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Endometrial stromal cells of women with recurrent miscarriage fail to discriminate between high- and low-quality human embryos.

ABSTRACT: BACKGROUND: The aetiology of recurrent miscarriage (RM) remains largely unexplained. Women with RM have a shorter time to pregnancy interval than normally fertile women, which may be due to more frequent implantation of non-viable embryos. We hypothesized that human endometrial stromal cells (H-EnSCs) of women with RM discriminate less effectively between high-and low-quality human embryos and migrate more readily towards trophoblast spheroids than H-EnSCs of normally fertile women. METHODOLOGY/PRINCIPAL FINDINGS: Monolayers of decidualized H-EnSCs were generated from endometrial biopsies of 6 women with RM and 6 fertile controls. Cell-free migration zones were created and the effect of the presence of a high-quality (day 5 blastocyst, n?=?13), a low-quality (day 5 blastocyst with three pronuclei or underdeveloped embryo, n?=?12) or AC-1M88 trophoblast cell line spheroid on H-ESC migratory activity was analyzed after 18 hours. In the absence of a spheroid or embryo, migration of H-EnSCs from fertile or RM women was similar. In the presence of a low-quality embryo in the zone, the migration of H-EnSCs of control women was inhibited compared to the basal migration in the absence of an embryo (P<0.05) and compared to the migration in the presence of high-quality embryo (p<0.01). Interestingly, the migratory response H-EnSCs of women with RM did not differ between high- and low-quality embryos. Furthermore, in the presence of a spheroid their migration was enhanced compared to the H-EnSCs of controls (p<0.001). CONCLUSIONS: H-EnSCs of fertile women discriminate between high- and low-quality embryos whereas H-EnSCs of women with RM fail to do so. H-EnSCs of RM women have a higher migratory response to trophoblast spheroids. Future studies will focus on the mechanisms by which low-quality embryos inhibit the migration of H-EnSCs and how this is deregulated in women with RM.

SUBMITTER: Weimar CH

PROVIDER: S-EPMC3405140 | biostudies-other | 2012

REPOSITORIES: biostudies-other

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Endometrial stromal cells of women with recurrent miscarriage fail to discriminate between high- and low-quality human embryos.

Weimar Charlotte H E CH Kavelaars Annemieke A Brosens Jan J JJ Gellersen Birgit B de Vreeden-Elbertse Johanna M T JM Heijnen Cobi J CJ Macklon Nick S NS

PloS one 20120725 7

<h4>Background</h4>The aetiology of recurrent miscarriage (RM) remains largely unexplained. Women with RM have a shorter time to pregnancy interval than normally fertile women, which may be due to more frequent implantation of non-viable embryos. We hypothesized that human endometrial stromal cells (H-EnSCs) of women with RM discriminate less effectively between high-and low-quality human embryos and migrate more readily towards trophoblast spheroids than H-EnSCs of normally fertile women.<h4>Me ...[more]

PMID: 22848492

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Project description:PURPOSEThe purpose of this paper is to study whether human preimplantation embryos regulate endometrial stromal cell (hESC) migration.METHODSPrimary hESCs were isolated from fertile patients undergoing hysterectomy for benign conditions (uterine scar niche n?=?3, dysmenorrhea n?=?2; no hormonal treatment). Migration and proliferation assays were performed by culturing decidualized or non-decidualized hESCs in the presence of embryo conditioned medium (ECM) from high-quality embryos (fragmentation ??20%) or from low-quality embryos (fragmentation >?20%) or in non-conditioned medium from the same dishes (control). ECM samples from 425 individually cultured human embryos were used in this study.RESULTSECM from high-quality embryos, i.e., with a low percentage of fragmentation, actively stimulated decidualized hESC migration (p?<?0.001). This effect was consistent throughout embryonic development from cleavage stage embryos with 2-7 cells (high quality vs. control; p?=?0.036), 8-18 cells (high quality vs. control; p?<?0.001) to morulae (high quality vs. control; p?=?0.003). Additionally, linear regression analysis showed that hESC migration was influenced by embryo quality (fragmentation, ? -?0.299; p?=?0.025) and not developmental stage (cell number, ? 0.177; p?=?0.176) or maternal age (? -?0.036; p?=?0.78). Opposite to decidualized hESCs, the migration response of non-decidualized hESCs was inhibited by ECM from high-quality embryos (p?=?0.019). ECM from low-quality embryos, i.e., with a high percentage of fragmentation, did not cause an altered migration response in decidualized hESCs (p?=?0.860) or non-decidualized hESCs (p?=?0.986). Furthermore, ECM of both high- and low-quality human embryos did not influence the number of proliferating cells (p?=?0.375) and the cell cycle time (p?=?0.297) of non-decidualized or decidualized hESCs.CONCLUSIONThis study reveals a mechanism by which high-quality human preimplantation embryos actively interact with the endometrium to increase their chances of successful implantation.

Project description:Study questionHow do high-quality human preimplantation embryos influence the endometrium to promote their own implantation?Summary answerHigh-quality human preimplantation embryos secrete a specific microRNA (miRNA), hsa-miR-320a, which promotes migration of human endometrial stromal cells (hESCs).What is known alreadyWe have previously shown that high-quality human preimplantation embryos excrete unknown factors that influence migration of hESCs.Study design, size, durationEmbryo excreted miRNAs, specifically those excreted by high-quality embryos, were identified and their effect on hESCs was determined by measuring the migration capacity and gene expression patterns of primary isolated hESCs.Participants/materials, setting, methodsEmbryo conditioned medium (ECM) from routine ICSI procedures was used to identify embryo excreted miRNAs. miRNome analyses were performed on ECM from individually cultured embryos with high morphological quality, with low morphological quality or empty control medium. MiRNA mimics and inhibitors were then used to further study the effect of miRNAs of interest on migration and gene expression of hESCs. Migration assays were performed using hESCs that were obtained from endometrial biopsies performed on hysterectomy specimens from women that received surgery for spotting due to a niche in a cesarean section scar.Main results and the role of chanceBy using miRNA mimics and inhibitors, we showed that hsa-miR-320a alone can stimulate migration of decidualized hESCs, accurately resembling the response typically triggered only by high-quality embryos. Transcriptome analysis further demonstrated that this effect is very likely mediated via altered expression of genes involved in cell adhesion and cytoskeleton organization.Limitations, reasons for cautionThe effect of hsa-miR-320a on hESCs was measured in vitro. Further studies on the in vivo effect of hsa-miR-320a are warranted.Wider implications of the findingsImplantation failure is one of the major success limiting factors in human reproduction. By secreting hsa-miR-320a, high-quality human preimplantation embryos directly influence hESCs, most likely to prime the endometrium at the implantation site for successful implantation. Together, our results indicate that hsa-miR-320a may be a promising target to further increase success rates in assisted reproduction.Study funding/competing interest(s)The study was funded by the Amsterdam University Medical Centers and the Amsterdam Reproduction & Development Research Institute. R.P.B., G.H. and S.M. have a patent on the use of hsa-miR-320a in assisted reproduction treatments pending.Trial registration numberN/A.

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Endometrial stromal cells of women with recurrent miscarriage fail to discriminate between high- and low-quality human embryos.

Publications

Endometrial stromal cells of women with recurrent miscarriage fail to discriminate between high- and low-quality human embryos.

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