• Boeckmans, Joost

Abstract

Non-alcoholicsteatohepatitis(NASH)isaseverechronicliverdiseasethat <br/>affectsabout5%ofthepopulation.NASHischaracterizedbyhepaticlipid <br/>accumulation,inflammationandfibrosisandcanprogresstocirrhosisand <br/>hepatocellularcarcinoma.Therearecurrentlynodrugsavailabletotreat <br/>NASH. Investigation of NASH traditionally relies on animal models, which are often notrepresentativeforthehumansituation.Therefore,theaimofthe <br/>doctoralthesiswastodevelopahuman-basedinvitromodelthatcan <br/>recapitulate the molecular and cellular mechanisms that drive NASH and can <br/>be used during anti-NASH drug development. Tothisend,wecreatedaNASH-specifichepaticenvironmentinvitroby exposing human stem cell-derived hepatic cells (hSKP-HPC), primary human hepatocytes (PHH) and human hepatic cell lines (HepG2 and HepaRG) to key NASH-inducingfactors.TheobtainedmodelsmirroredNASHcharacteristics and could be used to evaluate anti-lipogenic and anti-inflammatory propertiesofPPARagonists,aclassofanti-NASHdrugsthatareunder clinical evaluation. The hSKP-HPC-derived model most closely mimicked the PHH-mediated drug testing responses, highlighting its possible future position in preclinical drug development.<br/>Furthermore,geneticpredispositionofpatientstodevelopNASHcouldbe <br/>evaluatedinvitrousinghSKP-HPC,pavingthewayfortheinvestigationof <br/>patient-specific genetic etiologies of NASH. In conclusion, a pragmatic human- and disease-relevant stem cell-derived in vitroNASHmodelhasbeendevelopedthatcanbeimplementedindrug testing and personalized medicine.

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