This treatment had previously been shown to reduce the developmental potential of embryos to reach term. When such blastocysts were plated in embryonic stem cell media, their ability to form proliferative ICM/epiblast cultures was much reduced compared to FDA-approved Compound Library freshly-derived blastocysts. This effect could be partially ameliorated by genetic loss of TP53 and was not seen in corresponding TE outgrowths. The deduction made is that cell culture-induced stress/trophic Niraparib factor deprivation mediates cell death of ICM derivatives through a failure to prevent TP53 accumulation. Thus activation of either of two branches of the trophic factor- AKT pathway, namely either TP53 or BAD accumulation, leads to a specific loss of ICM derivatives with the epiblast more vulnerable than the hypoblast. Why is the epiblast most affected? Either the epiblast is exposed to fewer or lower levels of trophic factors and/or it is more dependent on the presence of trophic factors than the TE and hypoblast. In support of, the ICM and its derivatives are shielded from the environment, and thus diffusible trophic factors, by the trophectoderm. Only by Day 12 does the polar trophectoderm overlying the epiblast start to disappear, exposing the epiblast directly to maternal signals which could counteract a proapoptotic effect. In opposition to this line of reasoning is the consideration that the nondifferentiated ICM and hypoblast would both suffer similarly from such a TE-shielding effect, yet the hypoblast can survive under conditions where the epiblast does not. Thus, a differential cell survival response to signaling may be the deciding factor. In the mouse, in vitro models exist for all four early lineages. They are trophoblast stem cells for TE, embryonic stem cells for ICM/early epiblast, epiblast stem cells for post-implantation epiblast and extra embryonic endoderm stem cells for hypoblast. Of these, EpiSC are the most difficult to maintain, requiring mechanical dissociation for passaging in addition to a range of growth factors. As the epiblast lineage gives rise predominantly to the fetus itself, an increased sensitivity to signals from the environment may allow for the efficient weeding out of suboptimal cells ensuring the generation of a more robust and healthy individual and thus be of selective advantage.