Defective decidualization during and after severe preeclampsia reveals a possible maternal contribution to the etiology

Abstract

In preeclampsia (PE), cytotrophoblast (CTB) invasion of the uterus and spiral arteries is often shallow. Thus, the placenta’s role has been a focus. In this study, we tested the hypothesis that decidual defects are an important determinant of the placental phenotype. We isolated human endometrial stromal cells from nonpregnant donors with a previous pregnancy that was complicated by severe PE (sPE). Compared with control cells, they failed to decidualize in vitro as demonstrated by morphological criteria and the analysis of stage-specific antigens (i.e., IGFBP1, PRL). These results were bolstered by global transcriptional profiling data that showed they were transcriptionally inert. Additionally, we used laser microdissection to isolate the decidua from tissue sections of the maternal–fetal interface in sPE. Global transcriptional profiling revealed defects in gene expression. Also, decidual cells from patients with sPE, which dedifferentiated in vitro, failed to redecidualize in culture. Conditioned medium from these cells failed to support CTB invasion. To mimic aspects of the uterine environment in normal pregnancy, we added PRL and IGFBP1, which enhanced invasion. These data suggested that failed decidualization is an important contributor to down-regulated CTB invasion in sPE. Future studies will be aimed at determining whether this discovery has translational potential with regard to assessing a woman’s risk of developing this pregnancy complication.

Integrative analysis of the forkhead box A2 (FOXA2) cistrome for the human endometrium

“…The differentiation of ESCs into specialized decidual cells controls endometrial receptivity, embryo selection, embryo implantation, and placentation (12,54). In women, altered or failed endometrial decidualization is an essential contributor to later pregnancy complications, such as preeclampsia and pregnancy loss (13), and may be involved in fetal growth restriction and preterm labor (56)(57)(58). Recent evidence supports the idea that GE-derived factors regulate stromal cell decidualization and placental growth in mice (2,59) and humans (8)(9)(10)60).…”

“…Uterine glands are also postulated to impact stromal cell decidualization (2), which is essential for pregnancy establishment in humans and rodents (11,12). Recently, defective stromal cell decidualization in early pregnancy was linked to later pregnancy complications such as preeclampsia and miscarriage (13,14). Thus, uterine glands and, by inference, their secretions and products are essential determinants of the embryotrophic potential and functional capacity of the uterus for pregnancy.…”

Decidualization of the human endometrium

“…The major secretory products of decidual stromal cells include PRL and IGFBP‐1, two proteins that have been used as markers of decidualization. In the decidual–placental interface, those proteins have been suggested to stimulate trophoblast growth and invasion, to prevent immune rejection, to modulate uNK cell survival, and to promote angiogenesis . Therefore, they play an important role in decidualization and the control of trophoblast invasion.…”

“…This process is one of the most critical and remarkable events that occurs within the human endometrium during pregnancy. The impairment of this process leads to a variety of pregnancy disorders, including infertility, recurrent miscarriages, and uteroplacental disorders . Despite significant advances in assistive reproductive technology (ART), many couples experience infertility as a result of failed implantation of the fertilized embryo into the uterus and the subsequent loss of pregnancy.…”

Decreased NDRG1 expression is associated with pregnancy loss in mice and attenuates the in vitro decidualization of endometrial stromal cells

“…Following the progress of decidualization, F‐actin localization in hESCs showed cytoskeletal reorganization and shape changes that were consistent with the transformation from fibroblast to a decidual phenotype (Figure a; Garrido‐Gomez et al, ). As expected, the decidual markers PRL and insulin‐like growth factor binding protein 1 (IGFBP1) greatly increased upon decidualization (Figure b,c).…”