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.

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 Hsa-miR-222 Is Involved in Differentiation of Endometrial Stromal Cells in Vitro

Endocrinology ◽  
2009 ◽  
Vol 150 (10) ◽  
pp. 4734-4743 ◽  
Author(s):  
Kun Qian ◽  
Linli Hu ◽  
Hong Chen ◽  
Haixia Li ◽  
Na Liu ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Target Genes ◽  
Embryo Implantation ◽  
Endometrial Stromal Cells ◽  
Protein Levels ◽  
Mirna Genes ◽  
False Discovery ◽  
Decidual Cells ◽  
Expression Variance

Abstract Decidualization is a critical step during embryo implantation and characterized by the differentiation of endometrial stromal cells (ESCs) into decidual cells. Because miRNAs are important determinants of cellular fate specification, in this study, the miRNA expression in ESCs during in vitro decidualization was profiled by using a microarray. Significance analysis of microarrays revealed that 49 miRNA genes were differently (&gt;2-fold) expressed between the noninduced ESCs and induced ESCs with a false discovery rate of 0. The expression variance of hsa-miR-222, 221, 143, 101, 30d, 30c, 181b, 27b, 29b, 507, and 23a was validated by using quantitative PCR (P &lt; 0.05). Based on microRNA (miRNA) and mRNA expression variance and predicted target genes of miRNAs, a bioinformatic model of miRNAs controlling ESCs differentiation was formulated. Finally, we proved that down-regulation of has-miR-222 could decrease the number of cells in S phase during ESCs differentiation (P &lt; 0.05). Antisense oligonucleotides of has-miR-222 could increase reporter gene expression by targeting the 3′ untranslated regions of CDKN1C/p57kip2 mRNAs as well as increase CDKN1C/p57kip2 protein levels (P &lt; 0.05). In conclusion, our results suggest that a subset of miRNAs play a key role in gene reprogramming during ESCs decidualization and that hsa-miR-222 participates in ESC differentiation by regulating ESCs terminally withdrawing from the cell cycle.

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 Characterization of highly proliferative decidual precursor cells during the window of implantation in human endometrium

2020 ◽  
Author(s):  
Maria Diniz-da-Costa ◽  
Chow-Seng Kong ◽  
Katherine J Fishwick ◽  
Thomas Rawlings ◽  
Paul John Brighton ◽  
...  
Keyword(s):  
Single Cell ◽  
Stromal Cells ◽  
Embryo Implantation ◽  
Gene Signature ◽  
Human Endometrium ◽  
Sequencing Data ◽  
Endometrial Stromal Cells ◽  
Decidual Cells ◽  
Underlying Mechanisms

Pregnancy depends on the wholesale transformation of the endometrium, a process driven by differentiation of endometrial stromal cells (EnSC) into specialist decidual cells. Upon embryo implantation, decidual cells impart the tissue plasticity needed to accommodate a rapidly growing conceptus and invading placenta, although the underlying mechanisms are unclear. Here we characterize a discrete population of highly proliferative mesenchymal cells (hPMC) in midluteal human endometrium, coinciding with the window of embryo implantation. Single-cell transcriptomics demonstrated that hPMC express genes involved in chemotaxis and vascular transmigration. Although distinct from resident EnSC, hPMC also express genes encoding pivotal decidual transcription factors and markers, most prominently prolactin. We further show that hPMC are enriched around spiral arterioles, scattered throughout the stroma, and occasionally present in glandular and luminal epithelium. The abundance of hPMC correlated with the in vitro colony-forming unit activity of midluteal endometrium and, conversely, clonogenic cells in culture express a gene signature partially conserved in hPMC. Cross-referencing of single-cell RNA-sequencing data sets indicated that hPMC differentiate into a recently discovered decidual subpopulation in early pregnancy. Finally, we demonstrate that recurrent pregnancy loss is associated with hPMC depletion. Collectively, our findings characterize midluteal hPMC as novel decidual precursors that are likely derived from circulating bone marrow-derived mesenchymal stem/stromal cells and integral to decidual plasticity in pregnancy.

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 228.Progestin-induced proprotein convertase 6 is necessary for decidualisation of human endometrial stromal cells in vitro

2004 ◽  
Vol 16 (9) ◽  
pp. 228
Author(s):  
H. Okada ◽  
G. Nie ◽  
L. A. Salamonsen
Keyword(s):  
Real Time ◽  
Stromal Cells ◽  
Embryo Implantation ◽  
Functional Differentiation ◽  
Mrna Levels ◽  
Proprotein Convertase ◽  
Human Escs ◽  
Endometrial Stromal Cells ◽  
Mrna And Protein Expression

Decidualisation of human endometrium is an essential preparative event for successful establishment of pregnancy, and involves dramatic morphological and functional differentiation of the human endometrial stromal cells (ESCs). Proprotein convertase 6 (PC6) plays an important role in the processes of stromal cell decidualisation and embryo implantation in the mouse. PC6 is a member of the proprotein convertase family responsible for processing precursor proteins to their bioactive forms by selective proteolysis. In the present study we investigated the regulation of PC6 mRNA and protein expression in ESCs during decidualisation in vitro, and established a function for PC6 in decidualisation using morpholino antisense oligonucleotides (MOs). PC6 mRNA levels in ESCs during decidualisation were determined using quantitative real-time RT-PCR. 17β-oestradiol (E) plus medroxy-progesterone acetate (P) caused a significant increase in PC6 mRNA during decidualisation, whereas E alone did not increase PC6 mRNA expression. Consistent with the results of real-time PCR, much stronger PC6 immunostaining was observed in the cytoplasm of E plus P-treated ESCs (decidualised) compared to the E-treated ESCs (non-decidualised) on Day 12 of culture. This strong staining for PC6 was abolished by cotreatment with ZK 98299, a progesterone receptor antagonist. To investigate whether the induction of PC6 was necessary for decidualisation in vitro, MOs were used to block PC6 synthesis in cultured ESCs. PRL production, a typical marker for decidualisation, was significantly attenuated in decidualing ESCs following treatment with PC6 MOs in comparison to controls. These results suggest that PC6 plays a key role for decidualisation in human ESCs.

P–322 Addressing progesterone and cAMP signalling pathways for decidualization induction of endometrial stromal cells of patients with endometriosis

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
J Moyer ◽  
D Dunj. Baston-Buest ◽  
G Wennemuth ◽  
A Bielfeld ◽  
R Grümmer
Keyword(s):  
Stromal Cells ◽  
Day Treatment ◽  
Embryo Implantation ◽  
Flow Cytometric Analysis ◽  
Prolactin Secretion ◽  
In Vivo Model ◽  
Endometrial Stromal Cells ◽  
Simultaneous Application

Abstract Study question Which compounds/compound combinations are most effective in decidualization induction of endometrial stromal cells (ESCs) of patients with and without endometriosis? Summary answer Combination of compounds addressing different steps in the signalling cascade of decidualization induce decidualization more effectively than application of the individual compounds alone. What is known already Decidualization is the monthly recurring differentiation process of the ESCs in preparation for embryo implantation in human. Undifferentiated ESCs reveal an increased potential to proliferate and invade after retrograde menstruation. This may lead to the formation of ectopic lesions and the manifestation of the chronic gynaecological disease of endometriosis due to an impairment of the decidualization process. Study design, size, duration Compounds and compound combinations addressing the progesterone receptor- or the cAMP-mediated pathway were evaluated with regard to their own and their synergistic potential to induce decidualization of ESCs from women with (n = 10) and without (n = 10) endometriosis during a 6-day treatment. Participants/materials, setting, methods Human primary ESCs were isolated via enzymatic-mechanic digestion from eutopic endometrium from women with and without endometriosis and treated for 6 days in vitro with different progestins (progesterone, medoxyprogesterone acetate (MPA)), 8-Br-cAMP, forskolin, or phosphodiesterase (PDE)-inhibitor (Rolipram) alone or in combination. The degree of decidualization induction was quantified by morphological, biochemical (prolactin) and molecular (HAND2, FOXO1) parameters by means of ELISA, flow cytometric analysis, Realtime PCR and Western blot analysis. Main results and the role of chance After 6 days of treatment, decidualization was induced by forskolin as well as by 8-Br-cAMP whereas progestins or PDE alone hardly induced prolactin secretion by ESCs as a marker of decidualization. A change of morphology from undifferentiated fibroblast-like cells to rounded cells could be observed in parallel with the secretion of prolactin. Forskolin and 8-Br-cAMP-induced decidualization was significantly enhanced by MPA but not by progesterone. These effects were similar in ESCs from women with and without endometriosis. Moreover, forskolin-induced decidualization was significantly enhanced by simultaneous application of PDE. Interestingly, this effect was higher in cells of patients with endometriosis. An induction of decidualization in ESCs was associated with a parallel increase of the process-associated transcription factors HAND2 and FOXO1. This rise of transcription was markedly increased in combination with MPA but not with progesterone. Limitations, reasons for caution Endometrial tissue was obtained from women undergoing infertility treatment and thus may differ from the endometrium of fertile women. Results obtained from primary cells in vitro may not cover the in vivo situation in all respects. Wider implications of the findings: The results of this study provide baseline data for the development of a possible therapeutical approach to induce decidualization as a treatment option for endometriosis. Further research is required to determine the effectiveness of the in vitro tested compound combinations in an in vivo model. Trial registration number Not applicable

P-322 Addressing progesterone and cAMP signalling pathways for decidualization induction of endometrial stromal cells of patients with endometriosis

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
J Moyer ◽  
D Dunja Baston-Buest ◽  
G Wennemuth ◽  
A Bielfeld ◽  
R Grümmer
Keyword(s):  
Stromal Cells ◽  
Day Treatment ◽  
Embryo Implantation ◽  
Flow Cytometric Analysis ◽  
Prolactin Secretion ◽  
In Vivo Model ◽  
Endometrial Stromal Cells ◽  
Simultaneous Application

Abstract Study question Which compounds/compound combinations are most effective in decidualization induction of endometrial stromal cells (ESCs) of patients with and without endometriosis? Summary answer Combination of compounds addressing different steps in the signalling cascade of decidualization induce decidualization more effectively than application of the individual compounds alone. What is known already Decidualization is the monthly recurring differentiation process of the ESCs in preparation for embryo implantation in human. Undifferentiated ESCs reveal an increased potential to proliferate and invade after retrograde menstruation. This may lead to the formation of ectopic lesions and the manifestation of the chronic gynaecological disease of endometriosis due to an impairment of the decidualization process. Study design, size, duration Compounds and compound combinations addressing the progesterone receptor- or the cAMP-mediated pathway were evaluated with regard to their own and their synergistic potential to induce decidualization of ESCs from women with (n = 10) and without (n = 10) endometriosis during a 6-day treatment. Participants/materials, setting, methods Human primary ESCs were isolated via enzymatic-mechanic digestion from eutopic endometrium from women with and without endometriosis and treated for 6 days in vitro with different progestins (progesterone, medoxyprogesterone acetate (MPA)), 8-Br-cAMP, forskolin, or phosphodiesterase (PDE)-inhibitor (Rolipram) alone or in combination. The degree of decidualization induction was quantified by morphological, biochemical (prolactin) and molecular (HAND2, FOXO1) parameters by means of ELISA, flow cytometric analysis, Realtime PCR and Western blot analysis. Main results and the role of chance After 6 days of treatment, decidualization was induced by forskolin as well as by 8-Br-cAMP whereas progestins or PDE alone hardly induced prolactin secretion by ESCs as a marker of decidualization. A change of morphology from undifferentiated fibroblast-like cells to rounded cells could be observed in parallel with the secretion of prolactin. Forskolin and 8-Br-cAMP-induced decidualization was significantly enhanced by MPA but not by progesterone. These effects were similar in ESCs from women with and without endometriosis. Moreover, forskolin-induced decidualization was significantly enhanced by simultaneous application of PDE. Interestingly, this effect was higher in cells of patients with endometriosis. An induction of decidualization in ESCs was associated with a parallel increase of the process-associated transcription factors HAND2 and FOXO1. This rise of transcription was markedly increased in combination with MPA but not with progesterone. Limitations, reasons for caution Endometrial tissue was obtained from women undergoing infertility treatment and thus may differ from the endometrium of fertile women. Results obtained from primary cells in vitro may not cover the in vivo situation in all respects. Wider implications of the findings The results of this study provide baseline data for the development of a possible therapeutical approach to induce decidualization as a treatment option for endometriosis. Further research is required to determine the effectiveness of the in vitro tested compound combinations in an in vivo model. Trial registration number not applicable

scholarly journals FGIN-1-27 Inhibits Melanogenesis by Regulating Protein Kinase A/cAMP-Responsive Element-Binding, Protein Kinase C-β, and Mitogen-Activated Protein Kinase Pathways

2020 ◽  
Vol 11 ◽  
Author(s):  
Jinpeng Lv ◽  
Songzhou Jiang ◽  
Ying Yang ◽  
Ximei Zhang ◽  
Rongyin Gao ◽  
...  
Keyword(s):  
Protein Kinase ◽  
The Body ◽  
Tyrosinase Activity ◽  
Mitogen Activated Protein Kinase ◽  
Mushroom Tyrosinase ◽  
Mitogen Activated Protein ◽  
Element Binding Protein ◽  
Responsive Element

FGIN-1-27 is a synthetic mitochondrial diazepam binding inhibitor receptor (MDR) agonist that has demonstrated pro-apoptotic, anti-anxiety, and steroidogenic activity in various studies. Here we report, for the first time, the anti-melanogenic efficacy of FGIN-1-27 in vitro and in vivo. FGIN-1-27 significantly inhibited basal and α-melanocyte-stimulating hormone (α-MSH)-, 1-Oleoyl-2-acetyl-sn-glycerol (OAG)- and Endothelin-1 (ET-1)-induced melanogenesis without cellular toxicity. Mushroom tyrosinase activity assay showed that FGIN-1-27 did not directly inhibit tyrosinase activity, which suggested that FGIN-1-27 was not a direct inhibitor of tyrosinase. Although it was not capable of modulating the catalytic activity of mushroom tyrosinase in vitro, FGIN-1-27 downregulated the expression levels of key proteins that function in melanogenesis. FGIN-1-27 played these functions mainly by suppressing the PKA/CREB, PKC-β, and MAPK pathways. Once inactivated, it decreased the expression of MITF, tyrosinase, TRP-1, TRP-2, and inhibited the tyrosinase activity, finally inhibiting melanogenesis. During in vivo experiments, FGIN-1-27 inhibited the body pigmentation of zebrafish and reduced UVB-induced hyperpigmentation in guinea pig skin, but not a reduction of numbers of melanocytes. Our findings indicated that FGIN-1-27 exhibited no cytotoxicity and inhibited melanogenesis in both in vitro and in vivo models. It may prove quite useful as a safer skin-whitening agent.

Human chorionic gonadotropin improves endometrial receptivity by increasing the expression of homeobox A10

2020 ◽  
Vol 26 (6) ◽  
pp. 413-424
Author(s):  
Mengchen Zhu ◽  
Shanling Yi ◽  
Xiaomin Huang ◽  
Junan Meng ◽  
Haixiang Sun ◽  
...  
Keyword(s):  
Chorionic Gonadotropin ◽  
Human Chorionic Gonadotropin ◽  
Embryo Implantation ◽  
Endometrial Receptivity ◽  
Endometrial Stromal Cells ◽  
Healthy Control ◽  
Hcg Receptor ◽  
Methyltransferase 1

Abstract Homeobox A10 (HOXA10) is a characterized marker of endometrial receptivity. The mechanism by which hCG intrauterine infusion promotes embryo implantation is still unclear. This study seeks to investigate whether hCG improves endometrial receptivity by increasing expression of HOXA10. HOXA10 expression with human chorionic gonadotropin stimulation was analyzed in vitro and in vivo. Our results demonstrate that HOXA10 was decreased in the endometria of recurrent implantation failure patients compared to that in the healthy control fertile group, also we observed that hCG intrauterine infusion increased endometrial HOXA10 expression. HOXA10, blastocyst-like spheroid expansion area was increased, whereas DNA (cytosine-5-)-methyltransferase 1 was decreased when human endometrial stromal cells (hESCs) were treated with 0.2 IU/ml of hCG for 48 h. HOXA10 promoter methylation was also reduced after hCG treatment. Collagen XV (ColXV) can repress the expression of DNA (cytosine-5-)-methyltransferase 1, and hCG treatment increased the expression of ColXV. However, when the hESCs were treated with LH/hCG receptor small interfering RNA to knock down LH/hCG receptor, hCG treatment failed to repress DNA (cytosine-5-)-methyltransferase 1 expression or to increase ColXV expression. Our findings suggest that hCG may promote embryo implantation by increasing the expression of HOXA10.

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