Deciphering a distinct regulatory network of TEAD4, CDX2 and GATA3 in humans for trophoblast transition from embryonic stem cells.

The placenta is an essential organ for the fetus, but its regulatory mechanism for formation of functional trophoblast lineage remains elusive in humans. Although widely known in mice, TEAD4 and its downstream targets CDX2 and GATA3 have not been determined in human models. In this work, we used a human model of trophoblast transition from BAP (BMP4, A83-01 and PD173074)-treated human embryonic stem cells (hESCs) and performed multiple gain- and loss-of-function tests of TEAD4, CDX2 or GATA3 to study their roles during this process. Although hESCs with TEAD4 deletion maintain pluripotency, their trophoblast transition potentials are attenuated. This impaired trophoblast transition could be rescued by separately overexpressing TEAD4, CDX2 or GATA3. Furthermore, trophoblast transition from hESCs is also attenuated by knockout of CDX2 but remains unaffected with deletion of GATA3. However, CDX2-overexpressed hESCs maintain pluripotency, whereas overexpression of GATA3 in hESCs leads to spontaneous differentiation including trophoblast lineage. In brief, our findings using a human model of trophoblast transition from BAP-treated hESCs reveal transcription roles of TEAD4, CDX2 and GATA in humans that are different from those in mice. We hope that this evidence can aid in understanding the distinct transcriptional network regulating trophoblast development in humans.