Inadequate or inappropriate implantation and placentation during the establishment of human pregnancy is thought to lead to first trimester miscarriage, placental insufficiency and other obstetric complications. To create the placental blood supply, extravillous trophoblast (EVT) must adhere, migrate and invade through the decidualized uterine endometrium (the decidua) to engraft and remodel uterine spiral arteries. The local endometrial environment is likely to play a key role in regulating EVT invasion.
Recent evidence in women indicates that decidualization is important in the formation of a functional placenta, with impaired decidualization associated with recurrent miscarriage, preeclampsia and placenta accreta. The mechanisms by which decidual cells interact with EVT and the regulation of EVT invasion remain largely unknown. We hypothesised that appropriate decidual-EVT interactions are required for appropriate implantation and placentation. We used a co-culture and proteomics approach to investigate interactions between primary human endometrial stromal cells (HESC) and EVT.
Decidualization regulated EVT invasion in a gestational dependent manner: decidualized conditioned media (CM) enhanced EVT migration and invasion in EVTs isolated from placentas 6-9 weeks gestation, but suppressed migration and had no effect on invasion in EVTs isolated from placentas 10-12 weeks gestation. Decidualized CM upregulated EVT expression of proteins which enhance cell motility. Non-decidualized factors primarily induced protease expression by EVT which could induce a pro-inflammatory response; preeclampsia is a pro-inflammatory condition. In vitro, we found that EVT CM alone induced HESC decidualization, likely in part via EVT-secreted progesterone.
Overall, our studies highlight the importance of EVT-decidual cross-talk during implantation/placentation. Further, EVTs responded differently to decidualized CM dependent on their gestational age. This is physiologically relevant as maximal EVT migration and invasion is thought to occur during weeks 5-12 of gestation slowing at the end of the first trimester. Synchrony between the decidua and invading EVTs is likely critical for appropriate EVT invasion.