Embryonic stem cell-derived trophoblast differentiation: a comparative review of the biology, function, and signaling mechanisms

The development of the placenta is imperative for successful pregnancy establishment, yet the earliest differentiation events of the blastocyst-derived trophectoderm that forms the placenta remain difficult to study in humans. Human embryonic stem cells (hESC) display a unique ability to form trophoblast cells when induced to differentiate either by the addition of exogenous BMP4 or by the formation of cellular aggregates called embryoid bodies. While mouse trophoblast stem cells (TSC) have been isolated from blastocyst outgrowths, mouse ESC do not spontaneously differentiate into trophoblast cells. In this review, we focus on addressing the similarities and differences between mouse TSC differentiation and hESC-derived trophoblast differentiation. We discuss the functional and mechanistic diversity that is found in different species models. Of central importance are the unique signaling events that trigger downstream gene expression that create specific cellular fate decisions. We support the idea that we must understand the nuances that hESC differentiation models display so that investigators can choose the appropriate model system to fit experimental needs.