Human Liver Organoids as models for investigating drug-induced liver injury
type: CreativeWork
description: The liver is the primary organ involved in drug detoxification, hence being highly exposed to the risk of drug induced liver injury (DILI). DILI is the main cause for acute liver failure in western countries and post-marketing withdrawal of drugs. This is highly due to the poor identification of potential human hepatotoxins during the preclinical phase of drug discovery. It is not surprising that interspecies difference between animal models could generate diverse biological responses compared to the human liver. Similarly, the current-state-of-the-art human in vitro hepatic systems lack the cellular spatial arrangement and hepatocyte functionality observed in vivo. Identification of an in vitro hepatic system capable to reproduce the essential features of the human liver in vivo is thus beneficial to better understand DILI and how it is triggered. Historically, maintenance of primary hepatocyte in vitro has been challenging due the intrinsic finite proliferative capacity of these cells, the shortage of donor livers, and the inability to maintain their in vivo structural and functional identity in vitro. All of the above hurdles have been addressed with the advent of 3D epithelial structures called organoids, yet its use in the liver safety field is currently unexplored. Liver organoids have the great advantage to be highly proliferative, to maintain the identity of the tissue of origin, and to retain the bipotential ability to differentiate into hepatocyte organoids. In this Thesis, we generated an enhanced hepatocyte organoid system through the directed stepwise differentiation in vitro of progenitor liver organoids using chemically defined culture conditions. Validation of these organoids in the context of DILI, showed structural and functional formation of tubular like structures called bile canaliculi which are essential morphological structures for the hepatocytes to secrete drugs/metabolites and bile from the intracellular compartment. Drug distribution mappi…
abstract: The liver is the primary organ involved in drug detoxification, hence being highly exposed to the risk of drug induced liver injury (DILI). DILI is the main cause for acute liver failure in western countries and post-marketing withdrawal of drugs. This is highly due to the poor identification of potential human hepatotoxins during the preclinical phase of drug discovery. It is not surprising that interspecies difference between animal models could generate diverse biological responses compared to the human liver. Similarly, the current-state-of-the-art human in vitro hepatic systems lack the cellular spatial arrangement and hepatocyte functionality observed in vivo. Identification of an in vitro hepatic system capable to reproduce the essential features of the human liver in vivo is thus beneficial to better understand DILI and how it is triggered. Historically, maintenance of primary hepatocyte in vitro has been challenging due the intrinsic finite proliferative capacity of these cells, the shortage of donor livers, and the inability to maintain their in vivo structural and functional identity in vitro. All of the above hurdles have been addressed with the advent of 3D epithelial structures called organoids, yet its use in the liver safety field is currently unexplored. Liver organoids have the great advantage to be highly proliferative, to maintain the identity of the tissue of origin, and to retain the bipotential ability to differentiate into hepatocyte organoids. In this Thesis, we generated an enhanced hepatocyte organoid system through the directed stepwise differentiation in vitro of progenitor liver organoids using chemically defined culture conditions. Validation of these organoids in the context of DILI, showed structural and functional formation of tubular like structures called bile canaliculi which are essential morphological structures for the hepatocytes to secrete drugs/metabolites and bile from the intracellular compartment. Drug distribution mappi…
author: Kaluthantrige Don, Mewanthi Flaminia
language: eng
keywords: organoid, liver, stem cell, development, DILI
license: https://www.rioxx.net/licenses/all-rights-reserved/
date published: 2021-04-30
date modified: 2026-07-22T22:24:06Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.82715