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Human chorionic gonadotropin (hCG) modulation of TIMP1 secretion by human endometrial stromal cells facilitates extravillous trophoblast invasion in vitro.
- Source :
-
Human reproduction (Oxford, England) [Hum Reprod] 2013 Aug; Vol. 28 (8), pp. 2215-27. Date of Electronic Publication: 2013 May 21. - Publication Year :
- 2013
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Abstract
- Study Question: Are secreted extracellular matrix (ECM) remodelling elements, relevant to embryo implantation and placentation, modified by hCG in endometrial stromal cells (ESCs)?<br />Summary Answer: hCG decreases tissue inhibitor of metalloproteinase 1 (TIMP-1) secretion in ESCs, thereby facilitating extravillous trophoblast invasion in vitro.<br />What Is Known Already: Successful embryo implantation and placentation depend on the appropriate invasion of the trophoblast into the maternal endometrial stroma. hCG is one of the earliest embryo-derived secreted signals in the endometrium which abundantly expresses hCG receptors. However, there is little data concerning the effects of hCG on endometrial ECM remodelling with respect to embryo implantation.<br />Participants/materials, Setting, Methods: This study was conducted in an academic research laboratory within a tertiary-care hospital. Samples were collected from 36 women undergoing benign gynaecological surgery during the mid-secretory phase. ESCs were isolated and stimulated with hCG (10 UI/ml) or vehicle. Conditioned media (CM) were analysed to determine changes in the secreted profile of nine matrix metalloproteinases (MMPs) and three tissue-specific inhibitors of MMPs (TIMPs) using an ELISA array. Data were confirmed by gelatine zymography, western blot and ELISA. The HTR8/SVneo cell line served as a model for trophoblast cells. The invasive potential of trophoblast cells was assessed using Transwell invasion assays under CM or co-culture conditions with ECS and the role of regulated molecules was examined by using immunoprecipitation in CM prior to the assessment of invasive potential.<br />Main Results and the Role of Chance: MMP-2 levels increased 30%, whereas TIMP-1 levels decreased 20% in CM from ESCs stimulated with hCG (P < 0.05). Gelatine zymography confirmed an increase in MMP-2 activity (P < 0.05). ELISA and western blotting also confirmed the reduction in TIMP-1 upon hCG treatment (P < 0.05). Invasion assays revealed a ∼50% increase in invading HTR8/SVneo cells in chambers with hCG-stimulated ESCs compared with the control (P < 0.05). Immunodepletion of TIMP-1 from control ESC-CM partially resembled the effect of CM from hCG-stimulated ESCs in the trophoblast invasion assays.<br />Limitations, Reasons for Caution: The assays were performed in vitro and ESCs were not decidualized, therefore they reflected the very early stages of embryo implantation or the advanced stages when decidualization fails.<br />Wider Implications of the Findings: Our data suggest that hCG induces endometrial stromal extracellular remodelling by modulating secreted MMP-2 and TIMP-1. This regulation may be physiologically relevant because it increases the invasive potential of trophoblast-derived cells. At present, few data exist concerning the implications of hCG and endometrial ECM remodelling in embryo implantation. Hence, our results should be confirmed by further in vivo studies.<br />Study Funding/competing Interest(s): This work was funded by FONDECYT 11100443, PBCT-PSD51 (IDIMI) and FONDAP 15010006. None of the authors have any conflicts of interest to declare.
- Subjects :
- Adult
Enzyme-Linked Immunosorbent Assay
Extracellular Matrix metabolism
Female
Humans
Matrix Metalloproteinases metabolism
Middle Aged
Trophoblasts metabolism
Chorionic Gonadotropin physiology
Stromal Cells metabolism
Tissue Inhibitor of Metalloproteinase-1 metabolism
Trophoblasts physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2350
- Volume :
- 28
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Human reproduction (Oxford, England)
- Publication Type :
- Academic Journal
- Accession number :
- 23696542
- Full Text :
- https://doi.org/10.1093/humrep/det136