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Deregulation of the endometrial stromal cell secretome precedes embryo implantation failure
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Peter Durairaj, Ruban Rex, Aberkane, Asma, Polanski, Lukasz T., Maruyama, Yojiro, Baumgarten, Miriam N., Lucas, Emma S., Quenby, Siobhan, Chan, Jerry K. Y. , Raine-Fenning, Nick , Brosens, Jan J., Van de Velde, Hilde and Lee, Yie Hou (2017) Deregulation of the endometrial stromal cell secretome precedes embryo implantation failure. Molecular Human Reproduction . doi:10.1093/molehr/gax023 (In Press)
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Official URL: https://doi.org/10.1093/molehr/gax023
Abstract
STUDY QUESTION
Is implantation failure following ART associated with a perturbed decidual response in endometrial stromal cells (EnSCs)?
SUMMARY ANSWER
Dynamic changes in the secretome of decidualizing EnSCs underpin the transition of a hostile to a supportive endometrial microenvironment for embryo implantation; perturbation in this transitional pathway prior to ART is associated with implantation failure.
WHAT IS KNOWN ALREADY
Implantation is the rate-limiting step in ART, although the contribution of an aberrant endometrial microenvironment in IVF failure remains ill defined.
STUDY DESIGN, SIZE, DURATION
In vitro characterization of the temporal changes in the decidual response of primary EnSCs isolated prior to a successful or failed ART cycle. An analysis of embryo responses to secreted cues from undifferentiated and decidualizing EnSCs was performed. The primary clinical outcome of the study was a positive urinary pregnancy test 14 days after embryo transfer.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Primary EnSCs were isolated from endometrial biopsies obtained prior to IVF treatment and cryopreserved. EnSCs from 10 pregnant and 10 non-pregnant patients were then thawed, expanded in culture, subjected to clonogenic assays, and decidualized for either 2 or 8 days. Transcript levels of decidual marker gene [prolactin (PRL), insulin-like growth factor binding protein 1 (IGFBP1) and 11β-hydroxysteroid dehydrogenase (HSD11B1)] were analysed using real-time quantitative PCR and temporal secretome changes of 45 cytokines, chemokines and growth factors were measured by multiplex suspension bead immunoassay. The impact of the EnSC secretome on human blastocyst development was scored morphologically; and embryo secretions in response to EnSC cues analyzed by multiplex suspension bead immunoassay.
MAIN RESULTS AND THE ROLE OF CHANCE
Clonogenicity and induction of decidual marker genes were comparable between EnSC cultures from pregnant and non-pregnant group groups (P > 0.05). Analysis of 23 secreted factors revealed that successful implantation was associated with co-ordinated secretome changes in decidualizing EnSCs, which were most pronounced on Day 2 of differentiation: 17 differentially secreted proteins on Day 2 of decidualization relative to undifferentiated (Day 0) EnSCs (P < 0.05); 11 differentially secreted proteins on Day 8 relative to Day 2 (P < 0.05); and eight differentially secreted proteins on Day 8 relative to Day 0 (P < 0.05). By contrast, failed implantation was associated with a disordered secretome response. Blastocyst development was compromised when cultured for 24 h in medium conditioned by undifferentiated EnSCs when compared to decidualizing EnSCs. Analysis of the embryo microdroplets revealed that human blastocysts mount a secretory cytokine response to soluble decidual factors produced during the early (Day 2) but not late phase (Day 8) of differentiation. The embryo responses to secreted factors from decidualizing EnSCs were comparable between the pregnant and non-pregnant group (P > 0.05).
| Item Type: | Journal Article | ||||||
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| Subjects: | R Medicine > RG Gynecology and obstetrics | ||||||
| Divisions: | Faculty of Medicine > Warwick Medical School | ||||||
| Library of Congress Subject Headings (LCSH): | Human embryo -- Transplantation, Fertilization in vitro | ||||||
| Journal or Publication Title: | Molecular Human Reproduction | ||||||
| Publisher: | Oxford University Press | ||||||
| ISSN: | 1360-9947 | ||||||
| Official Date: | 18 April 2017 | ||||||
| Dates: |
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| Date of first compliant deposit: | 5 April 2017 | ||||||
| Number of Pages: | 10 | ||||||
| DOI: | 10.1093/molehr/gax023 | ||||||
| Status: | Peer Reviewed | ||||||
| Publication Status: | In Press | ||||||
| Access rights to Published version: | Restricted or Subscription Access | ||||||
| Funder: | University Hospitals Coventry and Warwickshire NHS Trust, University of Nottingham, Nurture Fertility, Medical Research Council (Singapore) (MRC) | ||||||
| Grant number: | NMRC/BNIG14NOV023 (MRC) |
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