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

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   Figure 1

   Schematic diagram of the cell signaling that dictates trophoblast (TB) differentiation in the mouse. (A) The nuclear localization of TEAD4 in the outer blastomeres of the embryo leads to a trophoblast-specific transcriptional program, which is selectively impaired in the inner cells of the embryo (i.e. the ICM). Inactive HIPPO signaling maintains YAP in an unphosphorylated state, resulting in translocation of YAP to the nucleus and thus induction of the TEAD4 transcriptional program in the outer cells of the embryo. (B) Trophoblast differentiation is not limited to Cdx2 induction (GATA3 induction results in trophoblast differentiation) and likewise CDX2 induction is not only limited to trophoblast differentiation but also results in extraembryonic ectoderm expansion. Black arrows indicate positive induction pathways. Blue arrows indicated enhancement of CDX2 leading to extraembryonic ectoderm expansion.
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   Figure 2

   Schematic of the cell signaling that dictates hESC self-renewal and differentiation induction by BMP4. Controversy exists as to whether BMP4 signaling results in trophoblast (TB) lineage differentiation or whether BMP4 along with the continuous presence of FGF result in primitive streak and mesendoderm derivatives and not trophoblast. Black arrows indicate inductive pathways for hESC self-renewal. Blue arrows indicate differentiation induction of hESC.
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   Figure 3

   Photomicrograph depicts EB-derived trophoblast outgrowths. Once the EB has adhered to the surface, outgrowths grow and move away from the EB core. The undifferentiated EB mass is circled left. With the EB core still maintaining the potential to differentiate into other tissue derivatives, interests lie in isolating cells near to the core, which make up a confluent cellular zone and isolating the cells at the farthest edge away from the core, which constitute the migratory zone of cells. Studies still remain to elucidate the potential gradient of differentiation that might exist resulting in various trophoblast subtypes. CTB, cytotrophoblasts; STB, syncytiotrophoblasts; EVTB, extravillous cytotrophoblasts; TGC, trophoblast giant cells. Scale bar=100 μm.

• © 2013 Society for Endocrinology