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1
Tapilskaya, Natalya I., Alevtina M. Savicheva, Kira V. Shalepo, Olga V. Budilovskaya, Aleksandr M. Gzgzyan, Olesya N. Bespalova, Tatiana A. Khusnutdinova, Anna A. Krysanova, Kseniia V. Obedkova, and Galina Kh Safarian. "Local Immune Biomarker Expression Depending on the Uterine Microbiota in Patients with Idiopathic Infertility." International Journal of Molecular Sciences 24, no. 8 (April 20, 2023): 7572. http://dx.doi.org/10.3390/ijms24087572.
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The endometrium has traditionally been considered sterile. Nowadays, active studies are performed on the female upper genital tract microbiota. Bacteria and/or viruses colonizing the endometrium are known to alter its functional properties, including receptivity and embryo implantation. Uterine cavity inflammation caused by microorganisms leads to disrupted cytokine expression, which, in turn, is mandatory for the successful implantation of the embryo. The present study assessed the vaginal and endometrial microbiota composition and its relation to the levels of cytokines produced by the endometrium in reproductive-aged women complaining of secondary infertility of unknown origin. The multiplex real-time PCR assay was applied for vaginal and endometrial microbiota analysis. The quantitative measurement of endometrial α-defensin (DEFa1), transforming growth factor (TGFβ1), and basic fibroblast growth factor (bFGF2) was carried out using the ELISA (Cloud-Clone Corporation (Katy, TX, USA; manufactured in Wuhan, China). A reliable decline in endometrial TGFβ1 and bFGF2 and an increase in DEFa1 were demonstrated in women with idiopathic infertility when compared to fertile patients. However, TGFβ1, bFGF2, and DEFa1 expression correlated reliably only with the presence of Peptostreptococcus spp. and HPV in the uterine cavity. The obtained results highlight the importance of local immune biomarker determination in the assessment of certain bacteria and viruses’ significance as causative agents of infertility.
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O'Leary, S., M. J. Jasper, G. M. Warnes, D. T. Armstrong, and S. A. Robertson. "Seminal plasma regulates endometrial cytokine expression, leukocyte recruitment and embryo development in the pig." Reproduction 128, no. 2 (August 2004): 237–47. http://dx.doi.org/10.1530/rep.1.00160.
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In pigs, uterine exposure to the constituents of semen is known to increase litter size but the underlying physiological mechanisms remain undefined. Studies in rodents and humans implicate immune modulating moieties in seminal plasma as likely candidates, acting through enhancing the receptivity of the female tract. In this study, the acute and longer term effects of seminal plasma on cytokine expression and leukocyte abundance in the pig endometrium during early pregnancy have been characterised. The reproductive tracts of gonadotrophin-primed pre-pubertal gilts treated with intrauterine infusions of either pooled seminal plasma or phosphate-buffered saline (PBS) were retrieved at 34 h, or on day 5 and day 9 after treatment. Seminal plasma elicited an endometrial inflammatory infiltrate comprised of predominantly macrophages and major histocompatibility complex class II+-activated macrophages and dendritic cells. The abundance of these cells was greatest at the pre-ovulatory (34 h) time-point and their increase relative to PBS-treated tissues was maintained until day 9 after seminal plasma treatment. Seminal plasma induced the expression of the cytokines, granulocyte macrophage colony-stimulating factor, interleukin-6 and monocyte chemoattractant protein-1, and the eicosanoid-synthesising enzyme cyclo-oxygenase-2. Expression was maximal 34 h after treatment but altered expression patterns as a consequence of seminal plasma induction persisted through early pregnancy. These changes were accompanied by altered dynamics in pre-implantation embryo development with an increase in the number of embryos and in their viability after seminal plasma treatment. Together, these findings implicate factors in seminal plasma in programming the trajectory of uterine cytokine expression and leukocyte trafficking during early pregnancy and in regulating pre-implantation embryo development in the pig.
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Park, Hye-Rin, Hee-Jung Choi, Bo-Sung Kim, Tae-Wook Chung, Keuk-Jun Kim, Jong-Kil Joo, Dongryeol Ryu, Sung-Jin Bae, and Ki-Tae Ha. "Paeoniflorin Enhances Endometrial Receptivity through Leukemia Inhibitory Factor." Biomolecules 11, no. 3 (March 16, 2021): 439. http://dx.doi.org/10.3390/biom11030439.
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Despite advances in assisted reproductive technology, treatment for deficient endometrial receptivity is a major clinical unmet need. In our previous study, the water extract of Paeonia lactiflora Pall. enhanced endometrial receptivity in vitro and in vivo via induction of leukemia inhibitory factor (LIF), an interleukin (IL)-6 family cytokine. In the present study, we found that paeoniflorin, a monoterpene glycoside, is the major active compound of P. lactiflora. Paeoniflorin significantly improved the embryo implantation rate in a murine model of mifepristone (RU486)-induced implantation failure. In addition, paeoniflorin increased the adhesion of human trophectoderm-derived JAr cells to endometrial Ishikawa cells through the expression of LIF in vitro. Moreover, using the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database of the human endometrium, we confirmed that LIF signaling is a key regulator for improving human endometrial receptivity. Therefore, these results suggest that paeoniflorin might be a potent drug candidate for the treatment of endometrial implantation failure by enhancing endometrial receptivity.
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Jones, Rebecca L., Chelsea Stoikos, Jock K. Findlay, and Lois A. Salamonsen. "TGF-β superfamily expression and actions in the endometrium and placenta." Reproduction 132, no. 2 (August 2006): 217–32. http://dx.doi.org/10.1530/rep.1.01076.
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Transforming growth factor β (TGFβ) superfamily members are closely associated with tissue remodelling events and reproductive processes. This review summarises the current state of knowledge regarding the expression and actions of TGFβ superfamily members in the uterus, during the menstrual cycle and establishment of pregnancy. TGFβs and activin β subunits are abundantly expressed in the endometrium, where roles in preparation events for implantation have been delineated, particularly in promoting decidualisation of endometrial stroma. These growth factors are also expressed by epithelial glands and secreted into uterine fluid, where interactions with preimplantation embryos are anticipated. Knockout models and embryo culture experiments implicate activins, TGFβs, nodal and bone morphogenetic proteins (BMPs) in promoting pre- and post-implantation embryo development. TGFβ superfamily members may therefore be important in the maternal support of embryo development. Following implantation, invasion of the decidua by fetal trophoblasts is tightly modulated. Activin promotes, whilst TGFβ and macrophage inhibitory cytokine-1 (MIC-1) inhibit, trophoblast migration in vitro, suggesting the relative balance of TGFβ superfamily members participate in modulating the extent of decidual invasion. Activins and TGFβs have similar opposing actions in regulating placental hormone production. Inhibins and activins are produced by the placenta throughout pregnancy, and have explored as a potential markers in maternal serum for pregnancy and placental pathologies, including miscarriage, Down’s syndrome and pre-eclampsia. Finally, additional roles in immunomodulation at the materno-fetal interface, and in endometrial inflammatory events associated with menstruation and repair, are discussed.
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Peng, Yaoming, Zhixing Jin, Haiou Liu, and Congjian Xu. "Impaired decidualization of human endometrial stromal cells from women with adenomyosis†." Biology of Reproduction 104, no. 5 (February 2, 2021): 1034–44. http://dx.doi.org/10.1093/biolre/ioab017.
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Abstract Differentiation of endometrial stromal cells (ESCs) into secretory decidualized cells (dESCs) is essential for embryo implantation. Adenomyosis is a common benign gynecological disease that causes infertility. However, whether adenomyosis affects decidualization of human ESCs is elusive. Primary eutopic ESCs were obtained from patients with adenomyosis (n = 9) and women with nonendometrial diseases (n = 12). We determined the capacity of decidualization of human ESCs by qRT-PCR, Edu proliferation assay, cytokine array, and ELISA assay. We found that the expression of decidualization markers (IGFBP1 and PRL) in ESCs of adenomyosis was reduced, concomitant with increased cell proliferation. Differential secretion of cytokines in dESCs, including CXCL1/2/3, IL-6, IL-8, MCP-1, VEGF-A, MIP-3α, OPN, SDF-1α, HGF, and MMP-9, was observed between adenomyosis and nonadenomyosis. Moreover, the expression of decidualization regulators (HOXA10 at both mRNA and protein levels, FOXO1, KLF5, CEBPB, and HAND2 at mRNA levels) in the eutopic endometrium of adenomyosis was lower than that of nonadenomyosis. We propose that ESCs from adenomyosis have defected ability to full decidualization, which may lead to a nonreceptive endometrium.
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Granot, I., Y. Gnainsky, and N. Dekel. "Endometrial inflammation and effect on implantation improvement and pregnancy outcome." REPRODUCTION 144, no. 6 (December 2012): 661–68. http://dx.doi.org/10.1530/rep-12-0217.
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Implantation failure, which is presently the major barrier in human fertility, is attributed, in many cases, to the failure of the uterus to acquire receptivity. The transition into a receptive uterus includes cellular changes in the endometrium and the modulated expression of different cytokines, growth factors, transcription factors, and prostaglandins. These molecules partake in the generation of an inflammatory response followed by the recruitment of immune cells. These cells have shown to be involved in the maternal immune tolerance toward the implanted embryo as well as in the maternal–fetus interaction during pregnancy. Most of the accumulated evidence indicates that embryo implantation is associated with an active Th1 inflammatory response while a Th2-humoral inflammation is required for pregnancy maintenance. Yet, recent findings suggest that a Th1 inflammatory response is also necessary for the acquisition of uterine receptivity. This notion was originally suggested by reports from our and other clinical centers worldwide that IVF patients with repeated implantation failure subjected to endometrial biopsy exhibit a substantial improvement in their chances to conceive. These findings, followed by the demonstration of an elevated pro-inflammatory cytokine/chemokine expression, as well as an increased abundance of immune cells, in the endometrium of these patients, raised the idea that acquisition of uterine receptivity is closely associated with an inflammatory response. This review summarizes the molecular and biochemical evidence that confirm this notion and proposes a mechanism by which injury-induced inflammation improves uterine receptivity and the subsequent pregnancy outcome.
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Martal, J., Nicole ChÊne, Sylvaine Camous, L. Huynh, F. Lantier, Paloma Hermier, R. L'Haridon, G. Charpigny, Madia Charlier, and G. Chaouat. "Recent developments and potentialities for reducing embryo mortality in ruminants: the role of IFN-t and other cytokines in early pregnancy." Reproduction, Fertility and Development 9, no. 3 (1997): 355. http://dx.doi.org/10.1071/r96083.
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This review considers the potential reduction of embryo mortality in vitro and in vivo in ruminants. Data on cytokines provided by different fields of reproductive immunology and biology were collated. Because of the crucial importance of the local interactions between the embryo and its dam, the expression of growth-factor and cytokine genes was analysed in the embryo proper, trophoblast, oviduct and endometrium by reverse transcriptase polymerase chain reaction in sheep and in cattle during the pre- and periimplantation periods. Many deleterious cytokines, such as tumour necrosis factor-α, intereron-γ (IFN-γ ), interleukin-2 (IL-2), and beneficial cytokines, such as transforming growth factor-β, leukaemia inhibiting factor, colony-stimulating factor-1 (CSF-1), ganulocyte–macrophage CSF, IL-1, IL-3, IL-4, IL-6, IL-10 and IFN-γ appeared to be involved in embryo survival in ruminants and other species. Their administration is efficient in a murine experimental model (CBA/J DBA/2) of embryonic and fetal mortality. For instance, recombinant ovine IFN-τ (roIFN-τ ) injected at the moment of implantation drastically reduces embryonic mortality in this model. In ruminants, roIFN-τ and recombinant bovine IFN-τ are very efficient in maintaining progesterone luteal secretion in cyclic animals. The involvement of IFN-τ in the mechanisms of maternal pregnancy recognition are particularly detailed in relation to inbition of 13,14 dihydro-15-keto-prostaglandin F2α (PGFM) pulses and oxytocin uterine receptivity. A synthetic model of the anti-luteolytic effects of IFN-τ on the endometrial cell is proposed. Finally, the particular potential of serum pregnancy-specific proteins (PSPs: PSPB, PSP60, pregnancy-associated glycoprotein) for monitoring embryo survival, with examples given for cattle and sheep is underlined.
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Takemura, Yuri, Yutaka Osuga, Toshimasa Yamauchi, Masaki Kobayashi, Miyuki Harada, Tetsuya Hirata, Chieko Morimoto, et al. "Expression of Adiponectin Receptors and Its Possible Implication in the Human Endometrium." Endocrinology 147, no. 7 (July 1, 2006): 3203–10. http://dx.doi.org/10.1210/en.2005-1510.
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Adiponectin, a pleiotropic cytokine, exerts its effects via the specific receptors AdipoR1 and AdipoR2. Whereas circulating adiponectin concentrations decrease in women with endometriosis and endometrial cancer, possible effects of adiponectin and the presence of the receptors in the endometrium have not been determined. In this study, we examined the expression of adiponectin receptors AdipoR1 and AdipoR2 in the human endometrium and assessed effects of adiponectin in endometrial cells. Expression of AdipoR1 and AdipoR2 in endometrial tissues was evaluated by real-time quantitative PCR, in situ hybridization, and Western blotting. The effects of adiponectin on phosphorylation of AMP-activated protein kinase, a regulator of energy homeostasis, in cultured endometrial stromal cells (ESCs) and epithelial cells (EECs) were studied by Western blotting. The effects of adiponectin on IL-1β-induced secretion of IL-6, IL-8, and monocyte chemoattractant protein 1 from cultured ESCs were determined using specific ELISAs. The expression of AdipoR1 and AdipoR2 was detected in the endometrium. The expression of both genes was increased in the midluteal phase, the period of embryo implantation. In situ hybridization revealed that both AdipoR1 and AdipoR2 appeared to be equally expressed in the epithelial cells and in the stromal cells. Adiponectin increased phosphorylation of AMP-activated protein kinase in ESCs and EECs. Adiponectin decreased IL-1β-induced secretion of IL-6, IL-8, and monocyte chemoattractant protein 1 from ESCs. These findings suggest that adiponectin exerts energy-homeostatic and antiinflammatory effects in the endometrium, and these effects might be relevant to pathological and physiological endometrium-related events such as implantation and endometriosis.
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Rao, Rajnish P., Bernd Fischer, and Polani B. Seshagiri. "Embryo-endometrial expression of leukemia inhibitory factor in the golden hamster (Mesocricetus auratus): increased expression during proestrous and window of implantation stages." Reproduction, Fertility and Development 20, no. 3 (2008): 440. http://dx.doi.org/10.1071/rd07154.
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Leukemia inhibitory factor (LIF) is a pleiotropic IL-6 family cytokine and its maternal uterine expression is critical for mouse blastocyst implantation. In the golden hamster (Mesocricetus auratus), although the blastocyst hatching phenomenon is quite interesting and LIF is shown to regulate hatching, information is not available on the embryonic and uterine expression of LIF and hormonal regulation of LIF expression during the peri-implantation period. The present investigation is aimed at studying embryonic and uterine expression of LIF during preimplantation hamster development. We observed embryonic expression of LIF mRNA and protein in the 8-cell, morula and blastocyst stages. In cycling females, uterine LIF mRNA expression was maximal during the oestrogen-dominant phase of the oestrous cycle, i.e. proestrous stage. Interestingly, during pregnancy, both LIF mRNA and protein were highly upregulated on Days 3.5 and 4 (‘window of implantation’), implying a role for this cytokine in blastocyst hatching and implantation. Cell type-specific localisation of LIF mRNA and protein was observed predominantly in luminal epithelium and uterine glands with faint staining being detected in the stroma. The hamster uterus encoded a ~4.2 kb LIF transcript whose coding region, when cloned and sequenced, showed a high degree of identity to the murine cDNA counterpart. These data demonstrate that: (1) hamster preimplantation embryos show LIF mRNA and protein expression; (2) uterine expression of LIF mRNA and protein was dependent on elevated levels of circulating oestrogen, and (3) there is a possible functional association of LIF with the peri-implantation development in the golden hamster.
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He, Yaping, Zhaogui Sun, Yan Shi, Yahong Jiang, Zhefu Jia, Yanbo Du, Lois A. Salamonsen, Zhuoya Li, and Jian Wang. "Immunosuppressive Factor MNSFβ Regulates Cytokine Secretion by Mouse Lymphocytes and Is Involved in Interactions between the Mouse Embryo and Endometrial Cells In Vitro." ISRN Immunology 2011 (November 24, 2011): 1–11. http://dx.doi.org/10.5402/2011/186541.
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Immune tolerance at the fetomaternal interface must be established during the processes of implantation and pregnancy. Monoclonal nonspecific suppressor factor beta (MNSFβ) is a secreted protein that possesses antigen-nonspecific immune-suppressive function. It was previously reported that intrauterine immunoneutralization of MNSFβ significantly inhibited embryo implantation in mice. In the present study, MNSFβ protein expression was up- or downregulated by overexpression or RNA interference, respectively, in HCC-94 cells and the culture supernatants used to determine effects of MNSFβ on the secretion of IL-4 and TNFα from mouse lymphocytes as detected by ELISA. A coculture model of mouse embryos and endometrial stromal cells was also utilized to determine the effects of a specific anti-MNSFβ antibody on hatching and growth of embryos in vitro. The results show that MNSFβ induced secretion of IL-4 and inhibited secretion of TNFα from mouse lymphocytes. Following immunoneutralization of MNSFβ protein in the HCC-94 supernatant, the stimulatory effect of MNSFβ on IL-4 secretion from mouse lymphocytes was reduced, while the inhibitory effect on secretion of TNFα was abrogated. Expression of MNSFβ was detected in both embryonic and endometrial stromal cells, and its immunoneutralization inhibited the hatching and spreading of embryos in an in vitro coculture model. These results indicated that MNSFβ may play critical roles during the peri-implantation process by regulating cytokine secretion of lymphocytes and by mediating the crosstalk between embryonic cells and endometrial stromal cells.
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Murakami, Keisuke, Yie Hou Lee, Emma S. Lucas, Yi-Wah Chan, Ruban Peter Durairaj, Satoru Takeda, Jonathan D. Moore, et al. "Decidualization Induces a Secretome Switch in Perivascular Niche Cells of the Human Endometrium." Endocrinology 155, no. 11 (November 1, 2014): 4542–53. http://dx.doi.org/10.1210/en.2014-1370.
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Abstract The endometrial perivascular microenvironment is rich in mesenchymal stem-like cells that express type 1 integral membrane protein Sushi domain containing 2 (SUSD2) but the role of these cells in the decidual transformation of this tissue in pregnancy is unknown. We used an antibody directed against SUSD2 (W5C5) to isolate perivascular (W5C5+) and nonperivascular (W5C5−) fibroblasts from mid-luteal biopsies. We show that SUSD2 expression, and hence the ratio of W5C5+:W5C5− cells, changes in culture depending on cell-cell contact and activation of the Notch signaling pathway. RNA sequencing revealed that cultures derived from W5C5+ progenitor cells remain phenotypically distinct by the enrichment of novel and established endometrial perivascular signature genes. In an undifferentiated state, W5C5+-derived cells produced lower levels of various chemokines and inflammatory modulators when compared with their W5C5− counterparts. This divergence in secretomes was switched and became more pronounced upon decidualization, which transformed perivascular W5C5+ cells into the dominant source of a range of chemokines and cytokines, including leukemia inhibitory factor and chemokine (C-C motif) ligand 7. Our findings suggest that the decidual response is spatially organized at the embryo-maternal interface with differentiating perivascular cells establishing distinct cytokine and chemokine profiles that could potentially direct trophoblast toward maternal vessels and govern local immune responses in pregnancy.
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Correia, E., E. Gómez, J. N. Caamaño, C. Díez, A. Balseiro, D. Martín, S. Carrocera, B. Trigal, and M. Muñoz. "120 EXPRESSION OF TUMOR NECROSIS FACTOR (TNF) AND ITS RECEPTOR TNFR2 IN BOVINE ENDOMETRIUM AND EMBRYOS DURING THE EARLY DEVELOPMENT." Reproduction, Fertility and Development 25, no. 1 (2013): 207. http://dx.doi.org/10.1071/rdv25n1ab120.
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Tumor necrosis factor alpha (TNF), a pleiotropic cytokine that could be involved in early embryo-maternal interactions (Muñoz et al. 2012 J. Proteome Res. 11, 751–766), binds to receptors TNFR1 and TNFR2. The TNFR2 mediates apoptotic and survival processes (Fischer et al. 2011 Cell. Signal. 23, 161–170) and its expression is hormonally regulated (Okuda et al. 2010 Mol. Cell. Endocrinol. 330, 41–48). In this work we analyzed the expression of TNFR2 by Western blot (WB) and immunocytochemistry (ICQ) and its co-localization with TNF by ICQ in bovine embryos and endometrium. Heifers that were transferred with multiple in vitro produced (IVP) embryos (n = 3) or sham transferred (n = 3) on Day 5 to horn ipsilateral to the corpus luteum were slaughtered on Day 8. Embryos were flushed and endometrial samples were collected from caruncular and intercaruncular regions in the middle and cranial horn thirds. Endometrial samples and Day 8 IVP embryos were subjected to ICQ, and the immunostaining pattern of TNFR2 and TNF was examined by confocal microscopy. Endometrial samples were also subjected to WB. Expression of TNRF2 was quantified by densitometry (immunoblots) and blind assessment (immunostaining). Data were analyzed using the GLM procedure of SAS Version 9.2 (SAS Institute Inc., Cary, NC, USA) and REGWQ test for means. Trophectoderm (TF) cells from blastocysts and uterine epithelial and stromal cells showed TNFR2 expression. TNF and TNRF2 were predominantly co-localised in embryos and endometrial samples, although occasionally they were detected independently. The presence of embryos increased TNFR2 in the basal glandular epithelia (P ≤ 0.05). Moreover, TNFR2 was higher in the intercaruncular than in the caruncular luminal epithelium (P = 0.07). The presence of embryos did not affect TNFR2 expression between cranial and middle horn thirds. However, the TNFR2 low-molecular-weight isoform (Lmw) in the caruncles and in the middle third of the uterine horn tended to increase in the presence of embryos (P ≤ 0.1). Interestingly, TNFR2 Lmw was more abundant in the middle caruncular region than in other endometrial regions (P < 0.05). Our findings suggest that TNF can mediate embryo-maternal communication in the uterus, acting both in the embryonic and maternal sides. In addition, although implantation does not begin in ruminants until elongation is complete, early bovine embryos seem to show an ability to interact with caruncles. Project AGL2009-10059 (MICINN). M. Muñoz, A. Balseiro, B. Trigal, and E. Correia are sponsored by RYC08-03454, Contrato de Investigación para Doctores grant from INIA, Cajastur, and FPU (AP2009-5265), respectively.
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Zhao, Yuechao, Sunghee Park, Milan K. Bagchi, Robert N. Taylor, and Benita S. Katzenellenbogen. "The Coregulator, Repressor of Estrogen Receptor Activity (REA), Is a Crucial Regulator of the Timing and Magnitude of Uterine Decidualization." Endocrinology 154, no. 3 (March 1, 2013): 1349–60. http://dx.doi.org/10.1210/en.2012-2026.
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Abstract Successful implantation and maintenance of pregnancy require the transformation of uterine endometrial stromal cells into distinct decidualized cells. Although estrogen and progesterone (P4) receptors are known to be essential for decidualization, the roles of steroid receptor coregulators in this process remain largely unknown. In this study, we have established a key role for the coregulator, repressor of estrogen receptor activity (REA), in the decidualization of human endometrial stromal cells (hESCs) in vitro and of the mouse uterus in vivo. Our studies revealed that the level of REA normally decreases to half as hESC decidualization proceeds and that uterine reduction of REA in transgenic heterozygous knockout mice or small interfering RNA knockdown of REA in hESC temporally accelerated and strongly enhanced the differentiation process, as indicated by changes in cell morphology and increased expression of biomarkers of decidualization, including P4 receptor. Findings in hESC cultured in vitro with estradiol, P4, and 8-bromo-cAMP over a 10-day period mirrored observations of enhanced decidualization response in transgenic mice with heterozygous deletion of REA. Importantly, gene expression and immunohistochemical analyses revealed changes in multiple components of the Janus kinase/signal transducer and activator of transcription pathway, including marked up-regulation of signal transducer and activator of transcription 3 and IL-11, master regulators of decidualization, and the down-regulation of several suppressor of cytokine signaling family members, upon reduction of REA. The findings highlight that REA physiologically restrains endometrial stromal cell decidualization, controlling the timing and magnitude of decidualization to enable proper coordination of uterine differentiation with concurrent embryo development that is essential for implantation and optimal fertility.
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Mackens, S., S. Santos-Ribeiro, A. Racca, D. Daneels, A. Koch, W. Essahib, W. Verpoest, et al. "The proliferative phase endometrium in IVF/ICSI: an in-cycle molecular analysis predictive of the outcome following fresh embryo transfer." Human Reproduction 35, no. 1 (January 1, 2020): 130–44. http://dx.doi.org/10.1093/humrep/dez218.
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Abstract Study question Does an early proliferative phase endometrial biopsy harvested during ovarian stimulation harbour information predictive of the outcome following fresh embryo transfer (ET) in that same cycle? Summary answer Transcriptome analysis of the whole-tissue endometrium did not reveal significant differential gene expression (DGE) in relation to the outcome; however, the secretome profile of isolated, cultured and in vitro decidualized endometrial stromal cells (EnSCs) varied significantly between patients who had a live birth compared to those with an implantation failure following fresh ET in the same cycle as the biopsy. What is known already In the majority of endometrial receptivity research protocols, biopsies are harvested during the window of implantation (WOI). This, however, precludes ET in that same cycle, which is preferable as the endometrium has been shown to adapt over time. Endometrial biopsies taken during ovarian stimulation have been reported not to harm the chances of implantation, and in such biopsies DGE has been observed between women who achieve pregnancy versus those who do not. The impact of the endometrial proliferative phase on human embryo implantation remains unclear, but deserves further attention, especially since in luteal phase endometrial biopsies, a transcriptional signature predictive for repeated implantation failure has been associated with reduced cell proliferation, possibly indicating proliferative phase involvement. Isolation, culture and in vitro decidualization (IVD) of EnSCs is a frequently applied basic research technique to assess endometrial functioning, and a disordered EnSC secretome has previously been linked with failed implantation. Study design, size, duration This study was nested in a randomized controlled trial (RCT) investigating the effect of endometrial scratching during the early follicular phase of ovarian stimulation on clinical pregnancy rates after IVF/ICSI. Of the 96 endometrial biopsies available, after eliminating those without fresh ET and after extensive matching in order to minimize the risk of potential confounding, 18 samples were retained to study two clinical groups: nine biopsies of patients with a live birth versus nine biopsies of patients with an implantation failure, both following fresh ET performed in the same cycle as the biopsy. We studied the proliferative endometrium by analysing its transcriptome and by isolating, culturing and decidualizing EnSCs in vitro. We applied this latter technique for the first time on proliferative endometrial biopsies obtained during ovarian stimulation for in-cycle outcome prediction, in an attempt to overcome inter-cycle variability. Participants/materials, setting, methods RNA-sequencing was performed for 18 individual whole-tissue endometrial biopsies on an Illumina HiSeq1500 machine. DGE was analysed three times using different approaches (DESeq2, EdgeR and the Wilcoxon rank-sum test, all in R). EnSC isolation and IVD was performed (for 2 and 4 days) for a subset of nine samples, after which media from undifferentiated and decidualized cultures were harvested, stored at −80°C and later assayed for 45 cytokines using a multiplex suspension bead immunoassay. The analysis was performed by partial least squares regression modelling. Main results and the role of chance After correction for multiple hypothesis testing, DGE analysis revealed no significant differences between endometrial samples from patients who had a live birth and those with an implantation failure following fresh ET. However secretome analysis after EnSC isolation and culture, showed two distinct clusters that clearly corresponded to the two clinical groups. Upon IVD, the secretome profiles shifted from that of undifferentiated cells but the difference between the two clinical groups remained yet were muted, suggesting convergence of cytokine profiles after decidualization. Limitations, reasons for caution Caution is warranted due to the limited sample size of the study and the in vitro nature of the EnSC experiment. Validation on a larger scale is necessary, however, hard to fulfil given the very limited availability of in-cycle proliferative endometrial biopsies outside a RCT setting. Wider implications of the findings These data support the hypothesis that the endometrium should be assessed not only during the WOI and that certain endometrial dysfunctionalities can probably be detected early in a cycle by making use of the proliferative phase. This insight opens new horizons for the development of endometrial tests, whether diagnostic or predictive of IVF/ICSI treatment outcome. Study funding/competing interest(s) This study was supported by Fonds Wetenschappelijk Onderzoek (FWO, Flanders, Belgium, 11M9415N, 1 524 417N), Wetenschappelijk Fonds Willy Gepts (WFWG G160, Universitair Ziekenhuis Brussel, Belgium) and the National Medicine Research Council (NMRC/CG/M003/2017, Singapore). There are no conflicts of interests. Trial registration number NCT02061228.
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Huang, Hong-Yuan, Yan Wen, Juan C. Irwin, Jan S. Kruessel, Yung-Kuei Soong, and Mary Lake Polan. "Cytokine-Mediated Regulation of 92-Kilodalton Type IV Collagenase, Tissue Inhibitor of Metalloproteinase-1 (TIMP-1), and TIMP-3 Messenger Ribonucleic Acid Expression in Human Endometrial Stromal Cells1." Journal of Clinical Endocrinology & Metabolism 83, no. 5 (May 1, 1998): 1721–29. http://dx.doi.org/10.1210/jcem.83.5.4810.
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Interleukin-1 (IL-1) is expressed in human endometrium and has been shown to play an integral role in local cellular interactions during implantation. In addition, the matrix metalloproteinase (MMP) and its inhibitor, the tissue inhibitor of metalloproteinase (TIMP), are crucial during implantation, mediating in vitro trophoblast penetration, and are regulated by several cytokines expressed by trophoblast cells. We have investigated the roles of IL-1β and transforming growth factor-β (TGFβ) in regulating TIMP-1, TIMP-3, and 92-kDa type IV collagenase messenger ribonucleic acid (mRNA) expression in human endometrial stromal cells using quantitative competitive PCR. Confluent stromal cell cultures treated with progesterone and estradiol for 9 days were stimulated with IL-1β, IL-1β plus anti-IL-1β antibody, TGFβ, and TGFβ plus anti-TGFβ antibody for an additional 24 h. Competitive complementary DNA fragments were constructed by deletion of a defined fragment from each of the target complementary DNA sequences and coamplified in quantitative competitive PCR as an internal standard. TIMP-1 and TIMP-3, but not 92-kDa type IV collagenase mRNA, were expressed in stromal cells. The 92-kDa type IV collagenase mRNA was only expressed after stimulation with IL-1β. IL-1β both augmented 92-kDa type IV collagenase mRNA expression and decreased TIMP-1 and TIMP-3 mRNA expression in a dose-dependent manner. Conversely, TGFβ augmented TIMP-1 and TIMP-3 mRNA expression, but did not affect 92-kDa type IV collagenase expression. IL-1 and TGFβ-mediated changes were both neutralized by specific antibodies. These results provide indirect evidence that IL-1 and TGFβ may play crucial roles at the embryo-maternal interface during trophoblast invasion by regulating stromal cell expression of TIMP-1, TIMP-3, and 92-kDa type IV collagenase, all of which are known to be important in trophoblast invasion.
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Cloke, Brianna, Kaisa Huhtinen, Luca Fusi, Takeshi Kajihara, Maria Yliheikkilä, Ka-Kei Ho, Gijs Teklenburg, et al. "The Androgen and Progesterone Receptors Regulate Distinct Gene Networks and Cellular Functions in Decidualizing Endometrium." Endocrinology 149, no. 9 (May 29, 2008): 4462–74. http://dx.doi.org/10.1210/en.2008-0356.
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Progesterone is indispensable for differentiation of human endometrial stromal cells (HESCs) into decidual cells, a process that critically controls embryo implantation. We now show an important role for androgen receptor (AR) signaling in this differentiation process. Decreased posttranslational modification of the AR by small ubiquitin-like modifier (SUMO)-1 in decidualizing cells accounted for increased responsiveness to androgen. By combining small interfering RNA technology with genome-wide expression profiling, we found that AR and progesterone receptor (PR) regulate the expression of distinct decidual gene networks. Ingenuity pathway analysis implicated a preponderance of AR-induced genes in cytoskeletal organization and cell motility, whereas analysis of AR-repressed genes suggested involvement in cell cycle regulation. Functionally, AR depletion prevented differentiation-dependent stress fiber formation and promoted motility and proliferation of decidualizing cells. In comparison, PR depletion perturbed the expression of many more genes, underscoring the importance of this nuclear receptor in diverse cellular functions. However, several PR-dependent genes encode for signaling intermediates, and knockdown of PR, but not AR, compromised activation of WNT/β-catenin, TGFβ/SMAD, and signal transducer and activator of transcription (STAT) pathways in decidualizing cells. Thus, the nonredundant function of the AR in decidualizing HESCs, centered on cytoskeletal organization and cell cycle regulation, implies an important role for androgens in modulating fetal-maternal interactions. Moreover, we show that PR regulates HESC differentiation, at least in part, by reprogramming growth factor and cytokine signal transduction.
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George, Ashley F., Karen S. Jang, Mette Nyegaard, Jason Neidleman, Trimble L. Spitzer, Guorui Xie, Joseph C. Chen, et al. "Seminal plasma promotes decidualization of endometrial stromal fibroblasts in vitro from women with and without inflammatory disorders in a manner dependent on interleukin-11 signaling." Human Reproduction 35, no. 3 (March 2020): 617–40. http://dx.doi.org/10.1093/humrep/deaa015.
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Abstract STUDY QUESTION Do seminal plasma (SP) and its constituents affect the decidualization capacity and transcriptome of human primary endometrial stromal fibroblasts (eSFs)? SUMMARY ANSWER SP promotes decidualization of eSFs from women with and without inflammatory disorders (polycystic ovary syndrome (PCOS), endometriosis) in a manner that is not mediated through semen amyloids and that is associated with a potent transcriptional response, including the induction of interleukin (IL)-11, a cytokine important for SP-induced decidualization. WHAT IS KNOWN ALREADY Clinical studies have suggested that SP can promote implantation, and studies in vitro have demonstrated that SP can promote decidualization, a steroid hormone-driven program of eSF differentiation that is essential for embryo implantation and that is compromised in women with the inflammatory disorders PCOS and endometriosis. STUDY DESIGN, SIZE, DURATION This is a cross-sectional study involving samples treated with vehicle alone versus treatment with SP or SP constituents. SP was tested for the ability to promote decidualization in vitro in eSFs from women with or without PCOS or endometriosis (n = 9). The role of semen amyloids and fractionated SP in mediating this effect and in eliciting transcriptional changes in eSFs was then studied. Finally, the role of IL-11, a cytokine with a key role in implantation and decidualization, was assessed as a mediator of the SP-facilitated decidualization. PARTICIPANTS/MATERIALS, SETTING, METHODS eSFs and endometrial epithelial cells (eECs) were isolated from endometrial biopsies from women of reproductive age undergoing benign gynecologic procedures and maintained in vitro. Assays were conducted to assess whether the treatment of eSFs with SP or SP constituents affects the rate and extent of decidualization in women with and without inflammatory disorders. To characterize the response of the endometrium to SP and SP constituents, RNA was isolated from treated eSFs or eECs and analyzed by RNA sequencing (RNAseq). Secreted factors in conditioned media from treated cells were analyzed by Luminex and ELISA. The role of IL-11 in SP-induced decidualization was assessed through Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas-9-mediated knockout experiments in primary eSFs. MAIN RESULTS AND THE ROLE OF CHANCE SP promoted decidualization both in the absence and presence of steroid hormones (P < 0.05 versus vehicle) in a manner that required seminal proteins. Semen amyloids did not promote decidualization and induced weak transcriptomic and secretomic responses in eSFs. In contrast, fractionated SP enriched for seminal microvesicles (MVs) promoted decidualization. IL-11 was one of the most potently SP-induced genes in eSFs and was important for SP-facilitated decidualization. LARGE SCALE DATA RNAseq data were deposited in the Gene Expression Omnibus repository under series accession number GSE135640. LIMITATIONS, REASONS FOR CAUTION This study is limited to in vitro analyses. WIDER IMPLICATIONS OF THE FINDINGS Our results support the notion that SP promotes decidualization, including within eSFs from women with inflammatory disorders. Despite the general ability of amyloids to induce cytokines known to be important for implantation, semen amyloids poorly signaled to eSFs and did not promote their decidualization. In contrast, fractionated SP enriched for MVs promoted decidualization and induced a transcriptional response in eSFs that overlapped with that of SP. Our results suggest that SP constituents, possibly those associated with MVs, can promote decidualization of eSFs in an IL-11-dependent manner in preparation for implantation. STUDY FUNDING/COMPETING INTEREST(S) This project was supported by NIH (R21AI116252, R21AI122821 and R01AI127219) to N.R.R. and (P50HD055764) to L.C.G. The authors declare no conflict of interest.
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Crosby, D. A., L. E. Glover, E. P. Brennan, P. Kelly, P. Cormican, B. Moran, F. Giangrazi, et al. "Dysregulation of the interleukin-17A pathway in endometrial tissue from women with unexplained infertility affects pregnancy outcome following assisted reproductive treatment." Human Reproduction 35, no. 8 (July 2, 2020): 1875–88. http://dx.doi.org/10.1093/humrep/deaa111.
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Abstract STUDY QUESTION Which transcriptomic alterations in mid-luteal endometrial scratch biopsies, taken prior to the assisted reproductive treatment (ART) treatment cycle are associated with unsuccessful pregnancy? SUMMARY ANSWER Dysregulated interleukin-17 (IL-17) pathway components are demonstrated in women who fail to become pregnant after ART. WHAT IS KNOWN ALREADY Implantation failure is now recognised as a critical factor in unexplained infertility and may be an important component of failed ART. STUDY DESIGN, SIZE, DURATION Using a prospective longitudinal study design, 29 nulliparous women with unexplained infertility undergoing ART were recruited between October 2016 and February 2018. Mid-luteal stage endometrium and matched serum samples were collected, and patients underwent a single embryo transfer in the subsequent cycle. RNA-seq analysis of endometrial biopsies was performed on the discovery cohort (n = 20). PARTICIPANTS/MATERIALS, SETTING, METHODS Gene set enrichment analysis of the differentially expressed genes (DEGs) was performed. Endometrium and serum were then prepared for IL-17A analysis by ELISA. MAIN RESULTS AND THE ROLE OF CHANCE There were 204 differentially expressed protein-coding genes identified in tissue from women who became pregnant (n = 9) compared with tissue from women who failed to become pregnant (n = 11) (false discovery rate; P < 0.05). Of the 204 DEGs, 166 were decreased while 38 were increased in the pregnant compared to the non-pregnant groups. Gene set enrichment analysis of the DEGs identified an over-representation of IL-17 and Pl3K-Akt signalling pathways. All the DEGs within the IL-17 signalling pathway (MMP3, MMP1, IL1β, LCN2, S100A9 and FOSL1) demonstrated decreased expression in the pregnant group. Serum IL-17 protein levels were increased in the non-pregnant discovery cohort (n = 11) and these findings were confirmed a validation cohort (n = 9). LIMITATIONS, REASONS FOR CAUTION Limitations of our study include the cohort size and the lack of aneuploidy data for the embryos; however, all embryos transferred were single good or top-quality blastocysts. WIDER IMPLICATIONS OF THE FINDINGS These findings demonstrate dysregulated IL-17 pathway components in women who fail to become pregnant after ART. Elevated serum levels of the pro-inflammatory cytokine IL-17 may predict failure of ART in women with unexplained infertility. Future trials of anti-IL-17 therapies in this cohort warrant further investigation. STUDY FUNDING/COMPETING INTEREST(S) Funding from the UCD Wellcome Institutional Strategic Support Fund, which was financed jointly by University College Dublin and the SFI-HRB-Wellcome Biomedical Research Partnership (ref 204844/Z/16/Z), is acknowledged. The authors have no competing interests. TRIAL REGISTRATION NUMBER NA.
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Paiva, P., K. Meehan, L. A. Salamonsen, and E. Dimitriadis. "525. ROLES FOR HUMAN CHORIONIC GONADOTROPHIN IN EMBRYO-ENDOMETRIAL CROSS-TALK DURING BLASTOCYST IMPLANTATION." Reproduction, Fertility and Development 21, no. 9 (2009): 124. http://dx.doi.org/10.1071/srb09abs525.
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Emerging evidence suggests an important role for the early embryo product human chorionic gonadotrophin (hCG) in embryo-endometrial interactions critical for successful embryo implantation1. The human endometrium is also a source of hCG, with maximal expression of hCG and its receptor, hCG/LHR, in endometrial epithelial cells during the window of implantation in vivo2,3, and in primary endometrial epithelial cells (EECs)3. Implantation is tightly regulated by growth and regulatory factors produced within the embryo-endometrial microenvironment. We hypothesise that embryo/endometrial-derived hCG mediates the molecular cross talk vital for successful implantation. The main objective of this study was to investigate the effect of hCG on the production of a selected cohort of 42 cytokines and growth factors by EECs. These included those with both known and previously unidentified roles during implantation. The secretory profile of cytokines/growth factors produced by EECs was also analysed. EECs (n=8 cultures) were isolated from biopsies collected from fertile cycling women. Cells were treated without or with recombinant hCG for 48 hr and conditioned media collected for quantitative analysis using LuminexTM multiplex technology. For the first time, a secretory profile of 42 cytokines and growth factors produced by EECs was established, as was the identification of fibroblast growth factor-2 (FGF-2) secretion by human endometrial epithelium. hCG (2 IU/ml) significantly increased the production of a number factors including those with known roles during trophoblast migration and adhesion (CX3CL1; 71±31%, CXCL10; 67±24%, CCL4; 87±12%), in trophoblast differentiation (IL-1α ; 68±31%) and with unidentified roles during implantation (CCL22; 78±40%, GM-CSF; 45±16%, FGF-2; 50±25%; all p<0.05). Upregulation of the known hCG regulated proteins, VEGF and LIF, validated this study. These findings clearly support roles for the embryo/endometrium via hCG in actively contributing to the molecular cross-talk during the early stages of implantation.
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You, Fang, Xin Du, Taiwei Zhang, Yang Wang, Yuxia Lv, and Li Zeng. "TJZYF Improves Endometrial Receptivity through Regulating VEGF and PI3K/AKT Signaling Pathway." BioMed Research International 2022 (September 23, 2022): 1–16. http://dx.doi.org/10.1155/2022/9212561.
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The endometrium receptivity was impaired by controlled ovarian hyperstimulation (COH), which would then lead to fertility issues and increased abortion clinically. In the present study, to explore the effectiveness of Tiaojing Zhuyun Formula (TJZYF) in improving endometrial receptivity of COH rats and the possible active ingredients and mechanisms, an approach of network pharmacology was performed and a COH animal model was established. As analyzed, stigmasterol and quercetin may be the active ingredients of TJZYF on improving endometrial receptivity and positive regulation of ion transport, the cytokine-mediated signaling pathway, and endocrine process, and vascular endothelial growth factor receptor signaling pathway may be involved. Eighty female rats were divided into four groups randomly: control, model, TJZYF, and TJZYF+si-VEGFA. COH rat models were constructed by injecting with human menopausal gonadotropin (HMG) and human chorionic gonadotropin (HCG). We found that both endometrial thickness and number of embryo implantations in model were substantially reduced vs. control. The gene and protein expressions of VEGF, PI3K, and p-Akt in the uterus were significantly reduced. TJZYF could increase the endometrial thickness and number of embryo implantations and enhance the expressions of VEGF, PI3K, and p-Akt in the uterus. In the TJZYF+si-VEGFA group, the effect of TJZYF was impaired. Generally, TJZYF could improve the endometrium receptivity and facilitate embryo implantation of COH rats by upregulating VEGF and enhancing the PI3K/Akt signaling pathway.
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Li, Xilong, Michael J. Large, Chad J. Creighton, Rainer B. Lanz, Jae-Wook Jeong, Steven L. Young, Bruce A. Lessey, Wilder A. Palomino, Sophia Y. Tsai, and Francesco J. DeMayo. "COUP-TFII Regulates Human Endometrial Stromal Genes Involved in Inflammation." Molecular Endocrinology 27, no. 12 (December 1, 2013): 2041–54. http://dx.doi.org/10.1210/me.2013-1191.
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Chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII; NR2F2) is an orphan nuclear receptor involved in cell-fate specification, organogenesis, angiogenesis, and metabolism. Ablation of COUP-TFII in the mouse uterus causes infertility due to defects in embryo attachment and impaired uterine stromal cell decidualization. Although the function of COUP-TFII in uterine decidualization has been described in mice, its role in the human uterus remains unknown. We observed that, as in mice, COUP-TFII is robustly expressed in the endometrial stroma of healthy women, and its expression is reduced in the ectopic lesions of women with endometriosis. To interrogate the role of COUP-TFII in human endometrial function, we used a small interfering RNA-mediated loss of function approach in primary human endometrial stromal cells. Attenuation of COUP-TFII expression did not completely block decidualization; rather it had a selective effect on gene expression. To better elucidate the role of COUP-TFII in endometrial stroma cell biology, the COUP-TFII transcriptome was defined by pairing microarray comparison with chromatin immunoprecipitation followed by deep sequencing. Gene ontology analysis demonstrates that COUP-TFII regulates a subset of genes in endometrial stroma cell decidualization such as those involved in cell adhesion, angiogenesis, and inflammation. Importantly this analysis shows that COUP-TFII plays a role in controlling the expression of inflammatory cytokines. The determination that COUP-TFII plays a role in inflammation may add insight into the role of COUP-TFII in embryo implantation and in endometrial diseases such as endometriosis.
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Liang, Yu, Junyan Han, Chanwei Jia, Yanmin Ma, Yonglian Lan, Ying Li, and Shuyu Wang. "Effect of Endometrial Injury on Secretion of Endometrial Cytokines and IVF Outcomes in Women with Unexplained Subfertility." Mediators of Inflammation 2015 (2015): 1–9. http://dx.doi.org/10.1155/2015/757184.
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In order to determine the effect of endometrial injury (EI) onin vitrofertilization (IVF) outcomes in women with unexplained subfertility and explore the relationship between EI and endometrial inflammatory cytokines, 66 women with unexplained subfertility undergoing IVF treatment were recruited. 38 patients in the EI group underwent EI in the mid-luteal phase of the cycle and 28 patients in the non-EI (NEI) group. According to the pregnancy outcome, the NEI and EI groups were divided into NEI-nonpregnant (NEI-NP), NEI-pregnant (NEI-P), EI-NP, and EI-P. All patients underwent aspiration of endometrial secretions immediately before embryo transfer. The concentrations of ten mediators were measured using Milliplex Magnetic Bead assay. The clinical pregnancy was significantly higher in the EI than in the NEI group. The concentrations of interleukin- (IL-) 6, IL-8, IL-12 (p70), IL-13, interferon- (IFN-)γ, monocyte chemotactic protein- (MCP-) 1, and vascular endothelial growth factor (VEGF) were significantly higher in the EI than the NEI group. The expression of IFN-γand VEGF in the EI-P was significantly increased compared to the EI-NP group. These findings suggest that, in women with unexplained subfertility, endometrial injury might be a potential method to improve clinical pregnancy rates by promoting the expression of IFN-γand VEGF.
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Hannan, N. J., R. L. Jones, and L. A. Salamonsen. "225.Expression of chemokines and their receptors at the human maternal - embryonic interface." Reproduction, Fertility and Development 16, no. 9 (2004): 225. http://dx.doi.org/10.1071/srb04abs225.
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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).
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Singh, Mohan, Parvesh Chaudhry, and Eric Asselin. "Bridging endometrial receptivity and implantation: network of hormones, cytokines, and growth factors." Journal of Endocrinology 210, no. 1 (March 3, 2011): 5–14. http://dx.doi.org/10.1530/joe-10-0461.
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The prerequisite of successful implantation depends on achieving the appropriate embryo development to the blastocyst stage and at the same time the development of an endometrium that is receptive to the embryo. Implantation is a very intricate process, which is controlled by a number of complex molecules like hormones, cytokines, and growth factors and their cross talk. A network of these molecules plays a crucial role in preparing receptive endometrium and blastocyst. Furthermore, timely regulation of the expression of embryonic and maternal endometrial growth factors and cytokines plays a major role in determining the fate of embryo. Most of the existing data comes from animal studies due to ethical issues. In this study, we comprehend the data from both animal models and humans for better understanding of implantation and positive outcomes of pregnancy. The purpose of this review is to describe the potential roles of embryonic and uterine factors in implantation process such as prostaglandins, cyclooxygenases, leukemia inhibitory factor, interleukin (IL) 6, IL11, transforming growth factor-β, IGF, activins, NODAL, epidermal growth factor (EGF), and heparin binding-EGF. Understanding the function of these players will help us to address the reasons of implantation failure and infertility.
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Paravati, R., N. De Mello, E. K. Onyido, L. W. Francis, K. Brüsehafer, K. Younas, S. Spencer-Harty, R. S. Conlan, D. Gonzalez, and Lavinia Margarit. "Differential regulation of osteopontin and CD44 correlates with infertility status in PCOS patients." Journal of Molecular Medicine 98, no. 12 (October 13, 2020): 1713–25. http://dx.doi.org/10.1007/s00109-020-01985-w.
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Abstract Endometrial receptivity is mediated by adhesion molecules at the endometrium-trophoblast interface where osteopontin (OPN) and CD44 form a protein complex that plays an important role in embryo recognition. Here, we undertook a prospective study investigating the expression and regulation of OPN and CD44 in 50 fertile and 31 infertile ovulatory polycystic ovarian syndrome (PCOS) patients in the proliferative and secretory phases of the natural menstrual cycle and in 12 infertile anovulatory PCOS patients. Endometrial biopsies and blood samples were evaluated for expression of OPN and CD44 using RT-PCR, immunohistochemistry and ELISA analysis to determine circulating levels of OPN, CD44, TNF-α, IFN-γ and OPN and CD44 levels in biopsy media. Our findings highlighted an increased level of circulating OPN and CD44 in serum from infertile patients that inversely correlated with expression levels in endometrial tissue and positively correlated with levels secreted into biopsy media. OPN and CD44 levels positively correlated to each other in serum and media from fertile and PCOS patients, as well as to circulating TNF-α and IFN-γ. In vitro analysis revealed that hormone treatment induced recruitment of ERα to the OPN and CD44 promoters with a concomitant increase in the expression of these genes. In infertile patients, inflammatory cytokines led to recruitment of NF-κB and STAT1 proteins to the OPN and CD44 promoters, resulting in their overexpression. These observations suggest that the endometrial epithelial OPN-CD44 adhesion complex is deficient in ovulatory PCOS patients and displays an altered stoichiometry in anovulatory patients, which in both cases may perturb apposition. This, together with elevated circulating and local secreted levels of these proteins, may hinder endometrium-trophoblast interactions by saturating OPN and CD44 receptors on the surface of the blastocyst, thereby contributing to the infertility associated with ovulating PCOS patients. Key messages • Endometrial epithelial OPN-CD44 adhesion complex levels are deficient in ovulatory PCOS patients contributing to the endometrial infertility associated with ovulating PCOS patients. • Circulating levels of OPN, CD44 and inflammatory cytokines TNF-α and IFN-γ are altered in infertile PCOS patients. • Increased levels of both OPN and CD44 in biopsy media and serum inversely correlate with endometrial expression of these markers in endometrial tissue. • In infertile PCOS patients, high levels of oestrogens and inflammatory cytokines stimulate the recruitment of transcription factors to the OPN and CD44 promoters to enhance gene transcription. • Our study identifies a novel crosstalk between the CD44-OPN adhesion complex, ERα, STAT1 and NF-κB pathways modulating endometrial receptivity.
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Cintra, Laís, Elena Carolina Recalde, Mateus Sudano, Fernanda Franchi, Anthony Castilho, and Fernanda Landim Alvarenga. "Effect of bovine endometrial mesenchymal cell conditioned medium on bovine embryo development." STUDIES IN ENVIRONMENTAL AND ANIMAL SCIENCES 3, no. 1 (March 23, 2022): 131–48. http://dx.doi.org/10.54020/seasv3n1-009.
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Endometrial mesenchymal stromal cell (eMSCs) secretes bioactive molecules such as cytokines and growth factors. MSCs conditioned media (CM) maintains the immunomodulation and regenerative potential properties of the cells that produced it. In this work CM was used during IVC as an alternative to deliver growth factors in bovine embryo culture medium to induce embryo development and reduce apoptosis. The percentage of embryos that underwent cleavage was similar (P>0.05) among CM, BSA and FBS groups, but blastocyst formation was higher (P<0.05) in FBS group. The total cell number was higher in CM group, but there was no significant differences in cell numbers or apoptotic index among the 3 experimental groups (P>0.05). The relative mRNA expression of ELOVL6 was higher in the CM group, of CASP3 in the BSA group and of ACSL3 and VEGF in the FBS group. Taken together, these data suggest that CM can be used as an alternative supplement in bovine IVF. The gene expression profile suggested that the use of CM inhibited an increase in the relative mRNA levels for CASP3. Moreover, the CM favored the total number cells, inhibited the percentage of cells in apoptosis and produces better quality embryo.
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Kumar, Sushma, Quanxi Li, Anuradha Dua, Yu-Kang Ying, Milan K. Bagchi, and Indrani C. Bagchi. "Messenger Ribonucleic Acid Encoding Interferon-Inducible Guanylate Binding Protein 1 Is Induced in Human Endometrium within the Putative Window of Implantation1." Journal of Clinical Endocrinology & Metabolism 86, no. 6 (June 1, 2001): 2420–27. http://dx.doi.org/10.1210/jcem.86.6.7534.
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The putative window of embryo implantation in the human opens between days 19–24 of the menstrual cycle. During this period, the endometrium undergoes distinctive structural and functional changes orchestrated by steroid hormones, growth factors, and cytokines to attain a receptive phase in which it acquires the ability to implant the developing embryo. A major challenge in the study of human reproduction is to identify the molecular signals that participate in the establishment of this critical receptive phase in the context of the natural cycle. Toward this goal, we analyzed human endometrial biopsies at various days of the menstrual cycle by employing messenger RNA (mRNA) differential display technique. We isolated several complementary DNAs representing genes that are either up- or down-regulated within the putative window of implantation. We identified one of these genes as that encoding interferon (IFN)-inducible guanylate-binding protein 1 (or GBP1), which possesses GTPase activity. Analysis of endometrial biopsies by Northern blotting and RT-PCR demonstrated that GBP1 mRNA is specifically induced at the midsecretory phase of the menstrual cycle. In situ hybridization analysis revealed that GBP1 mRNA expression is localized in the glandular epithelial cells as well as in the stroma in the immediate vicinity of the glands. We observed that treatment of human endometrial adenocarcinoma cell, Ishikawa, with IFN-γ or IFN-α markedly induced the expression of GBP1 mRNA. IFN-γ was, however, a more potent inducer of GBP1 than IFN-α. Consistent with this finding, the temporal profile of GBP1 expression during the menstrual cycle resembled that of IFN-γ mRNA more closely than that of IFN-α, predicting a regulatory role of IFN-γ in GBP1 expression in midsecretory human endometrium. Although the precise function of GBP1 in the receptive human uterus remains unclear, its unique expression overlapping the putative window of implantation suggests that it might serve as a useful marker of uterine receptivity in the human.
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Hakam, Miya Soukaina, Jose Maria Miranda-Sayago, Soren Hayrabedyan, Krassimira Todorova, Patrick Simon Spencer, Asma Jabeen, Eytan R. Barnea, and Nelson Fernandez. "Preimplantation Factor (PIF) Promotes HLA-G, -E, -F, -C Expression in JEG-3 Choriocarcinoma Cells and Endogenous Progesterone Activity." Cellular Physiology and Biochemistry 43, no. 6 (2017): 2277–96. http://dx.doi.org/10.1159/000484378.
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Background/Aims: Pregnancy success requires mandatory maternal tolerance of the semi/ allogeneic embryo involving embryo-derived signals. Expression levels of PreImplantation Factor (PIF), a novel peptide secreted by viable embryos, correlate with embryo development, and its early detection in circulation correlates with a favourable pregnancy outcome. PIF enhances endometrial receptivity to promote embryo implantation. Via the p53 pathway, it increases trophoblast invasion, improving cell survival / immune privilege. PIF also reduces spontaneous and LPS-induced foetal death in immune naïve murine model. We examined PIF effect on gene expression of human leukocyte antigen (HLA-G, -E -F and –C) and the influence of PIF on local progesterone activity in JEG-3 choriocarcinoma cells. Methods: PIF and progesterone (P4) effects on JEG-3 cells surface and intracellular HLA molecules was tested using monoclonal antibodies, flow cytometry, and Western blotting. PIF and IL17 effects on P4 and cytokines secretion was determined by ELISA. PIF and P4 effects on JEG-3 cells proteome was examined using 2D gel staining followed by spot analysis, mass spectrometry and bioinformatic analysis. Results: In cytotrophoblastic JEG-3 cells PIF increased intracellular expression of HLA-G, HLA-F, HLA-E and HLA-C and surface expression of HLA-G, HLA-E and HLA-C in dose and time dependent manner. In case of HLA-E, -F results were confirmed also by Western blot. Proteome analysis confirmed an increase in HLA-G, pro-tolerance FOXP3+ regulatory T cells (Tregs), coagulation factors and complement regulator. In contrast, PIF reduced PRDX2 and HSP70s to negate oxidative stress and protein misfolding. PIF enhanced local progesterone activity, increasing steroid secretion and the receptor protein. It also promoted the secretion of the Th1/Th2 cytokines (IL-10, IL-1β, IL-8, GM-CSF and TGF-β1), resulting in improved maternal signalling. Conclusion: PIF can generate a pro-tolerance milieu by enhancing the expression of HLA molecules and by amplifying endogenous progesterone activity. A Fast-Track clinical trial for autoimmune disease has been satisfactorily completed. The acquired data warrants PIF use for the treatment of early pregnancy disorders.
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Pandur, Edina, Ramóna Pap, Gergely Jánosa, Adrienn Horváth, and Katalin Sipos. "Fractalkine Improves the Expression of Endometrium Receptivity-Related Genes and Proteins at Desferrioxamine-Induced Iron Deficiency in HEC-1A Cells." International Journal of Molecular Sciences 24, no. 9 (April 27, 2023): 7924. http://dx.doi.org/10.3390/ijms24097924.
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Fractalkine (CX3CL1/FKN) is a unique chemokine belonging to the CX3C chemokine subclass. FKN exists in two forms: a membrane-bound form expressed by both endometrium cells and trophoblasts thought to be implicated in maternal–fetal interaction and a soluble form expressed by endometrium cells. Endometrium receptivity is crucial in embryo implantation and a complex process regulated by large numbers of proteins, e.g., cytokines, progesterone receptor (PR), SOX-17, prostaglandin receptors (PTGER2), and tissue inhibitors of metalloproteinases (TIMPs). It has also been reported that iron is important in fertility and affects the iron status of the mother. Therefore, iron availability in the embryo contributes to fertilization and pregnancy. In this study, we focused on the effect of iron deficiency on the secreted cytokines (IL-6, IL-1β, leukocyte inhibitory factor, TGF-β), chemokines (IL-8, FKN), and other regulatory proteins (bone morphogenic protein 2, activin, follistatin, PR, SOX-17, prostaglandin E2 receptor, TIMP2), and the modifying effect of FKN on the expression of these proteins, which may improve endometrium receptivity. Endometrial iron deficiency was mediated by desferrioxamine (DFO) treatment of HEC-1A cells. FKN was added to the cells 24 h and 48 h after DFO with or without serum for modelling the possible iron dependence of the alterations. Our findings support the hypothesis that FKN ameliorates the effects of anemia on the receptivity-related genes and proteins in HEC-1A cells by increasing the secretion of the receptivity-related cytokines via the fractalkine receptor (CX3CR1). FKN may contribute to cell proliferation and differentiation by regulating activin, follistatin, and BMP2 expressions, and to implantation by altering the protein levels of PR, SOX-17, PTGER2, and TIMP2. FKN mitigates the negative effect of iron deficiency on the receptivity-related genes and proteins of HEC-1A endometrium cells, suggesting its important role in the regulation of endometrium receptivity.
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Jasper, M. J., A. Care, J. D. Aplin, and S. A. Robertson. "111. LIF REGULATION OF EPITHELIAL CELL FUCOSYLTRANSFERASE EXPRESSION IN MOUSE ENDOMETRIUM DURING EARLY PREGNANCY." Reproduction, Fertility and Development 21, no. 9 (2009): 30. http://dx.doi.org/10.1071/srb09abs111.
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Fucosyltransferase (FUT) enzymes are key regulators of glycosylated structures mediating embryo attachment to uterine epithelial cells at implantation. The identity of local regulatory signals is unknown. We have previously shown that macrophage co-culture significantly increases epithelial cell FUT2 and FUT4 mRNA expression in vitro, and the effect of co-culture is replicated with macrophage conditioned media. We aimed to define the identity of macrophage-secreted agents active in regulating FUT expression in mouse uterine epithelial cells, and to investigate the importance of macrophages for FUT expression in vivo. FUT1, FUT2, and FUT4 mRNAs were measured by qRT-PCR and data was normalised to β-actin mRNA in mouse uterine epithelial cells after culture with cytokines known to be secreted by macrophages. mRNA was also quantified in luminal epithelium laser-microdissected from mouse uterus on day 4 after mating with intact males or seminal vesicle deficient (SVX) males, to induce normal or depleted uterine macrophage populations respectively. Lectin staining on day 4 pc was quantified using ImageJ software in an alternate model of transient, systemic macrophage ablation following diphtheria toxin administration to CD11b-DTR transgenic mice. Epithelial FUT2 mRNA expression was specifically enhanced in vitro by addition of rLIF (2 ng/ml) (mean relative expression ± SEM, control 100 ± 5.6; rLIF 162.1 ± 11.5). Depletion of macrophages by mating with seminal vesicle deficient males reduced epithelial FUT2 mRNA expression on day 4 pc (intact 100 ± 9.1; SVX 73.5 ± 8.6). Depletion of macrophages in the CD11b-DTR mouse model caused a 30% reduction in the expression of the resulting glycoprotein epitope (α1,2 fucose) as observed by intensity of endometrial epithelial UEA-1 staining (control 100 ± 10; CD11b-DTR 72 ± 9) 24 hr post diphtheria toxin administration. In conclusion, these data demonstrate that endometrial epithelial FUT2 mRNA synthesis in preparation for embryo implantation is mediated via LIF and potentially other factors secreted from macrophages recruited during the inflammatory response to insemination. Uterine macrophage abundance and phenotype may thus be a determinant of receptivity to implantation.
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Fernandes, Lidia Jacinta Nunes, and Eliana Mara Oliveira Lippe. "Pregnant mice submitted to Surgical Embryo Euthanasia (SEE) induce loss of expression of inducible nitric oxide synthase isoform and NO concentration in the maternal-fetal interface." Brazilian Journal of Biological Sciences 7, no. 15 (2020): 69–78. http://dx.doi.org/10.21472/bjbs(2020)071507.
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The well-succeeded pregnancy in humans and rodents is the consequence of close interaction between maternal and fetal cells with intervening of cytokines and chemical mediators. In this process a pregnant uterus subset NK cells - uterine Natural Killer cells (uNK cells) play a pivotal modulatory role under the influence of local physiological hypoxia and other alterations. The aim of the present work was to evaluate the expression and commitment of induced form of nitric oxide synthase (iNOS) and NO concentration in the homeostasis of pregnant uterus. It was used normal pregnant mice on gd 10th and those submitted to surgical intervention to induce mechanical lesion in the embryos (SEE). Uterine samples were collected at 0.5, 1, 2 and 6 h after embryo lesion and processed for paraffin embedding and tissue homogenate. The samples destinate for paraffin embedding was performed the Dolichos biflorus (DBA) lectin cytochemistry and anti-iNOS immunocytochemistry. The samples destinate to tissue homogenates were processed for SDS-PAGE and Western-blot using anti-iNOS and evaluate of NO concentration. The embryo-injured uterine segments showed hyperemia and hemorrhage at mesometrial region in which the DBA lectin reaction showed altered uNK cells suggesting the degranulation. Positive reaction with anti-iNOS was seen on uNK cells, trophoblast giant cells, endometrial stromal and decidual cells and smooth muscle cells in the normal pregnant uterus, but 1 and 2 h after embryo lesion, the iNOS labeling decreased or was absent only in uNK cells. The same results was obtained with NO concentration. These results confirm the unique constitutive expression of iNOS in the pregnant mice uterus, being the uNK cells the only one responsive against stress of embryo failure, besides showing that excessive NO produced by quick activation of uNK-iNOS should affect the local vascular permeability.
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Simón, Carlos, MarÍa José Gimeno, Amparo Mercader, José Enrique O’Connor, José RemohÍ, Mary Lake Polan, and Antonio Pellicer. "Embryonic Regulation of Integrins β3,α 4, and α1 in Human Endometrial Epithelial Cells in Vitro1." Journal of Clinical Endocrinology & Metabolism 82, no. 8 (August 1, 1997): 2607–16. http://dx.doi.org/10.1210/jcem.82.8.4153.
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In the present study, we examined the embryonic regulation ofβ 3 integrin in human endometrial epithelial cells (EEC) at the protein level and analyzed putative embryonic factors responsible for this regulation. The model employed is based on a clinical in vitro fertilization program in which single human embryos were cocultured with EEC until blastocyst stage and then transferred back to the uterus. After embryo transfer, EEC wells were divided according to the embryonic status reached: EEC with embryos that achieved the blastocyst stage, EEC with arrested embryos, and EEC without embryos. Immunostaining for β3 was positive in plasma membrane of EEC. Flow cytometry showed a mean percentage ofβ 3-stained cells of 24.1 ± 5.7 in EEC cocultured with embryos that achieved the blastocyst stage (n = 13) vs. 9.5 ± 1.6 (P < 0.05) in those EEC cultured with arrested embryos (n = 12). Immunostaining for α1 and α4 integrins was negative in EEC monolayers studied, regardless of the presence or absence of embryos, and these findings were confirmed by flow cytometry. The possibility that the embryonic IL-1 system and leukemia inhibitory factor were involved in the endometrial β3 up-regulation was investigated by neutralizing experiments demonstrating a significant inhibition of β3-stained cells when EEC monolayers were cultured in the presence of EEC/blastocyst-conditioned media with (n = 4) vs. without (n = 8) antihuman interleukin (IL)-1α + IL-1β (1.65% vs. 14.6%; P < 0.05). Dose-response experiments further demonstrated an up-regulation of β3 positive cells when IL-1α + IL-1β were added to the medium at a concentration of 10 pg/mL compared with control medium without added cytokines (40% vs. 20%, n = 4). The functional relevance of the EEC β3 up-regulation was tested using a mouse blastocyst adhesion assay. More mouse blastocysts attached to EEC previously in contact with human blastocyst (72.7%) compared with those EEC previously in contact with arrested embryos (40%). Our results demonstrate the selective effect of a developing human embryo on EEC expression of β3, which is maximal when a human blastocyst instead of an arrested embryo is considered. Furthermore, the embryonic IL-1 system seems to be involved in the EECβ 3 up-regulation, reinforcing the concept of precise paracrine cross-talk between blastocyst and endometrial epithelium during embryonic implantation.
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Ma, Xiao, Jing Wang, Likai Wang, Laiqing Yan, Yunjie Liu, Wenkui Ma, Pengyun Ji, Lu Zhang, and Guoshi Liu. "The Uterine Melatonergic Systems of AANAT and Melatonin Membrane Receptor 2 (MT2) Are Essential for Endometrial Receptivity and Early Implantation in Mice." International Journal of Molecular Sciences 24, no. 8 (April 12, 2023): 7127. http://dx.doi.org/10.3390/ijms24087127.
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In the current study, using Aanat and Mt2 KO mice, we observed that the preservation of the melatonergic system is essential for successful early pregnancy in mice. We identified that aralkylamine N-acetyltransferase (AANAT), melatonin receptor 1A (MT1), and melatonin receptor 1B (MT2) were all expressed in the uterus. Due to the relatively weak expression of MT1 compared to AANAT and MT2, this study focused on AANAT and MT2. Aanat and Mt2 KO significantly reduced the early implantation sites and the abnormal morphology of the endometrium of the uterus. Mechanistical analysis indicated that the melatonergic system is the key player in the induction of the normal nidatory estrogen (E2) response for endometrial receptivity and functions by activating the STAT signaling pathway. Its deficiency impaired the interactions between the endometrium, the placenta, and the embryo. The reduction in melatonin production caused by Aanat KO and the impairment of signal transduction caused by Mt2 KO reduced the uterine MMP-2 and MMP-9 activity, resulting in a hyperproliferative endometrial epithelium. In addition, melatonergic system deficiency also increased the local immunoinflammatory reaction with elevated local proinflammatory cytokines leading to early abortion in the Mt2 KO mice compared to the WT mice. We believe that the novel data obtained from the mice might apply to other animals including humans. Further investigation into the interaction between the melatonergic system and reproductive effects in different species would be worthwhile.
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Soczewski, Elizabeth, Esteban Grasso, Lucila Gallino, Vanesa Hauk, Laura Fernández, Soledad Gori, Daniel Paparini, Claudia Perez Leirós, and Rosanna Ramhorst. "Immunoregulation of the decidualization program: focus on the endoplasmic reticulum stress." Reproduction 159, no. 4 (April 2020): R203—R211. http://dx.doi.org/10.1530/rep-19-0391.
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Decidualization denotes the reprogramming of endometrial stromal cells that includes the secretion of different mediators like cytokines, chemokines, and the selective recruitment of immune cells. This physiological process involves changes in the secretome of the endometrial stromal cells leading to the production of immunomodulatory factors. The increased amount of protein secretion is associated with a physiological endoplasmic reticulum (ER) stress and the resulting unfolded protein response (UPR), allowing the expansion of ER and the machinery to assist the protein folding. Notably, the signaling pathways involved in the ER stress and the UPR are interconnected with the onset of a sterile inflammatory response, as well as with angiogenesis. Both of these processes have a key role in decidualization and placentation, therefore, alterations in them could lead to pregnancy complications. In this review, we will discuss how the induction of ER stress and the UPR processes that accompanies the decidualization are associated with embryo implantation and whether they might condition pregnancy outcome. The ER stress activates/triggers sensing proteins which, among others, induces kinase/RNAse-TXNIP expression, activating the NLRP3 inflammasome. This multiprotein system allows caspase-1 activation, which catalyzes the cleavage of the inactive IL-1β proform toward the mature secretory form, with pro-implantatory effects. However, the sterile inflammatory response should be later controlled in favor of a tolerogenic microenvironment to sustain pregnancy. In accordance, alterations of the ER stress and UPR processes can be reflected in recurrent implantation failures (RIF), recurrent pregnancy loss (RPL), or complications associated with deficient placentation, such as preeclampsia (PE).
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Salehi, Mohammad, Delsuz Rezaee, Mojgan Bandehpour, Bahram Kazemi, Saiyad Bastaminejad, and Sajad Najafi. "Cytokine changes and embryo attachment in mouse endometrial cells following treated with peripheral blood mononuclear cells (PBMCs) expressing ectopic hCG, and hCG–activated PBMCs." Asian Pacific Journal of Reproduction 12, no. 2 (2023): 90. http://dx.doi.org/10.4103/2305-0500.372380.
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Gopchuk, О. М., and Р. V. Samaniv. "Problems of the thin endometrium. New possibilities of FDE-5 inhibitors." Reproductive health of woman, no. 2 (April 29, 2022): 47–52. http://dx.doi.org/10.30841/2708-8731.2.2022.261807.
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The article is devoted to a review of the literature about the thin endometrium and its correction today. The problem of thin endometrium is very significant in cases of unsuccessful embryo implantation. There is no generally accepted approach to the definition of “thin endometrium” and ways of its correction in the literature. Phosphodiesterase type 5 (PDE5) inhibitors are considered to play a role in increasing endometrial thickness and improving pregnancy outcomes. Their action consists of various mechanisms, in particular, such as the induction of vasodilating effect through the effect on signaling to vascular smooth muscle, through the regulation of cell proliferation and induction of angiogenesis by increasing the expression of tumor suppressor factor (p53) and vascular endothelial growth factor A, the inhibition of inflammation by reducing the regulation of proinflammatory cytokines. Although PDE5 inhibitors increase the endometrial thickness through the various mechanisms, especially in women with thin endometrium, it does not necessarily mean that they have a positive effect in all clinical situations. Meanwhile, the successful outcome may be affected by the time of use of the drug, the type of infertility treatment, the main diseases such as pelvic disorders and inflammation. Therefore, there are ambiguous issues that need further research in this problem. Oral PDE5 inhibitors are also used as first-line therapy for the treatment of erectile dysfunction (ED), they have proven effectiveness, tolerability, action and couple satisfaction. Avanafil is the only selective inhibitor of the PDE5 isoenzyme with a low frequency of side effects compared to other drugs in this group. The high tolerability of these drugs has made them an attractive tool for the study of further physiological functions outside the ED with benefits for many non-sexual consequences.
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Swanson, Rebecca M., Riley D. Messman, and Caleb O. Lemley. "72 Seminal Plasma Uterine Priming Reduces Offspring Growth and Alters Uterine Artery Indices of Vascular Resistance in Embryo-Recipient Beef Cows." Journal of Animal Science 101, Supplement_1 (May 1, 2023): 59–60. http://dx.doi.org/10.1093/jas/skad068.070.
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Abstract Uterine priming with seminal plasma has been shown to alter endometrial gene expression as well as uterine cytokines and chemokines. However, the effects of seminal plasma uterine priming on uterine blood flow, fetal and postnatal offspring growth performance have yet to be elucidated. Therefore, we investigated the effects of pooled seminal plasma uterine priming at estrus on embryo crown-rump length, uterine blood flow, and birth weights. Commercial cows (n = 65) were synchronized, evaluated for standing estrus (day 0), and randomly assigned to treatment groups: seminal plasma or control. Seminal plasma treated cows (n = 27) received 0.5 mL of pooled seminal plasma from commercial bulls mismatched from embryo sire placed in their uterine body via artificial insemination rod2 hours after estrus detection (day 0). Control cows (n = 27) were passed through the chute without receiving treatment. On day 7, cows underwent non-surgical embryo transfer and were confirmed pregnant on day 35 via ultrasonography. Final treatment numbers were n = 9 seminal plasma and n = 7 control. On days 35, 40, and 45 embryo crown-rump length was measured via transrectal ultrasonography. On days 140, 180, 200 and 220, uterine artery hemodynamics were measured via Doppler ultrasonography. Birth weights were collected within 24 hours of birth. Data collected over time were analyzed using repeated measures of ANOVA with fixed effects of treatment, day, and their respective interaction. Birth weights and gestation length were analyzed using ANOVA. Embryo sire and dam, side of pregnancy, and fetal sex were included as covariates if P < 0.10. Covariance structure was selected based on lowest AIC and BIC. Embryo crown-rump length was decreased (P = 0.0483) among seminal plasma treated cows compared with controls. Embryo crown-rump length increased (P < 0.0001) by day. Total uterine blood flow increased (P < 0.0001) as gestation proceeded. Ipsilateral resistance index was increased (P = 0.0431) among seminal plasma treated cows compared with controls. Ipsilateral resistance index was increased (P = 0.0107) on day 180 of gestation compared with days 200 and 220 of gestation. Ipsilateral pulsatility index was decreased (P < 0.0001) on day 220 of gestation compared with days 140 and 180 of gestation. Contralateral blood flow was decreased (P = 0.0037) on day 140 of gestation compared with days 180, 200, and 220 of gestation. There were no differences in contralateral uterine artery blood flow, resistance index, or pulsatility index, or gestation length between treatment groups. Birth weights were decreased (P = 0.0102) among calves from seminal plasma treated cows compared with calves from control cows. In summary, seminal plasma uterine priming reduced offspring growth while increasing uterine artery resistance index, which indicates uterine vascular bed anomalies that persisted into the third trimester of pregnancy.
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Kravtsova, Elena I., Natalia V. Kolesnikova, Irina N. Lukoshkina, Kristina V. Uryupina, and Veronika A. Avakimyan. "Immunological and immunohistochemical features of endometrial implantation factor in healthy patients of late reproductive age." RUDN Journal of Medicine 27, no. 1 (March 27, 2023): 46–56. http://dx.doi.org/10.22363/2313-0245-2023-27-1-46-56.
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Аbstract. Relevance. The number of women of older reproductive age is steadily increasing, and repeated failures of Assisted Reproductive Technologies programs during the transfer of high-quality embryos indicate the possibility of disruption of embryo implantation processes associated with impaired receptivity and functionality of the endometrium. Morphological, immunological and immunohistochemical changes in the endometrium associated with age factor may be decisive for the formation of the «implantation window» and correction of these changes and may improve the outcomes of Assisted Reproductive Technologies for a cohort of patients of older reproductive age. The aim of the study - to expand the pathogenetic understanding of the violation of the implantation ability of the endometrium in healthy patients of older reproductive age. Materials and Methods. A prospective sample study of 46 patients (group 1), aged 38 to 45 years with an officially registered diagnosis of infertility lasting no more than 4 years, with a successful gynecological and obstetric history, who were about to have their first IVF attempt, was conducted. The patients were examined according to Order № 803n of the Ministry of Health of the Russian Federation. Additionally, the level of peripheral blood melatonin, the determination of progesterone, estrogen, HLA-DR (MHC II), CD56 (NK cells), CD138, leukemia inhibiting factor receptors in the endometrium were studied. Concentrations of IL-6, IL-10, TGFß, and VGEF were determined in the cervical secretion, with the calculation of the pro-inflammatory index, as the ratio of IL-6/IL-10 cu and the ratio of TGFß1/VEGF. Statistical data processing was performed using the Statistica 10.0 application software package (StatSoft, Inc., USA). Results and Discussion. In the group of healthy patients of older reproductive age, there is an imbalance of steroid receptors and secretory transformation of the endometrium against the background of relative hyperestrogenism, with a decrease in the reception of own hormones in the endometrium. A decrease in melatonin signals a disorder of pineal and pituitary control over ovarian cycling. There is a decrease in the expression of leukemia inhibiting factor. Signs of inactive chronic endometritis with an autoimmune component are monitored, confirmed by a pro-inflammatory cytokine balance. The predominance of fibrosis processes over angiogenesis processes is confirmed by an increase in the ratio of TGFß1/VEGF and highly resistant blood flow in the uterine arteries. Conclusion. Standard pre-gravidar preparation cannot compensate for all factors that violate the implantation potential of the endometrium in this cohort of patients and requires the development of new complex techniques that directly affect the diversity of all factors that ensure the natural extinction of reproductive potential in order to increase the effectiveness of Assisted Reproductive Technologies programs.
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Лучко, Е. В., and В. А. Басинский. "The Role of CD8+T-Lymphocytes of the Decidual Tissue in the Genesis of Early Miscarriage." Репродуктивное здоровье. Восточная Европа, no. 3 (November 4, 2021): 296–304. http://dx.doi.org/10.34883/pi.2021.11.3.003.
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Введение. Несмотря на достижения современной акушерско-гинекологической службы, одной из самых частых причин осложнений беременности в 1-м триместре остается ее преждевременное прерывание. По данным Всемирной организации здравоохранения, частота невынашивания беременности составляет от 10 до 20% всех клинически диагностированных беременностей. Многими авторами отмечено, что важная роль в благополучном течении беременности принадлежит децидуальной ткани эндометрия, которая принимает участие не только в обеспечении питания эмбриона, но и в предотвращении его иммунологического отторжения. В децидуальной оболочке при беременности наблюдается концентрация CD8+Тлимфоцитов, которые являются важной частью местных иммунных реакций. Выяснение механизмов, с помощью которых CD8+T-лимфоциты регулируют конкурирующие процессы толерантности к плоду и защиты от вторжения патогенов, имеет решающее значение для понимания протекания беременности на ранних сроках. Характер активности CD8+Т-лимфоцитов и продукция ими цитокинов в децидуальной оболочке также определяют успешность инвазии клеток трофобласта и последующее течение беременности. Цель. Оценка роли CD8+Т-лимфоцитов децидуальной ткани в развитии раннего невынашивания беременности. Материалы и методы. Проведен клинико-морфологический анализ 102 случаев невынашивания беременности, выявленных у женщин Гродненской области. Иммуногистохимическое исследование выполнили с использованием первичных антител к рецепторам СD8 в разведении 1:100 (clone C8/144B, Dako). Экспрессия маркера оценивалась количественно при помощи компьютерной программы Aperio Image Scope_v9.1.19.1567. Результаты. Уровень экспрессии CD8 в децидуальной ткани пациенток с невынашиванием беременности значимо ниже, чем при физиологической беременности (р<0,00008). Заключение. При уровне позитивности экспрессии CD8 в децидуальной ткани меньше либо равном 0,173 можно с чувствительностью 100% и специфичностью 95,8% прогнозировать невынашивание беременности. Introduction. Despite the achievements of the modern obstetric and gynecological service, the most common cause of pregnancy complications in the 1st trimester is its premature termination. According to the World Health Organization, miscarriage rates range from 10 to 20% of all clinically diagnosed pregnancies. Many authors noted that an important role in the successful course of pregnancy belongs to the decidual endometrial tissue, which is involved not only in providing nutrition to the embryo, but also in preventing immunological rejection. In the decidua during pregnancy there is a concentration of CD8+T-lymphocytes, which are an important part of local immune responses. Elucidating the mechanisms by which CD8+T-lymphocytes regulate the competing processes of fetal tolerance and defense against pathogen invasion is critical to understanding early pregnancy. The nature of the activity of CD8+T-lymphocytes and their production of cytokines in the decidua determines the success of the invasion of trophoblast cells and the subsequent course of pregnancy. Purpose. Assessment of the role of CD8+T-lymphocytes of decidual tissue in the development of early miscarriage. Materials and methods. A clinical and morphological analysis of 102 cases of miscarriage identified in women in the Grodno region was carried out. An immunohistochemical study was performed using primary antibodies to CD8 receptors at a dilution of 1: 100 (clone C8/144B, Dako). Marker expression was quantified using the Aperio Image Scope_v9.1.19.1567 computer program. Results.The level of CD8 expression in the decidual tissue of patients with miscarriage is significantly lower than during physiological pregnancy (p<0.00008). Conclusion. If the level of positivity of CD8 expression in decidual tissue is less than or equal to 0.173, it is possible to predict miscarriage with a sensitivity of 100% and a specificity of 95.8%.
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Cambra, Josep M., Amaia Jauregi-Miguel, Manuel Alvarez-Rodriguez, Inmaculada Parrilla, Maria A. Gil, Emilio A. Martinez, Cristina Cuello, Heriberto Rodriguez-Martinez, and Cristina A. Martinez. "Allogeneic Embryos Disregulate Leukemia Inhibitory Factor (LIF) and Its Receptor in the Porcine Endometrium During Implantation." Frontiers in Veterinary Science 7 (November 24, 2020). http://dx.doi.org/10.3389/fvets.2020.611598.
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Despite its advantages for pig breeding, embryo transfer (ET) has a major handicap: high embryo mortality during the pre- and implantation period, probably caused by divergent phenomena of tolerance between the immunologically unrelated (i.e., allogeneic) embryos and the recipient sow. Thus, to reach a similar maternal tolerance as in conventional breeding by artificial insemination (AI) would be the key to ET-success. For this reason, we studied the expression of the leukemia inhibitory factor (LIF) cytokine and its receptor in the pig endometrium during the implantation period (days 18 and 24) in sows subjected to ET (AL group) vs. post-cervical-AI controls (Hemi-AL group). Quantification of expression was performed at both mRNA (rt-qPCR) and protein (WB) levels. The expression of endometrial LIF on day 24 was considerably lower in ET than in AI pregnancies. Correlations between endometrial mRNA levels of LIF and LIF-R showed that, contrary to early AI-pregnancies, ET-pregnancies lack an inverse relation between cytokine and receptor levels. In conclusion, ET-pregnancies lack sufficient endometrial levels of LIF to develop adequate immunotolerance mechanisms to prevent the rejection of allogeneic ET-embryos.
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Liu, J., Y. Lin, X. Sun, and D. Zhang. "P-345 GM-CSF drives endometrial repair via p-STAT3 mediating angiogenesis." Human Reproduction 38, Supplement_1 (June 1, 2023). http://dx.doi.org/10.1093/humrep/dead093.703.
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Abstract Study question Does granulocyte macrophage colony-stimulating factor (GM-CSF) play a role in endometrial angiogenesis and can it be used as a new application for treating endometrial regeneration? Summary answer GM-CSF improves endometrial repair via promoting endometrial angiogenesis and may provide a novel insight and therapeutics for endometrial injury. What is known already GM-CSF is a cytokine normally expressed in the female reproductive tract and plays key roles in embryo implantation and subsequent development. Our previous study found that intraperitoneally （i.p.）injection of GM-CSF can significantly improve endometrial repair by promoting endometrial glandular cells proliferation and stromal cells migration, increasing the thickness of endometrium and embryo implantation in mice. However, whether GM-CSF is involved in endometrial angiogenesis is unknown. Study design, size, duration To observe whether angiogenesis is promoted by GM-CSF, the expression of angiogenic factor CD31 was evaluated after injection of GM-CSF into endometrial injured mice model. The effect of GM-CSF on vascular g regeneration was also explored by zebrafish embryo model of intersegmental vascular injury. Human umbilical vein vascular endothelial cells (HUVECs) were cultured in vitro, and the role of GM-CSF on HUVECs were examined through EdU, Tube formation, Scratch repair and Transwell assays. Participants/materials, setting, methods 20μl 90% ethanol was used to establish endometrial injured mice model. After modeling, compared with i.p. injection of GM-CSF and saline, observing whether GM-CSF had the effect of repairing angiogenesis of injured endometrium, by evaluating expression of CD31. Real-time PCR, Western Blot were used to verify differentially expressed levels of mRNA and protein. Western Blot was used to confirm protein location. ChIP was used to analyze stat3 regulation of GM-CSF. Main results and the role of chance GM-CSF promoted expression of angiogenic factor CD31 in the mice model of endometrial injury. GM-CSF can repair and regenerate the zebrafish embryo model of intersegmental vascular injury caused by Sorafenib. GM-CSF can promote angiogenesis by HUVECs proliferation and migration, and significantly increase the formation of vascular-like network structures In GM-CSF treatment group, the mRNA expression of VEGF, MMP2, Ang1, Ang2 and Tie2 mRNA in HUVECs cells increased significantly; GM-CSF can activate the phosphorylation expression levels of p-FAK, p-Src, p-ERK 1/2, p-STAT3, p-p38 MAPK, pc-Jun, p-CREB, p-Akt, and p-eNOS. And it can increase the expression of downstream VEGF and MMP2 proteins. GM-CSF treatment for 30 min can promote phosphorylation and translocation of STAT3 from cytoplasm to nucleus, thereby regulating the expression of VEGF and MMP2 downstream. While FAK inhibitors (PF573228) and STAT3 knockdown can abrogate GM-CSF effect on HUVECs. Limitations, reasons for caution The results at the cellular and animal level can’t be completely mimic human endometrial injury. In future, well-designed clinical trials are needed to investigate the efficacy and safety of GM-CSF for treatment of human endometrial vascular injury. Wider implications of the findings GM-CSF can promote the vascular regeneration in mice model of endometrial injury through p-STAT3. Our findings provide new ideas for clinical treatment of endometrial injury. Trial registration number Not applicable
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Corachán, A., A. B. Albert, E. Juárez-Barber, C. Vidal, J. Giles, D. Alecsandru, M. Cozzolino, A. Pellicer, and H. Ferrero. "P-370 Impaired endometrial decidualization with a hyperinflammation environment is involved in poor reproductive outcomes in adenomyosis patients." Human Reproduction 38, Supplement_1 (June 1, 2023). http://dx.doi.org/10.1093/humrep/dead093.727.
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Abstract Study question Do patients with adenomyosis have an impaired inflammatory state of the endometrium that could affect implantation and pregnancy? Summary answer Adenomyosis patients show increased proinflammatory cytokines expression and deregulated decidualization markers expression in eutopic endometrium which could lead to altered endometrial receptivity and impaired implantation. What is known already Adenomyosis is an estrogen-dependent chronic inflammatory condition, characterized by the presence of endometrial glands and stroma within the myometrium. Adenomyosis patients present altered decidualization and defective embryo-endometrium communication, resulting in implantation failure, miscarriage, and other fertility-related disorders. Although the underlying mechanisms of this infertility remain unknown, it is known that a favorable immune and inflammatory uterine environment is necessary for developmental pregnancy. It has been proposed that a uterine hyperinflammatory state could be involved in adenomyosis-related infertility. For this reason, we aim to evaluate the inflammatory and endometrial receptivity status during implantation in eutopic endometrium from adenomyosis patients. Study design, size, duration Sixteen endometrial samples were collected from infertile patients with and without adenomyosis undergoing hormonal replacement therapy before in vitro fertilization (IVF) at IVIRMA Valencia between January to December 2022. Participants/materials, setting, methods Eutopic endometrial samples were obtained at secretory phase (LH + 7) from patients diagnosed with adenomyosis (n = 8) by ultrasound or hysteroscopy and patients without gynecological diseases (control, n = 8). Total RNA extraction was performed to later determine the gene expression of the decidualization-related genes Prolactin (PRL), SPP1 and PAEP by qRT-PCR. In addition, proteins were extracted from eutopic endometrium using a lysis buffer and the relative expression levels of human cytokines were measured by Human Cytokine Array (Raybiotech). Main results and the role of chance Gene expression evaluation in endometrium from adenomyosis patients compared to control showed a significant downregulation of the key marker of decidualization PRL (fold change [fc] = 0.56, p = 0.0047) and a significant upregulation of SPP1 (fc = 1.75, p = 0.009) and PAEP (fc = 1.56, p = 0.0192), both involved in endometrial receptivity and in immune regulation. Regarding cytokines expression, array results showed upregulation of different interleukins (IL) involved in the mediation of the immune and inflammatory response previously described in adenomyosis. Specifically, IL1ß (12±19.63 vs. 1.37±2.77, p = 0.009) that regulates several inflammatory responses, including cell proliferation, differentiation, and apoptosis; and IL6 (584.7±121.8 vs. 488.4±57.44, p = 0.06) that acts on the inflammation and maturation of B cells, contributing to the development of autoimmune diseases. Similarly, cytokines related to the promotion of inflammation and cellular proliferation in endometriosis, IL17a (173.6±44.75 vs. 102.10±71.85, p = 0.04) and TNFβ (430.9±139.6 vs. 315.3±37.09, p = 0.04), were also upregulated in adenomyosis compared to control. There were also other cytokines upregulated with diverse functions like an anti-inflammation response, growth factors or immune modulation: IL5 (308.1±88.77 vs. 202.6±45.72, p = 0.01), IL2 (341.4±60.38 vs. 270.8±35.13, p = 0.014), TGFα (215.3±27.04 vs. 117.8±36.67, p = 0.002), IL31 (77.74±40.57 vs. 14±15.96, p = 0.0012), IL7 (739.1±147.1 vs. 511.8±103.7, p = 0.003) and IL15 (301.9±95.73 vs. 209.8±50.62, p = 0.03). Limitations, reasons for caution Our findings are limited by the relatively small sample size and inherent biological variability of human samples. Wider implications of the findings Adenomyosis patients showed impaired decidualization and a hyperinflammatory endometrial environment that could be affecting the endometrial receptivity and consequently, the embryo implantation. These findings open insight to further investigations to study the mechanism by which exaggerated inflammation affects fertility in the context of adenomyosis to define new management approaches. Trial registration number Not applicable
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Zhao, Yuhao, Dongmei He, Hong Zeng, Jiefeng Luo, Shuang Yang, Jingjing Chen, Raed K. Abdullah, and Nenghui Liu. "Expression and significance of miR-30d-5p and SOCS1 in patients with recurrent implantation failure during implantation window." Reproductive Biology and Endocrinology 19, no. 1 (September 8, 2021). http://dx.doi.org/10.1186/s12958-021-00820-2.
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Abstract Background Poor endometrial receptivity is a major factor that leads to recurrent implantation failure. However, the traditional method cannot accurately evaluate endometrial receptivity. Various studies have indicated that microRNAs (miRNAs) are involved in multiple processes of embryo implantation, but the role of miRNAs in endometrial receptivity in patients with recurrent implantation failure (RIF) remains elusive. In the present study, we investigated the presence of pinopodes and the roles of miR-30d-5p, suppressor of cytokine signalling 1 (SOCS1) and the leukaemia inhibitory factor (LIF) pathway in women with a history of RIF during the implantation window. Methods Endometrial tissue samples were collected between January 2018 to June 2019 from two groups of women who underwent in vitro fertilisation and embryo transfer (IVF-ET) or frozen ET. The RIF group included 20 women who underwent ≥ 3 ETs, including a total of ≥ 4 good-quality embryos, without pregnancy, whereas the control group included 10 women who had given birth at least once in the past year. An endometrial biopsy was performed during the implantation window (LH + 7). The development of pinopodes in the endometrial biopsy samples from all groups was evaluated using scanning electron microscopy (SEM). Quantitative reverse transcription-polymerase chain reaction and western blotting were used to investigate the expression levels of miR-30d-5p, SOCS1, and the LIF pathway. Results The presence of developed pinopodes decreased in patients with RIF on LH + 7. The expression level of miR-30d-5p decreased in the endometria during the implantation window of patients with RIF, whereas the mRNA and protein levels of SOCS1 were significantly higher in the RIF group than in the control group. Furthermore, a negative correlation was observed between the expression of miR-30d-5p and SOCS1 (r2 = 0.8362). In addition, a significant decrease in LIF and p-STAT3 expression was observed during the implantation window in patients with RIF. Conclusions MiR-30d-5p and SOCS1 may be potential biomarkers for endometrial receptivity. Changes in pinopode development and abnormal expression of miR-30d-5p, SOCS1 and LIF pathway in the endometrium could be the reasons for implantation failure.
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Namiki, Takafumi, Jumpei Terakawa, Harumi Karakama, Michiko Noguchi, Hironobu Murakami, Yoshinori Hasegawa, Osamu Ohara, Takiko Daikoku, Junya Ito, and Naomi Kashiwazaki. "Uterine epithelial Gp130 orchestrates hormone response and epithelial remodeling for successful embryo attachment in mice." Scientific Reports 13, no. 1 (January 16, 2023). http://dx.doi.org/10.1038/s41598-023-27859-y.
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AbstractLeukemia inhibitory factor (LIF) receptor, an interleukin 6 cytokine family signal transducer (Il6st, also known as Gp130) that is expressed in the uterine epithelium and stroma, has been recognized to play an essential role in embryo implantation. However, the molecular mechanism underlying Gp130-mediated LIF signaling in the uterine epithelium during embryo implantation has not been elucidated. In this study, we generated mice with uterine epithelium specific deletion of Gp130 (Gp130 ecKO). Gp130 ecKO females were infertile due to the failure of embryo attachment and decidualization. Histomorphological observation revealed that the endometrial shape and embryo position from Gp130 ecKO were comparable to those of the control, and uterine epithelial cell proliferation, whose attenuation is essential for embryo implantation, was controlled in Gp130 ecKO. Comprehensive gene expression analysis using RNA-seq indicates that epithelial Gp130 regulates the expression of estrogen- and progesterone-responsive genes in conjunction with immune response during embryo implantation. We also found that an epithelial remodeling factor, snail family transcriptional repressor 1 (Snai1), was markedly reduced in the pre-implantation uterus from Gp130 ecKO. These results suggest that not only the suppression of uterine epithelial cell proliferation, but also Gp130-mediated epithelial remodeling is required for successful implantation in mice.
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Li, Haixia, Ning Sun, Yaqiao Zhu, Wei Wang, Meihong Cai, Xiaohuan Luo, Wei Xia, and Song Quan. "Growth hormone inhibits the JAK/STAT3 pathway by regulating SOCS1 in endometrial cells <em>in vitro</em>: a clue to enhance endometrial receptivity in recurrent implantation failure." European Journal of Histochemistry 67, no. 1 (December 22, 2022). http://dx.doi.org/10.4081/ejh.2023.3580.
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Recurrent implantation failure (RIF) is defined as failure to achieve clinical pregnancy after at least 3 transfers of good-quality embryos by natural or artificial means. RIF is often a complex problem with a wide variety of etiologies and mechanisms as well as treatment options. In this study, using immunohistochemistry and Western blot, we demonstrated that the expression of leukemia inhibitory factor (LIF), Janus kinase 1 (JAK1), and signal transducer and activator of transcription 3 (STAT3) was increased, while that of suppressor of cytokine signaling 1 (SOCS1) was decreased in RIF patients. Growth hormone (GH) administration proved to have positive effects on embryo implantation in RIF patients, but the action mechanism of GH has not been elucidated yet. To this aim, we studied the effects of GH on the proliferation in vitro of endometrial adenocarcinoma Ishikawa cells. GH stimulated the expression of LIF and SOCS1, and through SOCS1 inhibits the expression of phosphorylated STAT3, and finally inhibits the occurrence of RIF. Excessive phosphorylation of STAT can lead to decreased endometrial receptivity and abnormal embryo implantation. We also examined the effects of LIF overexpression and an LIF inhibitor (EC330) on the JAK/STAT pathway. LIF promoted cell proliferation, and the up-regulation of LIF increased the expression of SOCS1 and JAK1/STAT3 pathway-related genes in Ishikawa cells. As GH can inhibit the JAK1/STAT3 pathway through LIF, we hypothesize that upregulating SOCS1 may be a potential approach to treat RIF at the molecular level. GH can inhibit the JAK1/STAT3 pathway through LIF, up-regulating SOCS1 to treat RIF at the molecular level.
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Niu, Zhihong, Mingjuan Zhou, Lan Xia, Shen Zhao, and Aijun Zhang. "Uterine cytokine profiles after low-molecular-weight heparin administration are associated with pregnancy outcomes of patients with repeated implantation failure." Frontiers in Endocrinology 13 (December 8, 2022). http://dx.doi.org/10.3389/fendo.2022.1008923.
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IntroductionLow molecular-weight heparin (LMWH) plays a role in repeated implantation failure (RIF), but outcomes are controversial. LMWH can potentially modulate local immune responses associated with the establishment and maintenance of pregnancy. The study aimed to explore the effects of LWMH in uterine inflammatory cytokine profiles and pregnancy outcomes of patients with repeated implantation failure (RIF) but without thrombophilia.MethodsWe compared clinical characteristics and reproductive outcomes among 326 patients with RIF, but not thrombophilia, undergoing frozen embryo transfer (FET) cycle with or without LMWH treatment. Endometrium secretions were aspirated from both groups after 3 days of progesterone administration before and after LMWH treatment. Cytokine mRNA expression was analyzed in primary endometrial cells in vitro.ResultsThe clinical and ongoing pregnancy rates did not significantly differ between the groups (31.5% vs. 24.4%, p = 0.15; 29.6% vs. 20.7%, p = 0.06). Concentrations of IL-6 and granulocyte-colony stimulating factor (G-CSF) in uterine secretions were significantly increased in the LWMH group, regardless of pregnancy outcomes (P < 0.05). And, in all patients treated with LWMH, those of secreted IL-6, IL-15 and G-CSF were significantly increased in pregnant group (P < 0.05). The expression of mRNA for G-CSF and IL-6 was significantly increased in human endometrial stromal cells in vitro (P < 0.05) after stimulation with LWMH (10 IU/mL).ConclusionsUterine cytokine profiles after LMWH administration are associated with pregnancy outcomes and LMWH may be beneficial for patients with three implantation failures who do not have coagulation disorders.
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Chang, Zhuo, Hai-xue Kuang, Xueming Zhou, Hui Zhu, Yang Zhang, Yin Fu, Qiang Fu, et al. "Temporal changes in cyclinD-CDK4/CDK6 and cyclinE-CDK2 pathways: implications for the mechanism of deficient decidualization in an immune-based mouse model of unexplained recurrent spontaneous abortion." Molecular Medicine 28, no. 1 (September 1, 2022). http://dx.doi.org/10.1186/s10020-022-00523-3.
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Abstract Background Deficient endometrial decidualization has been associated with URSA. However, the underlying mechanism is poorly understood. This study aimed to investigate the temporal cytokine changes and the involvement of CyclinD-CDK4/6 and CyclinE-CDK2 pathways in the regulation of the G1 phase of the cell cycle during decidualization in a murine model of URSA. Methods Serum and decidual tissues of mice were collected from GD4 to GD8. The embryo resorption and abortion rates were observed on GD8 and the decidual tissue status was assessed. In addition, PRL, Cyclin D, CDK6, CDK4, Cyclin E, CDK2 expression in mice were measured. Results URSA mice showed high embryo resorption rate and PRL, Cyclin D, Cyclin E CDK2, CDK4, CDK6 down-regulation during decidualization. The hyperactivated Cyclin D-CDK4/CDK6 and cyclin E/CDK2 pathways inhibit the decidualization process and leading to deficient decidualization. Conclusion Insufficient decidualization is an important mechanism of URSA. which is related to the decrease of Cyclin D、Cyclin E、 CDK2、CDK4 and CDK6 in decidualization process of URSA.
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Ma, Zhi, Huixia Yang, Mirjana Kessler, Markus Sperandio, Sven Mahner, Udo Jeschke, and Viktoria von Schönfeldt. "Targeting Aberrantly Elevated Sialyl Lewis A as a Potential Therapy for Impaired Endometrial Selection Ability in Unexplained Recurrent Miscarriage." Frontiers in Immunology 13 (June 28, 2022). http://dx.doi.org/10.3389/fimmu.2022.919193.
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BackgroundCarbohydrate Lewis antigens including sialyl Lewis A (sLeA), sialyl Lewis X (sLeX), Lewis X (LeX), and Lewis Y (LeY) are the commonest cell surface glycoconjugates that play pivotal roles in multiple biological processes, including cell adhesion and cell communication events during embryogenesis. SLeX, LeY, and associated glycosyltransferases ST3GAL3 and FUT4 have been reported to be involved in human embryo implantation. While the expression pattern of Lewis antigens in the decidua of unexplained recurrent miscarriage (uRM) patients remains unclear.MethodsParaffin-embedded placental tissue slides collected from patients experiencing early miscarriages (6–12 weeks) were analyzed using immunohistochemical (IHC) and immunofluorescent (IF) staining. An in vitro assay was developed using endometrial cell line RL95-2 and trophoblast cell line HTR-8/SVneo. Modulatory effect of potential glycosyltransferase on Lewis antigens expression was investigated by target-specific small interfering RNA (siRNA) knockdown in RL95-2 cells. HTR-8/SVneo cells spheroids adhesion assay was applied to investigate the intrinsic role of Lewis antigens in the abnormal implantation process of uRM. The expression of Lewis antigens in RL95-2 cells in response to the treatment with pro-implantation cytokine IL-1β was further measured by flow cytometry and immunocytochemical (ICC) staining.ResultsIHC staining revealed that Lewis antigens are mainly expressed in the luminal and glandular epithelium, IF staining further indicated the cellular localization at the apical membrane of the epithelial cells. FUTs, ST3GALs, and NEU1 located in both stromal and epithelial cells. We have found that the expression of sLeA, LeX, FUT3/4, and ST3GAL3/4 are significantly upregulated in the RM group, while FUT1 is downregulated. SLeX, LeY, ST3GAL6, and NEU1 showed no significant differences between groups. FUT3 knockdown in RL95-2 cells significantly decreased the expression of sLeA and the spheroids adhesion to endometrial monolayer. Anti-sLeA antibody can remarkably suppress both the basal and IL-1β induced adhesion of HTR-8/SVneo spheroids to RL95-2 cells monolayer. While further flow cytometry and ICC detection indicated that the treatment of RL95-2 cells with IL-1β significantly increases the surface expression of LeX, but not sLeA.ConclusionsSLeA, LeX, and pertinent glycosyltransferase genes FUT1/3/4 and ST3GAL3/4 are notably dysregulated in the decidua of uRM patients. FUT3 accounts for the synthesis of sLeA in RL95-2 cells and affects the endometrial receptivity. Targeting aberrantly elevated sLeA may be a potential therapy for the inappropriate implantation in uRM.
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Jiang, Y., M. Varshney, A. Reyes Palomares, J. Inzunza, and K. A. Rodriguez-Wallberg. "P-805 Gene expression of human endometrial organoids hormonally treated in vitro for 28 days." Human Reproduction 38, Supplement_1 (June 1, 2023). http://dx.doi.org/10.1093/humrep/dead093.217.
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Abstract Study question Does gene expression of human endometrial organoids (EO) mimic the in vivo response to a 28- days substitutive hormonal treatment? Summary answer Gene expression profile of human EO exposed to 28-day hormone treatment showed correspondence with the phases of the menstrual cycle in vivo. What is known already The recent development of human EO demonstrated their translational potential for reproductive medicine. Current studies testing functional response to hormones of EO are based on short-term responsiveness to estrogen (E2), progesterone (P4) and differentiation factors up to 10 days. It is unknown how organoids can be used to faithfully reproduce and/or model a complete menstrual cycle of 28 days. High-throughput analyses on endometrium have identified specific markers available for characterizing differentiation and functional aspects related to secretory activity and receptivity to implantation. Study design, size, duration Experimental research was carried out including 4 endometrial biopsies donated by women with normal endometrium function, recruited at an academic center for assisted reproduction between 2022-06-15 to 2022-07-28. These endometrial biopsies were processed for organoid derivation and culture. The EO were hormonally treated in vitro and analyzed for gene expression. Participants/materials, setting, methods Human endometrial biopsies were enzymatically digested to isolate endometrial glands, embedded in matrigel and cultivated in a spinning bioreactor to achieve organoid formation. Thereafter EO were treated as following: 1) E2: (day 0–28); 2) E2 + P4: E2 (day 0–28), P4 (day 14–28); 3) E2 + P4 + dibutyryl cyclic Adenosine monophosphate (dbcAMP): E2 (day 0–28) + P4 (day 14–28) + dbcAMP (day 14–28) or 4) control group. Main results and the role of chance A total of 10 markers were selected for functional analysis and 3 showed a pattern of interest. The target gene expression included Forkhead box O1 (FOXO1), involved in regulating endometrium receptivity in human; progesterone associated endometrium protein (PAEP), a major protein in glandular endometrium secretions; and secreted phosphoprotein 1 (SPP1), an extracellular cytokine that increases in endometrium during the receptive phase. Gene expression of FOXO1, PAEP and SPP1 showed a significant increase in the organoids exposed to complete hormonal cycle, compared to controls. PAEP and SPP1 gene expression was lower up to day 21 but upregulated to 15-fold relative to non-treated group by day 28. This pattern recapitulates a similar response to the physiological conditions in vivo in the human endometrium. Although gene expression patterns followed similar trends, individual biopsies had slight variations in gene expression along 28-day hormone treatment. The 28 day-hormone treatment can stimulate EO for recapitulating histological and functional aspects. The dynamics resembled a timely correlation with gene expression changes accounting for some specific markers mostly involved in receptivity, and thus reinforcing the potential application of EO for further research purposes. Limitations, reasons for caution In vitro organoid culture conditions may have some influence over responsiveness and gene expression that requires further optimization to reproduce uterine environment in vitro and for other conditions related to infertility in a completely defined culture system. Wider implications of the findings Our findings enable the opportunity to expand experimental research over endometrial disorders affecting different stages of the menstrual cycle and also to improve research related to embryo-endometrium interactions. Trial registration number This research has been funded by grants from The Swedish Cancer Society, The Swedish Childhood Cancer Foundation, The Cancer Research Funds of Radiumhemmet, The Swedish Cancer Association BRO, the Stockholm County Council (CIMED) and Karolinska Institutet.
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Heusler, Martha, Rebekka Einenkel, Jens Ehrhardt, Damián Oscar Muzzio, and Marek Zygmunt. "Low Abundance Fusobacterium Nucleatum Supports Early Pregnancy Development – An In Vitro Study." Frontiers in Immunology 12 (August 31, 2021). http://dx.doi.org/10.3389/fimmu.2021.698045.
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Pregnancy success depends greatly on a balanced immune homeostasis. The detection of bacterial components in the upper reproductive tract in non-pregnant and pregnant women raised questions on its possible beneficial role in reproductive health. The local conditions that allow the presence of bacteria to harmonize with the establishment of pregnancy are still unknown. Among the described bacterial species in endometrial and placental samples, Fusobacterium nucleatum was found. It has been observed that F. nucleatum can induce tumorigenesis in colon carcinoma, a process that shares several features with embryo implantation. We propose that low concentrations of F. nucleatum may improve trophoblast function without exerting destructive responses. Inactivated F. nucleatum and E. coli were incubated with the trophoblastic cell lines HTR8/SVneo, BeWo, and JEG-3. Viability, proliferation, migratory capacity, invasiveness and the secretion of chemokines, other cytokines and matrix metalloproteinases were assessed. The presence of F. nucleatum significantly induced HTR8/SVneo invasion, accompanied by the secretion of soluble mediators (CXCL1, IL-6 and IL-8) and metalloproteinases (MMP-2 and MMP-9). However, as concentrations of F. nucleatum increased, these did not improve invasiveness, hindered migration, reduced cell viability and induced alterations in the cell cycle. Part of the F. nucleatum effects on cytokine release were reverted with the addition of a TLR4 blocking antibody. Other effects correlated with the level of expression of E-cadherin on the different cell lines tested. Low amounts of F. nucleatum promote invasion of HTR8/SVneo cells and induce the secretion of important mediators for pregnancy establishment. Some effects were independent of LPS and correlated with the expression of E-cadherin on trophoblasts.