Conventional human pluripotent stem cells at the primed pluripotent state are capable of generating all the embryonic lineages. However, their extraembryonic trophectoderm potentials is limited. It remains unclear how to expand their developmental potential to trophectoderm lineages. Now, writing in the journal Science China Life Sciences, a team of researchers from Peking University found that the extraembryonic trophoblast potentials can be re-activated in human primed pluripotent stem cells through transient treatment of a chemical cocktail of epigenetic regulators. This novel approach to in vitro generation of human trophoblast lineages holds significant promise, particularly in advancing the understanding of trophoblast-related diseases such as miscarriage and preeclampsia.
To activate trophoblast developmental potentials in human primed pluripotent stem cells, the researchers performed a chemical screen and found that a transient treatment of three epigenetic regulators (VPA, DZNep, and JQKD82), which targeted HDAC2, EZH2, and KDM5, can efficiently enable the generation of trophectoderm-like cells from human primed pluripotent stem cells. The induced trophectoderm-like cells can further develop into trophoblast stem cells, which have the ability to differentiate to extravillous trophoblasts and syncytiotrophoblasts.
Because previous studies showed that human primed pluripotent stem cells can generate amniotic-like cells which share several molecular features with trophoblast cells, Chen et al. further compared the transcriptome of these induced trophoblast stem cells with reported trophoblast stem cells and amniotic-like cells derived from human primed pluripotent stem cells. They showed that the chemically induced trophoblast stem cells are clearly distinguished from amniotic-like cells. Instead, they resembled classical trophoblast stem cells at the global transcriptomic level.
To explore the epigenetic changes during the induction process, Chen et al. also performed CUT&Tag analysis at different time points. They found that the pretreatment of small molecules significantly reduced both the H3K27me3 and H3K4me3 modifications in the primed specific gene loci. They also showed that direct knocking down the chemical targets of epigenetic regulators, such as HDAC2, EZH1/2, and KDM5s, can also activate trophoblast developmental potentials in human primed pluripotent stem cells. These findings further highlighted the important roles of epigenetic regulation in resetting the developmental potentials of human pluripotent cells.
The study performed by Chen et al. provides novel mechanistic insight into the epigenetic mechanisms governing extraembryonic developmental potency in humans. Furthermore, the method for generating huan trophoblast stem cells offers a viable alternative to the conventional approaches for deriving human trophoblast stem cells from human embryos or placentas. This advancement is advantageous for in vitro studies of placental development and related diseases. Additionally, the human trophoblast stem cells derived from human primed pluripotent stem cells could be instrumental in creating in vitro human synthetic embryo models, especially for modeling the post-implantation developmental stages.
