired LDL-cholesterol uptake Modified from Norata et al. EHJ 2013 Identification of informative famillies displaying: - A spontaneously low LDL-C level (FHBL) - A hypercolesterolemia without cardiovascular disease (CIC Thorax, Matthieu Pichelin, Marie Marrec) Absence of mutations in known genes involved in FH (LDLR, PCSK9, APOB, ANGPTL3) (Jocelyne Magré, Jean-Jacques Schott)
- 3. 3 The Scientist Magazine April 2016 Si-Tayeb et al.Disease Models & Mechanisms 2016 Patient Urine-derived cells hiPS cells in vitro study of familial hypercholesterolemia Hepatocytes © l’institut du thorax Modeling FH in vitro from an urine sample - the power of hiPS cells
- 4. 4 From hiPS cellstoward hepatocytes – back to developmental biology He: precardiac mesoderm End: endoderm Lb: liver bud E: endothelial cells STM: Septum transversum d0 d5 d10 d15 d20 Hepatocytes Definitif Endoderm Hepatic progenitors Specified Definitif Endoderm Human pluripotent stem cells Si-Tayeb et al. Developmental Cell 2010 Si-Tayeb et al. Hepatology 2010
- 5. 5 Fluorescent LDL uptakeanalyzed by flow cytometry Phenotype reproduced in vitro Familial hypercholesterolemia in a petri-dish Phenotype pharmacologicaly reversed in vitro Si-Tayeb, Idriss et al. Disease Models & Mechanims 2016
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- 7. 7 A promising modelthat needs further maturation by adding a third dimension Nature review 2004
- 8. 8 Liver A promising modelthat needs further maturation by adding a third dimension Amandine Caillaud Méryl Roudaut
- 9. 9 A new differentiationprotocol for a new environment Cytokines d0 d5 d10 d15 d20 Hepatocytes Definitif Endoderm Hepatic progenitors Specified Definitif Endoderm Human pluripotent stem cells Méryl Roudaut
- 10. 10 CYP450 basal activitiesand induction CYP450 2C9 (ibuprofen) Diclofenac -> 4OH-Diclofenac CYP450 1A2 (caffein) Phenacetin-> Acetaminophen CYP450 2A6 Nicotine-> Cotinine CYP450 2E1 (ethanol) Chlorzoxazone-> 6-0H-Chlorzoxazone Méryl Roudaut (nM) (nM) (nM)(nM)
- 11. 11 CYP450 basal activitiesand induction CYP450 3A4 Testosteron-> 6ß-OH-testosteron 0 100 200 300 400 500 0 10 20 30 40 50 60 70 nmol/L Minutes CYP3A4 activity (nmol/L/min/well) Basal activity Induced activity 0 50 100 150 200 250 Basal activity Induced activityActivitypercentage CYP3A4 activity * Méryl Roudaut (nM)
- 12. 12 Conclusion and perspectives hiPS cells -> Genetic variability Hepatic cells -> Phenotypic screening 3D 2D 6 puits 96 puits
- 13. 13 Conclusion and perspectives Liver NASH Fibrosis
- 14. www.umr1087@univ-nantes.fr L’unité de recherche de l’institut du thorax Inserm UMR 1087 / CNRS UMR 6291 Nantes, France Daniel Buren et Patrick Bouchain, Les Anneaux, Quai des Antilles, Nantes, création pérenne Estuaire 2007 © Martin Argyroglo/LVAN L’institut du thorax CARIOUBertrand LE MAY Cédric MAGRE Jocelyne PRIEUR Xavier PICHELIN Matthieu ARNAUD Lucie AYER Audrey BLANCHARD Claire Wargny Matthieu MOREAU François CHADEUF Gilliane DIJK Wienecke THEDREZ Aurélie SI-TAYEB Karim IDRISS Salam CAILLAUD Amandine GIRARDEAU Aurore ROUDAUT Méryl CANTAT Pierre-Alexandre LORANT Victoria HCS Pharma MAUBON Nathalie MAUBON Gregory SOUGUIR Zied VANDENHAUTE Elodie