Rapid retinoic acid-induced trophectoderm model from human induced pluripotent stem cells

A limited number of accessible and representative models of human trophoblast cells currently exist for disease modeling and improving our understanding of placentation. Current stem cell models involve either a transition through a naïve stem cell fate or precise dynamic control of multiple interacting growth factor and small molecule cues. Here, we show that simple exposure of hiPSCs to two small molecules, retinoic acid (RA) and the Wnt signaling agonist CHIR 99021 (CHIR), results in rapid, synergistic upregulation of CDX2, an important transcription factor for trophectoderm cell induction and maintenance of the trophoblast cell population. RA+CHIR-treated cells have a transcriptional profile with high similarity to that of primary trophectoderm cells, and they can also be further differentiated into cells with features of syncytiotrophoblasts and extravillous trophoblasts. We assessed RA+CHIR-treated cells for the established set of criteria defining a trophectoderm cell model, and the cells possess all of the features necessary to be considered a valid model. Taken together, our data demonstrate the development of a simple method for the generation of functional trophoblast-like cells that can be used to better understand mechanisms and interactions involving the placenta.