Polygenic basis of DILI using in vitro NAM-Polygenic basis of DILI using in vitro NAM

Video Transcription

Video Summary

Johnny Sexton (University of Michigan) introduces Dr. Takanori Takebe, a physician-scientist and leader in stem cell biology, liver organoids, and translational medicine. Takebe directs the Center for Stem Cell Organoid Research and Medicine at Cincinnati Children’s and holds roles in Japan. Sexton highlights Takebe’s landmark 2013 Nature work on vascularized human liver “buds,” subsequent advances including large-scale organoid phenotyping for MASH and multizonal liver organoids that mimic liver lobule metabolism, and recognitions ranging from major awards to an Ig Nobel.<br /><br />Takebe presents how iPSC-derived liver organoids (HLOs) bridge “chaotic” pluripotent differentiation and overly simplified 2D hepatocyte cultures, providing stable 3D polarized architecture and scalability for drug testing. He describes improved canalicular network formation and functional assays showing polarized efflux transporters and bile acid transport readouts, while noting limitations such as relatively immature uptake transporter expression.<br /><br />He then focuses on drug-induced liver injury (DILI), especially cholestatic/mixed forms. Using scalable HLO screening and comparisons to primary hepatocytes, his group profiled many compounds and incorporated donor genetics. Leveraging international DILI consortia, they developed a polygenic risk score (PRS/PLS-based) using tens of thousands of SNPs that predicts susceptibility to cholestatic DILI, including validation with the failed drug TAK-875 and independent clinical cohorts. Mechanistic analyses link high-risk scores to mitochondrial/ER stress pathways (electron transport, TCA cycle, UPR).<br /><br />In Q&A, Takebe suggests mitochondrial signatures mainly reflect hepatocyte stress, discusses aging links, notes organoids can model early injury signals but need added immune components/perfusion for inflammation, and outlines paths to faster patient-specific models (accelerated iPSC workflows or direct reprogramming).

Keywords

Takanori Takebe

iPSC-derived liver organoids

human liver buds

vascularized organoids

drug-induced liver injury (DILI)

cholestatic liver injury

polygenic risk score (PRS)

MASH organoid phenotyping

mitochondrial and ER stress pathways

Cincinnati Children’s organoid research