title: Human induced pluripotent stem cells and their use in drug discovery for toxicity testing.
abstract: Predicting human safety risks of novel xenobiotics remains a major challenge, partly due to the limited availability of human cells to evaluate tissue-specific toxicity. Recent progress in the production of human induced pluripotent stem cells (hiPSCs) may fill this gap. hiPSCs can be continuously expanded in culture in an undifferentiated state and then differentiated to form most cell types. Thus, it is becoming technically feasible to generate large quantities of human cell types and, in combination with relatively new detection methods, to develop higher-throughput in vitro assays that quantify tissue-specific biological properties. Indeed, the first wave of large scale hiSC-differentiated cell types including patient-derived hiPSCS are now commercially available. However, significant improvements in hiPSC production and differentiation processes are required before cell-based toxicity assays that accurately reflect mature tissue phenotypes can be delivered and implemented in a cost-effective manner. In this review, we discuss the promising alignment of hiPSCs and recently emerging technologies to quantify tissue-specific functions. We emphasize liver, cardiovascular, and CNS safety risks and highlight limitations that must be overcome before routine screening for toxicity pathways in hiSC-derived cells can be established.
authors.affiliation: Molecular Toxicology Section, Global Safety Assessment, AstraZeneca Pharmaceuticals LP, Z138, 35 Gatehouse Park, Waltham, MA 02451, United States. clay.scott@astrazeneca.com
authors.forename: Clay W
authors.initials: CW
authors.lastname: Scott
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Peters
authors.forename: Yvonne P
authors.initials: YP
authors.lastname: Dragan
mesh_terms: D018929:Cell Culture Techniques; D002490:Central Nervous System / Q000166:cytology / Q000187:drug effects; D055808:Drug Discovery / Q000379:methods*; D004353:Drug Evaluation, Preclinical; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects; D008099:Liver / Q000166:cytology / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects; D044968:Regenerative Medicine / Q000639:trends; D018675:Toxicity Tests / Q000379:methods*