Conserved and divergent features of trophoblast stem cells

Abstract

Trophoblast stem cells (TSCs) are a proliferative multipotent population derived from the trophectoderm of the blastocyst, which will give rise to all the functional cell types of the trophoblast compartment of the placenta. The isolation and culture of TSCs in vitro represent a robust model to study mechanisms of trophoblast differentiation into mature cells both in successful and diseased pregnancy. Despite the highly conserved functions of the placenta, there is extreme variability in placental morphology, fetal-maternal interface, and development among eutherian mammals. This review aims to summarize the establishment and maintenance of TSCs in mammals such as primates, including human, rodents, and nontraditional animal models with a primary emphasis on epigenetic regulation of their origin while defining gaps in the current literature and areas of further development. FGF signaling is critical for mouse TSCs but dispensable for derivation of TSCs in other species. Human, simian, and bovine TSCs have much more complicated requirements of signaling pathways including activation of WNT and inhibition of TGFβ cascades. Epigenetic features such as DNA and histone methylation as well as histone acetylation are dynamic during development and are expressed in cell- and gestational age-specific pattern in placental trophoblasts. While TSCs from different species seem to recapitulate some select epigenomic features, there is a limitation in the comprehensive understanding of TSCs and how well TSCs retain placental epigenetic marks. Therefore, future studies should be directed at investigating epigenomic features of global and placental-specific gene expression in primary trophoblasts and TSCs.

Keywords: epigenetics; epigenomics; placenta; trophoblast stem cells.

Figure 1:

Epigenetics features involved in chromatin remodeling and transcriptional activation or silencing. A) DNA demethylases remove, whereas DNA methyltransferases (DNMTs) add methyl groups to DNA cytosine residues to allow (or prevent) binding of transcription factors (TF) leading to activation (or silencing) of gene expression, respectively. B) Histone methyltransferases (HMTs) add methyl group to histone tails at promoters or enhancers and the site of methylation dictates active or repressive transcription. C) Histone acetyl transferases (HATs) actively add acetyl group to the histone tails and activates gene transcription whereas, histone deacetylases (HDACs) remove the activating acetyl modification from histones and inhibits transcriptional activity. RNAPII=RNA polymerase II, me1=mono-methylation, me3=tri-methylation, H3K4=histone 3 lysine 4 residue, H3K9=Histone 3 lysine 9 residue, and H3K27=Histone 3 lysine 27 residue.