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.
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