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Investigation of the metabolomic crosstalk between liver sinusoidal endothelial cells and hepatocytes exposed to paracetamol using organ-on-chip technology
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International audience. Organ-on-chip technology is a promising in vitro approach recapitulating humanphysiology for the study of responses to drug exposure. Organ-on-chip cell cultureshave paved new grounds for testing and understanding metabolic dose-responseswhen evaluating pharmaceutical and environmental toxicity. Here, we present ametabolomic investigation of a coculture of liver sinusoidal endothelial cells (LSECs,SK-HEP-1) with hepatocytes (HepG2/C3a) using advanced organ-on-chip technology.To reproduce the physiology of the sinusoidal barrier, LSECs were separated fromhepatocytes by a membrane (culture insert integrated organ-on-chip platform). Thetissues were exposed to acetaminophen (APAP), an analgesic drug widely used as axenobiotic model in liver and HepG2/C3a studies. The differences between the SK-HEP-1, HepG2/C3a monocultures and SK-HEP-1/HepG2/C3a cocultures, treated ornot with APAP, were identified from metabolomic profiles using supervised multivariateanalysis. The pathway enrichment coupled with metabolite analysis of thecorresponding metabolic fingerprints contributed to extracting the specificity of eachtype of culture and condition. In addition, we analysed the responses to APAPtreatment by mapping the signatures with significant modulation of the biologicalprocesses of the SK-HEP-1 APAP, HepG2/C3a APAP and SK-HEP-1/HepG2/C3aAPAP conditions. Furthermore, our model shows how the presence of the LSECsbarrier and APAP first pass can modify the metabolism of HepG2/C3a. Altogether, thisstudy demonstrates the potential of a “metabolomic-on-chip” strategy for pharmaco-metabolomic applications predicting individual response to drugs.
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