Abstract
The number of molecules identified to be involved in communication between placenta and decidua is fast expanding. Previously, we showed that NODAL expressed in maternal endometrial stromal cells is able to affect NODAL and STOX1 expression in placental extravillous trophoblasts. The effect of maternal NODAL on placental NODAL expression is achieved via Activin A, while preliminary data suggests that maternal NODAL affects STOX1 expression in trophoblasts potentially via IGF1. In the current study, T-HESC endometrial stromal cells were treated with siRNAs against NODAL after which IGF1 mRNA expression was determined by quantitative RT-PCR, while IGF1 secretion was measured by ELISA. Recombinant IGF1 and inhibitors of the MAPK and PI3K/AKT pathways were added to SGHPL-5 extravillous trophoblasts after which the effects on STOX1 mRNA and STOX1 protein expression were determined. The effect of IGF1 and the MAPK and PI3K/AKT inhibitors on the invasive capacity of SGHPL-5 cells was investigated by performing invasion assays. We found that T-HESC cells treated with NODAL siRNAs showed significant upregulation of IGF1 mRNA expression and IGF1 protein secretion. Addition of IGF1 to SGHPL-5 cell media significantly upregulated STOX1 mRNA and protein expression. Using inhibitors of the PI3K/AKT and MAPK pathway showed that the effect of IGF1 on STOX1 expression is accomplished via MAPK signaling. Secondly, PI3K inhibition independently leads to reduced STOX1 expression which can be rescued by adding IGF1. IGF1 was unable to influence the invasive capacity of SGHPL-5 cells, while inhibiting the PI3K/AKT pathway did reduce the invasion of these cells. To conclude, here we show that downregulated NODAL expression in endometrial stromal cells, previously associated with pre-eclampsia like symptoms in mice, increases IGF1 secretion. Increased levels of IGF1 lead to increased expression levels of STOX1 in extravillous trophoblasts via the MAPK pathway, hereby identifying a novel signaling cascade involved in maternal-fetal communication.
Highlights
During early pregnancy extravillous trophoblasts invade the placental bed, modify the spiral arteries from low flow, high resistance to high flow, low resistance vessels in order to reach the demands of the developing fetus [1]
As the IGF axis controls fetal growth, and reduced fetal growth is associated with abnormal placental development [7], the aim of this study was to investigate if the effect of decidual NODAL on STOX1 expression in the extravillous trophoblast is mediated by IGF1
T-HESC cells were treated with siRNAs against NODAL (Fig 1A) which led to an upregulation of IGF1 mRNA expression (Fig 1B)
Summary
During early pregnancy extravillous trophoblasts invade the placental bed, modify the spiral arteries from low flow, high resistance to high flow, low resistance vessels in order to reach the demands of the developing fetus [1]. Problems in placental development can lead to early pregnancy loss and growth restriction of the fetus, but can lead to diseases occurring in the mother such as pre-eclampsia and HELLP syndrome. In a human in vitro model system in which conditioned media from decidua tissues was added to extravillous trophoblast cells a similar effect of decidual NODAL on placental NODAL and STOX1 expression was observed [4]. Preliminary results obtained from a human TGF-Beta/BMP signaling pathway PCR array on decidua tissues and endometrial stromal samples with downregulated NODAL expression showed upregulated levels of IGF1 mRNA (S1 Fig). As the IGF axis controls fetal growth, and reduced fetal growth is associated with abnormal placental development [7], the aim of this study was to investigate if the effect of decidual NODAL on STOX1 expression in the extravillous trophoblast is mediated by IGF1
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