Human iPSC-derived renal organoids engineered to report oxidative stress can predict drug-induced toxicity
Mark L. Lawrence, Mona Elhendawi, Marina A. Morlock, Wei Liu, S. Liu, Anwar A. Palakkan, L.F. Seidl, Peter Hohenstein, Anna-Karin Sjögren, Jamie A. Davies
Abstract
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.