Development of Human Stem Cell-Based Model for Developmental Toxicity Testing

XING JIANGWA

Publication

Development of Human Stem Cell-Based Model for Developmental Toxicity Testing

XING JIANGWA

Abstract

A human pluripotent stem cell (hPSC)-based in vitro model, which recapitulated both cell differentiation and collective cell migration during embryogenesis, was developed to identify teratogenic compounds. Mesoendoderm differentiation was first induced only to the periphery of circular micropatterned hPSC (?P-hPSC) colonies, where spatially polarized integrin adhesions competed to recruit Rho-ROCK activated myosin II away from E-cadherin mediated cell-cell junctions to promote differentiation. Next, these mesoendoderm cells underwent directed collective cell migration and formed an annular mesoendoderm pattern which was similar as in vivo. When treated with known teratogens, these two cellular processes were disrupted and the morphology of the mesoendoderm pattern was altered. By quantifying the morphological changes of the mesoendoderm pattern, the ?P-hPSC model could capture the dose-dependent effects of teratogenicity and 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.