(770a) Human Embryonic Stem Cell Models of Early Human Placental Development
AIChE Annual Meeting
Friday, November 18, 2016 - 8:30am to 8:48am
The use of human embryonic stem cells (hESCs) to develop TB models has gained significant interest since it was first reported that hESCs treated with Bone Morphogenetic Protein (BMP) differentiate into TB-like cells. The use of hESC-derived TB as a model system is attractive because it overcomes several challenges associated with studies on TB development discussed above. However, lack of understanding of the mechanistic basis of TB differentiation of hESCs is a major impediment for widespread acceptance of hESC-derived TB as a model system for early placental development. Why hESCs, believed to be epiblast-like, can access TB fate remains an enigma. In contrast to mouse embryonic stem cells (mESCs), hESCs have been reported to readily differentiate to TB-like cells upon treatment with Bone Morphogenetic Protein (BMP) and/or inhibitors of the Activin/Nodal. However, whether hESCs can give rise to bona fide TB has been a subject of intense debate. A role for BMP in trophectodermal differentiation has not been identified in the mouse. It has been postulated that mESCs are epigenetically restricted from TB differentiation through hypermethylation of the Elf5 promoter region. Analogously, hESCs are hypermethylated at the ELF5-2b promoter locus, whereas early placental TB is hypomethylated, suggesting a similar epigenetic restriction. Furthermore, unlike placental TB, hESC-derived TB has been reported to not downregulate HLA class I antigens.
We have shown that bona fide TB can indeed be obtained from hESCs, and they possess key markers of placental TB such as hypomethylation of the ELF5 promoter locus and downregulation of HLA class I antigens. Whether the hESC-derived TB can function as bona fide trophoblasts during placental development cannot be experimentally tested. Nevertheless, a surrogate criterion is whether the response of hESC-derived TB towards their signaling environment is similar to those of primary TB. Transforming Growth factor-beta (TGFÎ²) suppresses epithelial to mesenchymal transformation (EMT) and invasive TB formation from placental TBsÂ and epidermal growth factor (EGF) triggers syncytialization of placental TBs. Our studies show that hESC-derived TB behave similarly, i.e. EGF treatment leads to formation of multinucleate syncytiotrophoblast (STB) and inhibition of Activin/Nodal signaling leads to EMT and formation of invasive TBs. Importantly, we have also identified conditions for selective differentiation of hESC-derived TB to invasive TB or STB lineages in monolayer cultures. Here we specifically discuss the role of BMP signaling in TB fate acquisition in hESCs, and subsequent differentiation to specialized TB subtypes.