Human iPSC-derived renal organoids engineered to report oxidative stress can predict drug-induced toxicity
M.L. Lawrence,
M. Elhendawi,
M. Morlock,
W. Liu,
S. Liu,
A. Palakkan,
L.F. Seidl,
P. Hohenstein,
A.K. Sjögren,
J.A. Davies
Affiliations
M.L. Lawrence
Deanery of Biomedical Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD UK
M. Elhendawi
Deanery of Biomedical Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD UK; Clinical Pathology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
M. Morlock
R&D Graduate, R&D, AstraZeneca, Gothenburg, Sweden
W. Liu
SynthSys Centre for Synthetic and Systems Biology, UK Centre for Mammalian Synthetic Biology, School of Biological Sciences, University of Edinburgh, C.H Waddington Building, Max Born Crescent, Edinburgh, EH9 3BF, UK
S. Liu
Deanery of Biomedical Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD UK
A. Palakkan
Deanery of Biomedical Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD UK
L.F. Seidl
Deanery of Biomedical Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD UK
P. Hohenstein
Leiden University Medical Center, Leiden University, Leiden, the Netherlands; The Roslin Institute, The University of Edinburgh, Midlothian, UK
A.K. Sjögren
CVRM Safety, Clinical Pharmacology and Safety Science, R&D, AstraZeneca, Gothenburg, Sweden
J.A. Davies
Deanery of Biomedical Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD UK; Corresponding author
Summary: Advances in regenerative medicine have led to the construction of many types of organoids, which reproduce important aspects of endogenous organs but may be limited or disorganized in nature. While their usefulness for restoring function remains unclear, they have undoubted usefulness in research, diagnostics, and toxicology. In toxicology, there is an urgent need for better models for human kidneys. We used human iPS-cell (hiPSC)-derived renal organoids to identify HMOX1 as a useful marker of toxic stress via the oxidative stress pathway, and then constructed an HMOX1 reporter in hiPSCs. We used two forms of hiPSC-derived HMOX1-reporter renal organoids to probe their ability to detect nephrotoxicants in a panel of blind-coded compounds. Our results highlight the potential usefulness, and some limitations, of HMOX1-reporter renal organoids as screening tools. The results may guide development of similar stress-reporting organoid assays for other stem-cell-derived organs and tissues.
