经过工程改造以报告氧化应激的人诱导多能干细胞衍生的肾类器官能够预测药物诱导的毒性。
Human iPSC-derived renal organoids engineered to report oxidative stress can predict drug-induced toxicity.
作者信息
Lawrence M L, Elhendawi M, Morlock M, Liu W, Liu S, Palakkan A, Seidl L F, Hohenstein P, Sjögren A K, Davies J A
机构信息
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.
出版信息
iScience. 2022 Feb 7;25(3):103884. doi: 10.1016/j.isci.2022.103884. eCollection 2022 Mar 18.
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.
再生医学的进展已促使多种类器官的构建，这些类器官再现了内源性器官的重要方面，但在性质上可能存在局限性或结构紊乱。虽然它们在恢复功能方面的效用尚不清楚，但在研究、诊断和毒理学方面具有毋庸置疑的用途。在毒理学领域，迫切需要更好的人类肾脏模型。我们利用人诱导多能干细胞（hiPSC）来源的肾类器官，通过氧化应激途径将血红素加氧酶1（HMOX1）鉴定为毒性应激的有用标志物，然后在hiPSC中构建了一个HMOX1报告基因。我们使用两种形式的hiPSC来源的HMOX1报告基因肾类器官，来探究它们在一组盲编码化合物中检测肾毒性物质的能力。我们的结果突出了HMOX1报告基因肾类器官作为筛选工具的潜在效用及一些局限性。这些结果可能会指导针对其他干细胞来源的器官和组织开发类似的应激报告类器官检测方法。
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