A method for human teratogen detection by geometrically confined cell differentiation and migration

Unintended exposure to teratogenic compounds can lead to various birth defects; however current animal-based testing is limited by time, cost and high inter-species variability. Here, we developed a human-relevant in vitro model, which recapitulated two cellular events characteristic of embryogenesis, to identify potentially teratogenic compounds. We spatially directed mesoendoderm differentiation, epithelial-mesenchymal transition and the ensuing cell migration in micropatterned human pluripotent stem cell (hPSC) colonies to collectively form an annular mesoendoderm pattern. Teratogens could disrupt the two cellular processes to alter the morphology of the mesoendoderm pattern. Image processing and statistical algorithms were developed to quantify and classify the compounds’ teratogenic potential. We not only could measure dose-dependent effects but also correctly classify species-specific drug (Thalidomide) and false negative drug (D-penicillamine) in the conventional mouse embryonic stem cell test. This model offers a scalable screening platform to mitigate the risks of teratogen exposures in human.Singapore. Agency for Science, Technology and ResearchJanssen Pharmaceutical Ltd. (Grant R-185-000-182-592)Janssen Pharmaceutical Ltd. (Grant R-185-000-228-592)Singapore-MIT Alliance Computational and Systems Biology Flagship Project (C-382-641-001-091)Mechanobiology Institute, Singapore (R-714-001-003-271