NASH patient liver derived organoids exhibit patient specific NASH phenotypes and drug responses

Abstract

AbstractTo determine if patient liver derived organoids can in principle be a useful experimental model for non alcoholic staetohepatitis (NASH), we derived to our knowledge for the first time bipotent ductal organoids from endstage NASH patient livers, and for comparison from normal donor livers. We found that all tested NASH liver derived organoids exhibited a profound failure to dedifferentiate from the hepatic state back to the biliary state, consistent with the known poor regenerative capacity of NASH livers. Indeed, RNAseq on all tested NASH organoid populations confirmed down regulation of multiple cell cycle pathways. NASH liver derived hepatically differentiated organoids can slowly expand as monolayers, significantly simplifying microscopic quantitation: The monolayers show variable, but overall significantly increased lipid droplet accumulation in response to free fatty acids. Transcriptome analysis of NASH organoids reveals strong upregulation of a wide variety of pro inflammatory pathways in a NASH patient specific manner. Surprisingly, NASH liver derived organoids are highly diverse not only regarding their cytochrome cytochrome p450 metabolism and inflammatory response, but also react differentially to known antisteatotic, anti inflammatory and antifibrotic drugs, raising the possibility of using NASH patient liver biopsy derived organoids for personalized drug screening and therapy.One Sentence SummaryNASH patient liver derived organoids replicate NASH liver phenotypes in a patient specific manner and exhibit profound differences in their response to drugs that are currently used in NASH clinical trials.