Simulation of Embryonic Environments Produced by the Effect of Estradiol on Induced Pluripotent Stem Cells

Estradiol (E2) is one of the sex steroid hormones, whose various well-known functions include control of the female reproductive system, causing breast cancers, and inhibiting arterial sclerosis. In this study to investigate how E2 affected cell differentiation of induced pluripotent stem cells (iPSCs), we used different methods to culture hiPSCs, the undifferentiated state, longterm culture without passages (natural differentiation), embryoid bodies (EBs), and accelerated differentiation by activin, focusing on marker gene expression, including Brachyury, hepatocyte nuclear factor (HNF) 3β, estrogen receptor α, and other markers. When iPSCs began to differentiate by responding to E2, Brachyury expression decreased regardless of the amount of E2, cell line, or protocol. Other markers were up or down-regulated, but did not show any tendency except in the early stage of EBs. The definite timing that E2 had the strongest effect on the aspect of differentiation was the EB stage analogous to gastrulation, in which E2 repressed Brachyury expression and induced HNF3β at its restricted amount. These results suggest that the first target of E2 is the gastrulation stage.