Trisomy 21 is associated with variable defects in cytotrophoblast differentiation along the invasive pathway

Abstract

Aneuploid cells in the placenta are associated with poor pregnancy outcomes, but the mechanisms are unclear. Here, we examined the cytotrophoblast (CTB) differentiation pathway that leads to uterine invasion in pregnancies complicated by trisomy 21 (T21) as compared with their normal counterparts. Surprisingly, we observed a wide spectrum of T21 effects. Morphologically, some samples appeared near normal, while others had extensive fibrinoid deposition and apoptosis of CTBs at the maternal-fetal interface (confirmed by TUNEL labeling). At a molecular level, the cells' expression of stage-specific molecules was variably misregulated. At one end of the spectrum, samples with less apoptosis had relatively normal staining patterns. At the other end, samples with extensive apoptosis showed significantly decreased staining for these antigens. Additional studies confirmed that the effects we observed had functional consequences, because the cells exhibited marked phenotypic alterations in vitro, including a large increase in MMP-9 production, which distinguishes the effects of T21 on CTBs from those of preeclampsia. The morphologic, phenotypic, and functional differences among CTBs from pregnancies complicated by T21 illustrate the importance of the interplay between fetal/placental genotype and maternal influences on pregnancy outcome. Furthermore, our data may explain why a significant number of these pregnancies end in spontaneous abortion while others survive to term.

Trophoblast differentiation during embryo implantation and formation of the maternal-fetal interface

“…For example, in the case of trisomy 21, the ability of cytotrophoblasts to fuse into syncytiotrophoblasts is impaired (Figure 3) (S14). Additionally, cytotrophoblast differentiation along the pathway that leads to uterine invasion is dysregulated, as shown by abnormal expression of stage-specific antigens that are modulated during this process as well as a high rate of apoptosis among this subpopulation of cells (99). We speculate that the latter observations explain the high rate of fetal loss in these pregnancies (see Figure 3).…”

Perinatal Loss of Ts65Dn Down Syndrome Mice

“…Nonetheless, up to 75% of all DS fetuses identified during the first trimester and around 50% of DS fetuses identified during the second trimester are lost before term (Morris et al 1999;Spencer 2001). Although placental abnormalities in DS have been suspected, specific reasons for this extensive fetal loss have not been conclusively identified (Frendo et al 2000;Debieve et al 2001;Wright et al 2004).…”

Human Placental Development Is Impaired by Abnormal Human Chorionic Gonadotropin Signaling in Trisomy 21 Pregnancies

“…In trisomy 21-affected pregnancies, the CTs fuse poorly or tardily, and the resulting defect in ST formation is associated with a decrease in hCG synthesis and secretion (12). We recently demonstrated that hCG secreted by trisomy of chromosome 21 (T21)-affected CTs is abnormally glycosylated (13), and Fisher and colleagues (14) have described variable defects in CT differentiation along the invasive pathway.…”