A high-throughput screen for teratogens using human pluripotent stem cells.

Area of Science:

• Toxicology
• Developmental Biology
• Stem Cell Biology

Background:

• High-throughput human cell-based assays are needed to reduce animal testing for identifying hazardous chemicals.
• Human-specific teratogens like thalidomide highlight the importance of human cell-teratogenicity assays.

Purpose of the Study:

• To describe and validate a human pluripotent stem cell test (hPST) for identifying teratogens.
• To benchmark hPST in vitro findings against traditional preclinical toxicology and human teratogenic outcomes.

Main Methods:

• A 3-day directed differentiation of human embryonic stem cells into a monolayer.
• Measuring the reduction in nuclear translocation of the transcription factor SOX17 in mesendodermal cells to assess teratogenic risk.

Main Results:

• Decreased nuclear SOX17 in the hPST model strongly correlated with in vivo teratogenicity.
• The hPST demonstrated 94% accuracy in identifying teratogens among 71 drug-like compounds and 15 environmental toxicants.
• High-throughput screening of 300 kinase inhibitors confirmed the hPST platform's utility for drug safety prediction.

Conclusions:

• The hPST assay is a robust predictor of teratogenicity.
• This assay offers an improvement over existing in vitro models for teratogenicity assessment and drug safety prediction.