Integration of metabolomic and transcriptomic profiles of hiPSCs-derived hepatocytes in a microfluidic environment
2020
Danoy, Mathieu | Poulain, Stéphane | Jellali, Rachid | Gilard, Françoise | Kato, Sachi | Plessy, Charles | Kido, Taketomo | Miyajima, Atsushi | Sakai, Yasuyuki | Leclerc, Eric | Laboratory for Integrated Micro Mechatronics Systems (LIMMS) ; University of Tokyo [Tokyo] = Tōkyō teikoku daigaku (UTokyo)-Centre National de la Recherche Scientifique (CNRS) | Centre de Ressources Biologiques - [Nancy] (CRB Nancy) ; Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy) | Biomécanique et Bioingénierie (BMBI) ; Université de Technologie de Compiègne (UTC)-Centre National de la Recherche Scientifique (CNRS) | Institut des Sciences des Plantes de Paris-Saclay (IPS2 (UMR_9213 / UMR_1403)) ; Université d'Évry-Val-d'Essonne (UEVE)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE) | RIKEN Center for Life Science Technologies (RIKEN CLST) ; RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN) | Institut de génétique et biologie moléculaire et cellulaire (IGBMC) ; Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS) | University of Tokyo [Tokyo] = Tōkyō teikoku daigaku (UTokyo) | ANR-16-RHUS-0005,iLite,iLite(2016)
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Show more [+] Less [-]English. The differentiation of human induced pluripotent stem cells (hiPSCs) into functional hepatocytes has the potential to solve the shortage of human primary liver cells and would be of use in drug screening. In this frame, we developed a hiPSCs maturation strategy in microfluidic biochips, using a liver-on-chip approach, a promising technology mimicking in vivo physiology. Hepato-like tissues differentiated in biochips presented advanced liver features, including ALB and CYP3A4 expressing cells. The metabolomics and transcriptomics profiles of hepato-likes cells differentiated either in biochips or Petri dishes were integrated to compare their functionalities. The multi-omics analysis revealed 41 metabolites and 302 genes differentially expressed. Overall, biochip environment lead to higher degree of hepatic differentiation demonstrated by an increase in the metabolic production of lipids, fatty acids and biliary acids, which was confirmed at the transcriptome level by the modulation of expression for genes involved in related signaling pathways. This observation was correlated with higher production of fructose in biochips, together with down-regulation of genes engaged in glycolysis. In parallel, increased activity of the Krebs cycle, pentose phosphate shuffle, and fatty acid beta oxidation was observed in tissues cultured in Petri. Besides, the modulation of nitrogen metabolism was observed in transcriptomic data and confirmed by an intense production of glutamine, putrescine and creatinine and by the higher consumption of spermidine measured in Petri.
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