Abstract

Human Stem Cell-Derived Renal Cells and High-Throughput Nephrotoxicity Prediction

Jacqueline Chuah, Lab Officer, Institute of Bioengineering and Nanotechnology, A*Star

The kidney is a major target for compound-induced toxicity. Animal-free alternative methods are required by governmental agencies and various industries to decrease costs and increase the throughput of nephrotoxicity prediction. We have developed the first accurate and pre-validated in vitro models for predicting compound-induced nephrotoxicity in humans (Loo and Zink, 2017; Chuah and Zink, 2017; Kandasamy et al., 2015; Li et al., 2014; Li et al., 2013; Su et al., 2014; Su et al., 2016). Our models include the first and only pre-validated and predictive stem cell-based renal in vitro models (Li et al., 2014; Kandasamy et al., 2015; Chuah and Zink, 2017). The most advanced of these models is based on induced pluripotent stem cell (iPS)-derived renal proximal tubular (PTC)-like cells. A rapid one-step protocol has been established for the generation of PTC-like cells in 8 days of differentiation, and these cells can be directly used for compound screening (Kandasamy et al., 2015). Alternatively, PTC-like cells can be applied after cryopreservation. By combining iPS-derived renal cell-based assays with machine learning methods, a test balanced accuracy of 87% could be achieved with respect to nephrotoxicity prediction (Kandasamy et al., 2015; Chuah and Zink, 2017). In addition, underlying mechanisms of drug-induced cellular injury could be correctly identified. We have also established a high-content screening (HCS) platform that combines high-content imaging of renal cells with automated phenotypic profiling and machine learning methods (Su et al., 2016). The automated HCS platform has a test balanced accuracy ranging between 82%-89%, depending on the human renal cell type used (Su et al., 2016; Loo and Zink, 2017). Based on these technologies we are currently developing a portfolio of platforms for the prediction of compound-induced toxicity to various organs. In addition, a kidney-on-chip platform for repeated dose testing is under development. This platform appears to be suitable for the assessment of the human dose response.