Mesenchymal Stem Cells-Induced Trophoblast Invasion Is Reduced in Patients with a Previous History of Preeclampsia

Abstract

Endometrial stromal cells play an important role in reproductive success, especially in implantation and placentation. Although Mesenchymal stem cells (MSCs) have been studied to assess decidualization disorders in preeclampsia (PE), their role during trophoblast invasion remains unclear. This study aims to determine: (i) whether MSCs isolated from menstrual fluid (MenSCs) from nulliparous, multiparous, and women with a previous history of preeclampsia exhibited different patterns of proliferation and migration and (ii) whether reproductive history (i.e., prior pregnancy or prior history of PE) was able to produce changes in MenSCs, thus altering trophoblast invasion capacity. MenSCs were collected from nulliparous and multiparous women without a history of PE and from non-pregnant women with a history of PE. Proliferation and migration assays were performed on MenSCs with sulforhodamine B and transwell assays, respectively. Trophoblast invasion was analyzed by culturing HTR-8/SVneo trophospheres on a matrigel overlying MenSCs for 72 h at 5% O2, simulating a 3D implantation model. A previous history of pregnancy or PE did not impact the proliferative capacity or migratory behavior of MenSCs. Following exposure to physiological endometrial conditions, MenSCs demonstrated upregulated expression of IGFBP-1 and LIF mRNA, decidualization and window of implantation markers, respectively. The mRNA expression of VIM, NANOG, and SOX2 was upregulated upon trophosphere formation. Relative to co-culture with multiparous MenSCs, co-culture with PE-MenSCs was associated with reduced trophoblast invasion. The findings of this study suggest a potential role for communication between maternal MenSCs and invading trophoblast cells during the implantation process that could be implicated in the etiology of PE.

FOXM1 Participates in Trophoblast Migration and Early Trophoblast Invasion: Potential Role in Blastocyst Implantation

“…Successful implantation requires effective maternal-embryonic communication [2][3][4]27]. Using an in vitro 3D trophoblast invasion model, we have confirmed that trophoblast cells were only able to migrate from the trophosphere and invade through the MATRIGEL in the presence of MenSCs of endometrial origin, which was pre-treated with the endometrial mimic, suggesting that MenSCs secrete important factors that trigger the motility and invasion of the trophoblast cells, as described previously [10,23,24]. More importantly, FOXM1 mRNA expression was significantly higher in those trophoblast cells that invaded greater into the MATRIGEL, i.e., the trophospheres that were co-cultured with MATRIGEL and MenSCs compared to pre-invasion trophospheres.…”

“…During implantation, trophoblast invasion of the uterine lining depends on the communication between the trophectoderm and the maternal decidua and involves the migration and invasion of the trophoblast cells from out of the blastocyst and through various layers of the endometrium, accompanied by the degradation of the extracellular matrix and stroma [5,10]. In order to understand whether FOXM1 is involved in trophoblast invasion during implantation, we used an in vitro 3D trophoblast invasion model [23,24] that mimics the processes of migration and early invasion of the trophoblast and assessed the expression of FOXM1 in trophoblast cells. This assay consists of generating, in vitro, blastocyst like-structures (trophospheres) and co-culturing them onto a layer of MATRIGEL and mesenchymal stem cells isolated from menstrual fluid (MenSCs), mimicking the extracellular matrix and the endometrial stromal cells, respectively (Figure 4A).…”

Decreased PPP1R3G in pre-eclampsia impairs human trophoblast invasion and migration via Akt/MMP-9 signaling pathway

“…37 Current opinions support the view that trophoblast cell invasion is crucial for the development of PE. 38–40 The current experimental results demonstrated that PPP1R3G knockdown suppressed the proliferation, invasion, and migration abilities, but had no discernible effect on apoptosis in HTR-8/SVneo trophoblast cells. Thus, it can be speculated that PPP1R3G might be involved in the pathogenesis of PE through modulating trophoblast cell behavior.…”

A Review of the Studies on Placental Mesenchymal Stem Cells and Their Exosomes Applied to Preeclampsia

“…Salomon et al [21] found 12 differentially expressed exosome miRNAs between normal pregnancy and preeclampsia pregnancy, among which the increased expression levels of miR-486-1-5p and miR-486-2-5p were most significant in the preeclampsia group. To sum up, changes in miRNA content in exosomes lead to abnormal cell growth, adhesion, migration and invasion, and ultimately affect endothelial cells, resulting in systemic endothelial dysfunction and impaired angiogenesis [22] . The current study is still limited, and more studies are needed to further clarify the differences in expression and mechanism of action of these miRNAs in preeclampsia.…”