title: Accurate prediction of drug-induced liver injury using stem cell-derived populations.
abstract: Despite major progress in the knowledge and management of human liver injury, there are millions of people suffering from chronic liver disease. Currently, the only cure for end-stage liver disease is orthotopic liver transplantation; however, this approach is severely limited by organ donation. Alternative approaches to restoring liver function have therefore been pursued, including the use of somatic and stem cell populations. Although such approaches are essential in developing scalable treatments, there is also an imperative to develop predictive human systems that more effectively study and/or prevent the onset of liver disease and decompensated organ function. We used a renewable human stem cell resource, from defined genetic backgrounds, and drove them through developmental intermediates to yield highly active, drug-inducible, and predictive human hepatocyte populations. Most importantly, stem cell-derived hepatocytes displayed equivalence to primary adult hepatocytes, following incubation with known hepatotoxins. In summary, we have developed a serum-free, scalable, and shippable cell-based model that faithfully predicts the potential for human liver injury. Such a resource has direct application in human modeling and, in the future, could play an important role in developing renewable cell-based therapies.
authors.affiliation: Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom; FibromEd Products Ltd., Edinburgh Bio-Quarter, Edinburgh, United Kingdom; Medical Research Council Centre for Inflammation, Edinburgh, United Kingdom; Discovery Toxicology, Bristol-Myers Squibb, Princeton, New Jersey, USA; Department of Oncology, Second Military Medical University, Shanghai Changzheng Hospital, Shanghai, People's Republic of China.
authors.forename: Dagmara
authors.initials: D
authors.lastname: Szkolnicka
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Farnworth
authors.forename: Baltasar
authors.initials: B
authors.lastname: Lucendo-Villarin
authors.forename: Christopher
authors.initials: C
authors.lastname: Storck
authors.forename: Wenli
authors.initials: W
authors.lastname: Zhou
authors.forename: John P
authors.initials: JP
authors.lastname: Iredale
authors.forename: Oliver
authors.initials: O
authors.lastname: Flint
authors.forename: David C
authors.initials: DC
authors.lastname: Hay
mesh_terms: D002454:Cell Differentiation / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000628:therapy*; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D003603:Cytotoxins / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D053595:Embryonic Stem Cells / Q000166:cytology*; D022781:Hepatocytes / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D039904:Pluripotent Stem Cells / Q000166:cytology; D011237:Predictive Value of Tests; D033581:Stem Cell Transplantation
chemical_list: D016895:Culture Media, Serum-Free; D003603:Cytotoxins
keywords: Cytochrome P450; Drug metabolism; Drug toxicity; Human embryonic stem cells; Liver; iPSC