Opportunities for use of human iPS cells in predictive toxicology

Abstract

Toxicity assessment is a major challenge for cost-effective drug development, and there is great need for better tools to accurately predict adverse drug reactions. Technological advances are empowering new cell-based assays for predictive toxicology, and these assays are critically dependent on the cell source. Here we describe the properties of human induced pluripotent stem (iPS) cells that make them a promising cell source for toxicity assessment and highlight progress to date and important roadblocks remaining.

Figure 1

Generation and utilization of human iPS cells in predictive toxicology. Somatic cells from skin, blood, fat or other tissues can be obtained from consenting donors for transcription factor-based reprogramming to iPS cells. The starting material can provide broad genetic diversity and represent distinct disease phenotypes as well as adverse drug reactions. The iPS cells are differentiated into specific cell lineages which can be characterized in vitro using a wide range of assays for toxicity.

Figure 2

Toxicity assays using human iPS cell-derived cardiomyocytes. (A) Electrophysiological toxicity was assayed using the perforated patch clamp technique on single human iPSC-derived cardiomyocytes. Action potential duration was shortened by the L-type Ca²⁺ channel blocker nifedipine (upper) and prolonged by the hERG K⁺ channel blocker E-4031 (lower). Scale bars; 100ms by 20mV. (B) Biochemical toxicity was assayed by measuring ATP, GSH, and Caspase activity using CellTiter-, GSH-, and Caspase-Glo® 3/7 assay kits, respectively, in a 96 well format of cultured iPS cell-derived cardiomyocytes. Imatinib (Gleevac) produced a dose-dependent decrease in cell viability (ATP decrease) and increased oxidative stress (reduction in GSH) without activating apoptotic pathways (unchanged caspase).