scholarly journals Adiponectin limits differentiation and trophoblast invasion in human endometrial cells

2017 ◽  
Vol 59 (3) ◽  
pp. 285-297 ◽  
Author(s):  
Fabien Duval ◽  
Esther Dos Santos ◽  
Hadia Moindjie ◽  
Valérie Serazin ◽  
Nelly Swierkowski-Blanchard ◽  
...  
Keyword(s):  
Connexin 43 ◽  
Embryo Implantation ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Trophoblast Invasion ◽  
Human Escs ◽  
Trophoblastic Cell ◽  
Endometrial Stromal Cells ◽  
Human Trophoblast ◽  
Endometrial Cells ◽  
Decidual Cells

Successful human embryo implantation requires a proper differentiation of endometrial stromal cells (ESCs) into decidual cells, during a process called decidualization. ESCs express specific molecules, such as prolactin, insulin-like growth factor-binding protein-1 (IGFBP-1) and connexin-43. Decidual cells are also involved in the control of trophoblast invasion, by secreting various factors, such as matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). Adiponectin is an adipokine with insulin-sensitizing, anti-inflammatory and anti-proliferative effects. At the embryo–maternal interface, adiponectin promotes differentiation and invasion of human trophoblastic cells. We hypothesize that the effects of adiponectin on endometrium could counteract its pro-invasive effects previously described in the human trophoblast. In this context, we have firstly demonstrated that adiponectin downregulates IGFBP-1 and connexin-43 mRNA expressions, as well as prolactin secretion in ESCs, suggesting an anti-differentiative effect of adiponectin. Secondly, we found that invasive capacities of trophoblastic cell line HTR-8/SVneo are reduced in the presence of conditioned media from ESC cultured in the presence of adiponectin. Adiponectin’s anti-invasive action is associated with a decreased activity of MMP-2 and MMP-9, and an increased TIMP-3 mRNA expression in ESCs. Finally, adiponectin receptors (ADIPOR1 and ADIPOR2) knockdown abolishes the anti-differentiative and anti-invasive effects of adiponectin in human ESCs. Altogether, our results suggest that adiponectin reduces the decidualization process and inversely induces the production of endometrial factors that limit trophoblast invasion. Thus, through a dual control in trophoblast and endometrial cells, adiponectin appears as a pivotal actor of the embryo implantation process.

scholarly journals Preimplantation factor modulates trophoblastic invasion throughout the decidualization of human endometrial stromal cells

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Esther Dos Santos ◽  
Hadia Moindjie ◽  
Valérie Sérazin ◽  
Lucie Arnould ◽  
Yoann Rodriguez ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Human Embryo ◽  
Connexin 43 ◽  
Embryo Implantation ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Trophoblast Invasion ◽  
Synthetic Analog ◽  
Endometrial Stromal Cells ◽  
Human Trophoblast ◽  
Decidual Cells

Abstract Background Successful human embryo implantation requires the differentiation of endometrial stromal cells (ESCs) into decidual cells during a process called decidualization. ESCs express specific markers of decidualization, including prolactin, insulin-like growth factor-binding protein-1 (IGFBP-1), and connexin-43. Decidual cells also control of trophoblast invasion by secreting various factors, such as matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases. Preimplantation factor (PIF) is a recently identified, embryo-derived peptide with activities at the fetal-maternal interface. It creates a favorable pro-inflammatory environment in human endometrium and directly controls placental development by increasing the human trophoblastic cells’ ability to invade the endometrium. We hypothesized that PIF’s effects on the endometrium counteract its pro-invasive effects. Methods We tested sPIF effect on the expression of three decidualization markers by RT-qPCR and/or immunochemiluminescence assay. We examined sPIF effect on human ESC migration by performing an in vitro wound healing assay. We analyzed sPIF effect on endometrial control of human trophoblast invasion by performing a zymography and an invasion assay. Results Firstly, we found that a synthetic analog of PIF (sPIF) significantly upregulates the mRNA expression of IGFBP-1 and connexin-43, and prolactin secretion in ESCs - suggesting a pro-differentiation effect. Secondly, we showed that the HTR-8/SVneo trophoblastic cell line’s invasive ability was low in the presence of conditioned media from ESCs cultured with sPIF. Thirdly, this PIF’s anti-invasive action was associated with a specifically decrease in MMP-9 activity. Conclusion Taken as a whole, our results suggest that PIF accentuates the decidualization process and the production of endometrial factors that limit trophoblast invasion. By controlling both trophoblast and endometrial cells, PIF therefore appears to be a pivotal player in the human embryo implantation process.

scholarly journals Homeobox genes in endometrium: from development to decidualization

2020 ◽  
Vol 64 (1-2-3) ◽  
pp. 227-237
Author(s):  
Nancy Ashary ◽  
Saniya Laheri ◽  
Deepak Modi
Keyword(s):  
Cell Transformation ◽  
Dominant Role ◽  
Embryo Implantation ◽  
Trophoblast Invasion ◽  
Endometrial Stromal Cells ◽  
Ample Evidence ◽  
Endometrial Cells ◽  
Optimal Functioning ◽  
Decidual Cells ◽  
Mullerian Ducts

The eutherian species evolved an elaborate uterus to allow viviparity. For successful pregnancy, the uterus must not only be differentiated, but must also function optimally and any defects in uterus differentiation and/or function can lead to infertility. The homoebox gene HOXA10 has emerged to be a key player in both uterine development and its optimal functioning in adulthood. Within the Abd-B family, the posterior Hoxa genes play a dominant role in anterio-posterior segmentation of the Müllerian ducts in mammals, with Hoxa10 having a central role in uterine segmentation. In the adult endometrium, HOXA10 is expressed by endometrial cells and is regulated in a cyclic manner under the influence of ovarian steroids. During embryo implantation, expression of HOXA10 is increased in endometrial stromal cells by signals from the embryo to govern stromal cell transformation to decidual cells. Once decidualization is initiated, HOXA10 is rapidly downregulated to activate expression of pro-invasive factors to promote trophoblast invasion. We propose that HOXA10 governs embryo implantation in a three-step process: 1) acquisition of endometrial receptivity, 2) responding to signals from the blastocyst to modify receptive endometrium for decidualization 3) making the decidua conductive for trophoblast invasion and placentation. There is currently ample evidence that expression of HOXA10 is deregulated in a variety of “endometriopathies” such as endometriosis and endometrial cancers. Overall, HOXA10 appears to be the master regulator of endometrial health and a central determinant of fertility in mammals.

scholarly journals The autophagy protein, FIP200 (RB1CC1) mediates progesterone responses governing uterine receptivity and decidualization†

2020 ◽  
Vol 102 (4) ◽  
pp. 843-851 ◽  
Author(s):  
Arin K Oestreich ◽  
Sangappa B Chadchan ◽  
Alexandra Medvedeva ◽  
John P Lydon ◽  
Emily S Jungheim ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Embryo Implantation ◽  
Conditional Knockout ◽  
Trophoblast Invasion ◽  
Uterine Receptivity ◽  
Human Escs ◽  
Embryo Survival ◽  
Endometrial Stromal Cells ◽  
Cellular Changes ◽  
Decidual Cells

Abstract Successful establishment of pregnancy depends on steroid hormone-driven cellular changes in the uterus during the peri-implantation period. To become receptive to embryo implantation, uterine endometrial stromal cells (ESCs) must transdifferentiate into decidual cells that secrete factors necessary for embryo survival and trophoblast invasion. Autophagy is a key homeostatic process vital for cellular homeostasis. Although the uterus undergoes major cellular changes during early pregnancy, the precise role of autophagy in uterine function is unknown. Here, we report that conditional knockout of the autophagy protein FIP200 in the reproductive tract of female mice results in reduced fecundity due to an implantation defect. In the absence of FIP200, aberrant progesterone signaling results in sustained uterine epithelial proliferation and failure of stromal cells to decidualize. Additionally, loss of FIP200 impairs decidualization of human ESCs. We conclude that the autophagy protein FIP200 plays a crucial role in uterine receptivity, decidualization, and fertility. These data establish autophagy as a major cellular pathway required for uterine receptivity and decidualization in both mice and human ESCs.

scholarly journals Exometabolomic analysis of decidualizing human endometrial stromal and perivascular cells

2020 ◽  
Author(s):  
Sarah Harden ◽  
Jieliang Zhou ◽  
Maria Diniz-da-Costa ◽  
Emma S. Lucas ◽  
Liang Cui ◽  
...  
Keyword(s):  
Time Course ◽  
Embryo Implantation ◽  
Cellular Reprogramming ◽  
Trophoblast Invasion ◽  
Perivascular Cells ◽  
Endometrial Stromal Cells ◽  
Signalling Molecules ◽  
Spatiotemporal Information ◽  
Decidual Cells ◽  
Acid Metabolites

ABSTRACTDifferentiation of endometrial fibroblasts into specialized decidual cells controls embryo implantation and transforms the cycling endometrium into a semi-permanent, immune-protective matrix that accommodates the placenta throughout pregnancy. This process starts during the midluteal phase of the menstrual cycle with decidual transformation of perivascular cells (PVC) surrounding the terminal spiral arterioles and endometrial stromal cells (EnSC) underlying the luminal epithelium. Decidualization involves extensive cellular reprogramming and acquisition of a secretory phenotype, essential for coordinated placental trophoblast invasion. Secreted metabolites are an emerging class of signalling molecules. Here, we used liquid chromatography-mass spectrometry to characterise the dynamic changes in metabolite secretion (exometabolome) of primary PVC and EnSC decidualized over 8 days. We identified 79 annotated metabolites differentially secreted upon decidualization, including prostaglandin, sphingolipid, and hyaluronic acid metabolites. Secreted metabolites encompassed 21 metabolic pathways, most prominently glycerolipid and pyrimidine metabolism. Although temporal exometabolome changes were comparable between decidualizing PVC and EnSC, 32 metabolites were differentially secreted across the decidualization time-course. Further, targeted metabolomics demonstrated a conspicuous difference in xanthine secretion between decidualized PVC and EnSC. Taken together, our findings indicate that the metabolic footprints generated by different decidual subpopulations encode spatiotemporal information that may be important for optimal embryo implantation.

scholarly journals 225.Expression of chemokines and their receptors at the human maternal - embryonic interface

2004 ◽  
Vol 16 (9) ◽  
pp. 225 ◽  
Author(s):  
N. J. Hannan ◽  
R. L. Jones ◽  
L. A. Salamonsen
Keyword(s):  
Cell Lines ◽  
Expression Patterns ◽  
Embryo Implantation ◽  
Receptor Expression ◽  
Trophoblast Invasion ◽  
Epithelial Cell Line ◽  
Embryonic Cells ◽  
Trophoblast Cells ◽  
Endometrial Cells ◽  
Decidual Cells

Human embryo implantation is a complex process involving attachment of the developing blastocyst to the receptive endometrial epithelium, and subsequent trophoblast invasion through decidua. This is regulated by crosstalk between the maternal and embryonic cells, however little is known about the factors involved in enabling and directing trophoblast invasion. Chemokines are cytokines that regulate leukocyte chemotaxis via stimulation of adhesion molecules and cell migration. We have previously shown that two chemokines, fractalkine and MCP-3, are produced by endometrial epithelial and decidual cells, maximally around the time of implantation and early pregnancy (1, 2). We hypothesized that endometrially derived fractalkine and MCP-3 are important for the attachment/invasion of fetal trophoblast cells during implantation. To investigate this, expression of fractalkine, MCP-3 and their receptors (CX3CR1, CCR1, CCR2, CCR3 and CCR5) were assessed in cell types present at the maternal-embryonic interface. RNA, extracted from three trophoblast cell lines (JEG-3 and two trophoblast-choriocarcinoma hybrids), a human epithelial cell line (HES), primary endometrial epithelial cells, mid-secretory endometrium and placental tissue, was subjected to RT-PCR for the chemokines and receptors. Both chemokines were produced by endometrial and placental cells. Chemokine receptor expression was more variable, CX3CR1, CCR1, 2 and 3 were expressed by one or more of the trophoblast cells lines while CX3CR1, CCR1, 2 and 5 were expressed by endometrial cells. Marked differences in expression patterns in the different cell lines highlight the importance of studies to select those cell lines of most physiological relevance: in this case, one that most closely resembles early invasive trophoblasts. These data confirm that chemokines are produced by maternal and embryonic cells during implantation and the strong expression of their receptors on trophoblast cells supports a role for chemokines in embryo implantation. Further, these studies have characterized a number of trophoblast cells for future trophoblast migration and attachment assays. (1) Hannan, N., et al. JCEM (in press). (2) Jones, R., et al. JCEM (in press).

scholarly journals Exometabolomic Analysis of Decidualizing Human Endometrial Stromal and Perivascular Cells

2021 ◽  
Vol 9 ◽  
Author(s):  
Sarah L. Harden ◽  
Jieliang Zhou ◽  
Seley Gharanei ◽  
Maria Diniz-da-Costa ◽  
Emma S. Lucas ◽  
...  
Keyword(s):  
Time Course ◽  
Embryo Implantation ◽  
Cellular Reprogramming ◽  
Trophoblast Invasion ◽  
Perivascular Cells ◽  
Endometrial Stromal Cells ◽  
Time Resolved ◽  
Spatiotemporal Information ◽  
Decidual Cells ◽  
Purine Pathway

Differentiation of endometrial fibroblasts into specialized decidual cells controls embryo implantation and transforms the cycling endometrium into a semi-permanent, immune-protective matrix that accommodates the placenta throughout pregnancy. This process starts during the midluteal phase of the menstrual cycle with decidual transformation of perivascular cells (PVC) surrounding the terminal spiral arterioles and endometrial stromal cells (EnSC) underlying the luminal epithelium. Decidualization involves extensive cellular reprogramming and acquisition of a secretory phenotype, essential for coordinated placental trophoblast invasion. Secreted metabolites are an emerging class of signaling molecules, collectively known as the exometabolome. Here, we used liquid chromatography-mass spectrometry to characterize and analyze time-resolved changes in metabolite secretion (exometabolome) of primary PVC and EnSC decidualized over 8 days. PVC were isolated using positive selection of the cell surface marker SUSD2. We identified 79 annotated metabolites differentially secreted upon decidualization, including prostaglandin, sphingolipid, and hyaluronic acid metabolites. Secreted metabolites encompassed 21 metabolic pathways, most prominently glycerolipid and pyrimidine metabolism. Although temporal exometabolome changes were comparable between decidualizing PVC and EnSC, 32 metabolites were differentially secreted across the decidualization time-course. Further, targeted metabolomics demonstrated significant differences in secretion of purine pathway metabolites between decidualized PVC and EnSC. Taken together, our findings indicate that the metabolic footprints generated by different decidual subpopulations encode spatiotemporal information that may be important for optimal embryo implantation.

scholarly journals Possible roles of the cAMP-mediators EPAC and RAP1 in decidualization of rat uterus

Reproduction ◽  
2014 ◽  
Vol 147 (6) ◽  
pp. 897-906 ◽  
Author(s):  
Kazuya Kusama ◽  
Mikihiro Yoshie ◽  
Kazuhiro Tamura ◽  
Takiko Daikoku ◽  
Tsutomu Takarada ◽  
...  
Keyword(s):  
Embryo Implantation ◽  
Camp Signaling ◽  
Human Escs ◽  
Endometrial Stromal Cells ◽  
Camp Analog ◽  
Decidual Cells ◽  
Element Binding Protein ◽  
Implantation Sites ◽  
Responsive Element

The optimal decidualization of endometrial stromal cells (ESCs) following embryo implantation is one of the critical steps to establish pregnancy in rodents and humans. This step is intricately regulated by ovarian hormones. Using in vitro human ESCs model, we previously showed that activation of a cAMP mediator, exchange protein directly activated by cAMP (EPAC), promotes ovarian steroid- or cAMP analog-induced decidualization. However, expressions and functions of EPAC and RAP1 in the uterus during pregnancy have not yet been examined. In this study, we found that the expression of EPAC2 and RAP1 was markedly upregulated in the decidual cells at the implantation sites on days 7 and 9 of pregnancy in rats. Furthermore, both delayed-implantation and artificial decidualization models showed that EPAC2 and RAP1 expression was enhanced in decidual cells. Significant activation of cAMP-responsive element-binding protein (CREB), a central transcriptional factor of cAMP signaling, was observed in decidual cells. These spatiotemporal expressions of protein related EPAC pathway are overlapped by sites with activated cAMP signaling, indicating the association of EPAC signaling with decidualization. Strikingly, further studies in in vitro rat decidualization model showed that the cAMP analog and medroxyprogesterone stimulated the expression of decidual markers, while knockdown of EPAC1/2 and RAP1 attenuated the expressions of these markers. Together, these findings suggest that EPAC and RAP1 are the crucial factors for endometrial decidualization in rat pregnancy.

scholarly journals Progesterone-Dependent Induction of Phospholipase C-Related Catalytically Inactive Protein 1 (PRIP-1) in Decidualizing Human Endometrial Stromal Cells

Endocrinology ◽  
2016 ◽  
Vol 157 (7) ◽  
pp. 2883-2893 ◽  
Author(s):  
Joanne Muter ◽  
Paul J. Brighton ◽  
Emma S. Lucas ◽  
Lauren Lacey ◽  
Anatoly Shmygol ◽  
...  
Keyword(s):  
Phospholipase C ◽  
Stromal Cells ◽  
Nuclear Translocation ◽  
Scaffold Protein ◽  
Trophoblast Invasion ◽  
Differentiation Markers ◽  
Endometrial Stromal Cells ◽  
Decidual Cells ◽  
Phosphoinositide 3 Kinase ◽  
Inactive Protein

Decidualization denotes the transformation of endometrial stromal cells into specialized decidual cells. In pregnancy, decidual cells form a protective matrix around the implanting embryo, enabling coordinated trophoblast invasion and formation of a functional placenta. Continuous progesterone (P4) signaling renders decidual cells resistant to various environmental stressors, whereas withdrawal inevitably triggers tissue breakdown and menstruation or miscarriage. Here, we show that PLCL1, coding phospholipase C (PLC)-related catalytically inactive protein 1 (PRIP-1), is highly induced in response to P4 signaling in decidualizing human endometrial stromal cells (HESCs). Knockdown experiments in undifferentiated HESCs revealed that PRIP-1 maintains basal phosphoinositide 3-kinase/Protein kinase B activity, which in turn prevents illicit nuclear translocation of the transcription factor forkhead box protein O1 and induction of the apoptotic activator BIM. By contrast, loss of this scaffold protein did not compromise survival of decidual cells. PRIP-1 knockdown did also not interfere with the responsiveness of HESCs to deciduogenic cues, although the overall expression of differentiation markers, such as PRL, IGFBP1, and WNT4, was blunted. Finally, we show that PRIP-1 in decidual cells uncouples PLC activation from intracellular Ca2+ release by attenuating inositol 1,4,5-trisphosphate signaling. In summary, PRIP-1 is a multifaceted P4-inducible scaffold protein that gates the activity of major signal transduction pathways in the endometrium. It prevents apoptosis of proliferating stromal cells and contributes to the relative autonomy of decidual cells by silencing PLC signaling downstream of Gq protein-coupled receptors.

414. The contraceptive potential of a long-acting IL-11 inhibitor

2008 ◽  
Vol 20 (9) ◽  
pp. 94
Author(s):  
E. Menkhorst ◽  
L. Salamonsen ◽  
L. Robb ◽  
E. Dimitriadis
Keyword(s):  
Nature Medicine ◽  
Embryo Implantation ◽  
Hormonal Contraceptive ◽  
Cyclin D3 ◽  
Human Reproduction ◽  
Luminal Epithelium ◽  
Endometrial Stromal Cells ◽  
Decidual Cells ◽  
Implantation Sites ◽  
Long Acting

Interleukin 11 (IL-11) signalling is essential for the establishment of pregnancy in mice, through its action on the differentiation of uterine endometrial stromal cells (decidualisation), a critical process during embryo implantation. IL-11Rα deficient mice are infertile due to defective decidualisation1. IL-11 expression peaks between days (D) 4.5–9.5 of pregnancy (D0: day of plug) in mouse decidua. We examined the effect of administering (intraperitoneal [IP] injection or vaginal gel) a PEGylated IL-11 antagonist (PEGIL-11A) on decidualisation and pregnancy outcome in mice. The sera half-life of PEGIL-11A (IC50 2.8nM) following IP injection was 24h, compared with <1 h for the non-PEGylated antagonist (IC50 0.26nM). Following IP injection, PEGIL-11A localised to decidual cells and blocked the IL-11 decidual target protein, cyclin D3. IP injection of 600µg/application PEGIL-11A (or PEG control) at 1000 h and 1600 h on D3 and 1000 h on D4 (n = 4/group), resulted in smaller implantation sites than controls on D6 due to retarded mesometrial decidual formation. On D10, severe decidual destruction was visible: implantation sites contained regions of haemorrhage and the uterine luminal epithelium had reformed, suggesting a return to oestrous cycling. Following vaginal application in aqueous placebo gel, PEGIL-11A localised to decidual cells. Vaginal application of 200µg/application PEGIL-11A (or control) twice daily from D2 to D5 (n = 4/group), resulted in smaller implantation sites than controls on D6 due to partial inhibition of mesometrial decidual formation. This study demonstrates that PEGIL-11A blocked IL-11 action in the uterus, resulting in total pregnancy loss, equivalent to the IL-11Rα deficient mouse. In women, IL-11 and its receptor are produced by the uterine luminal and glandular epithelium during the period of uterine receptivity2, suggesting that IL-11 may act during initial blastocyst attachment to the luminal epithelium as well as stromal decidualisation. This study provides proof-of-principle for the development of a novel, non-hormonal contraceptive for women. (1) Robb L et al. Nature Medicine 1998; 4: 303–308. (2) Dimitriadis E et al. Molecular Human Reproduction 2000; 6: 907–914.

scholarly journals The Cytokine Gene CXCL14 Restricts Human Trophoblast Cell Invasion by Suppressing Gelatinase Activity

Endocrinology ◽  
2009 ◽  
Vol 150 (12) ◽  
pp. 5596-5605 ◽  
Author(s):  
HaiBin Kuang ◽  
Qi Chen ◽  
Ying Zhang ◽  
Li Zhang ◽  
HongYing Peng ◽  
...  
Keyword(s):  
Trophoblast Cell ◽  
Trophoblast Invasion ◽  
Trophoblast Cells ◽  
Human Trophoblast ◽  
Gelatinase Activity ◽  
Invasion And Migration ◽  
Human Pregnancy ◽  
Decidual Cells ◽  
And Migration ◽  
Maternal Fetal Interface

Abstract Well-controlled trophoblast invasion into uterine decidua is a critical process for the normal development of placenta, which is tightly regulated by various factors produced within the trophoblast-endometrial microenvironment. CXCL14 is involved in tumor growth and metastasis, and its expression in placenta is temporally regulated during pregnancy. However, the role of CXCL14 in trophoblast function during human pregnancy is not clear. In this study, by using RT-PCR through human pregnancy, we found that CXCL14 was selectively expressed at early but not late pregnancy. Immunostaining revealed that CXCL14 proteins were strongly expressed in villous cytotrophoblasts and moderately in decidualized stromal cells but very weakly in syncytiotrophoblasts and extravillous trophoblasts. The effect of CXCL14 on trophoblast invasion were examined by using human villous explants cultured on Matrigel and further proved by invasion and migration assay of primary trophoblast cells and trophoblast cell line HTR-8/SVneo. Our data showed that CXCL14 significantly inhibited outgrowth of villous explant in vitro; this effect is due to suppression of trophoblast invasion and migration through regulating matrix metalloproteinases activities, whereas the trophoblast proliferation was not affected. Moreover, because a receptor for CXCL14 has not been identified, we performed further cell-specific CXCL14 binding activities with regard to different cell types within the maternal-fetal interface. Our data revealed that CXCL14 could specifically bind to trophoblast cells but not decidual cells from the maternal-fetal interface. These results suggest that CXCL14 plays an important role in regulating trophoblast invasion through an autocrine/paracrine manner during early pregnancy.

Sign in / Sign up

Export Citation Format

Share Document