A hypoxia-induced Rab pathway regulates embryo implantation by controlled trafficking of secretory granules
In many mammalian species, embryo implantation and processes of early pregnancy occur in a hypoxic environment. However, the mechanisms underlying maternal adaptation to hypoxia during early pregnancy remain unclear. This work has uncovered an important mechanism in mammalian reproduction and development by identifying maternal secretory granules that mediate molecular dialogue between the maternal tissue compartments during early pregnancy. This dialogue, which is the molecular basis of adaptation to hypoxia, is critical for embryo implantation and establishment of pregnancy.
N-glycosylation of uterine endometrium determines its receptivity.
Abstract Glycosylation alters the molecular and functional features of glycoproteins, which is closely related with many physiological processes and diseases. During "window of implantation", uterine endometrium transforms into a receptive status to accept the embryo, thereby establishing successful embryo implantation. In this article, we aimed at investigating the role of N-glycosylation, a major modification type of glycoproteins, in the process of endometrial receptivity establishment. Results found that human uterine endometrial tissues at mid-secretory phase exhibited Lectin PHA-E+L (recognizes the branched N-glycans) positive N-glycans as measured by the Lectin fluorescent staining analysis. By utilizing in vitro implantation model, we found that de-N-glycosylation of human endometrial Ishikawa and RL95-2 cells by tunicamycin (inhibitor of N-glycosylation) and peptide-N-glycosidase F (PNGase F) impaired their receptive ability to human trophoblastic JAR cells. Meanwhile, N-glycosylation of integrin αvβ3 and leukemia inhibitory factor receptor (LIFR) are found to play key roles in regulating the ECM-dependent FAK/Paxillin and LIF-induced STAT3 signaling pathways, respectively, thus affecting the receptive potentials of endometrial cells. Furthermore, in vivo experiments and primary mouse endometrial cells-embryos coculture model further verified that N-glycosylation of mouse endometrial cells contributed to the successful implantation. Our results provide new evidence to show that N-glycosylation of uterine endometrium is essential for maintaining the receptive functions, which gives a better understanding of the glycobiology of implantation. © 2019 Wiley Periodicals, Inc. KEYWORDS: N-glycosylation, LIFR; avβ3; embryo implantation; endometrial receptivity PMID: 31276203 DOI: 10.1002/jcp.29022
Morphological, Ultrastructural, and Molecular Aspects of In Vitro Mouse Embryo Implantation on Human Endometrial Mesenchymal Stromal Cells in The Presence of Steroid Hormones as An Implantation Model
Cell J. 2018 Oct;20(3):369-376. doi: 10.22074/cellj.2018.5221. Epub 2018 May 15.
Rahimipour M1, Salehnia M1, Jafarabadi M2.
OBJECTIVE: This experimental study aimed to evaluate the effects of 17β-estradiol (E2) and progesterone (P4) on the interaction between mouse embryo and human endometrial mesenchymal stromal cells, and gene expressions related to implantation [αV and β3 integrins, interleukin-1 receptor (IL-1R), and leukemia inhibitory factor receptor (LIFR)] using an in vitro twodimensional model. MATERIALS AND METHODS: In this experimental study, the endometrial stromal cells were isolated enzymatically and mechanically, and cultured to the fourth passage. Next, their immunophenotype was confirmed by flow cytometric analysis as mesenchymal stromal cells. The cells were cultured as either the experimental group in the presence of E2 (0.3 nmol) and P4 (63.5 nmol) or control group without any hormone treatment. Mouse blastocysts were co-cultured with endometrial mesenchymal stromal cells in both groups for 48 hours. Their interaction was assessed under an inverted microscope and scanning electron microscopy (SEM). Expressions of αV and β3 integrins, LIFR, and IL-1R genes were analyzed by real-time reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Similar observations were seen in both groups by light microscopy and SEM. We observed the presence of pinopode-like structures and cell secretions on the apical surfaces of endometrial mesenchymal stromal cells in both groups. The trophoblastic cells expanded and interacted with the mesenchymal monolayer cells. At the molecular level, expression of IL-1R significantly increased in the hormonal treated group compared to the control (P≤0.05). Expressions of the other genes did not differ. CONCLUSION: This study has shown that co-culture of endometrial mesenchymal stromal cells with mouse embryo in media that contained E2 (0.3 nmol) and P4 (63.5 nmol) could effectively increase the expression of IL-1R, which is involved in embryo implantation. However, there were no significant effects on expressions of αV and β3 integrins, LIFR, and on the morphology and ultrastructure of endometrial mesenchymal stromal cells. Copyright© by Royan Institute. All rights reserved. KEYWORDS: Estrogen; Implantation; Interleukin-1 Receptor; Mesenchymal Stromal Cells; Progesterone PMID: 29845791 PMCID: PMC6004996 [Available on 2018-09-01] DOI: 10.22074/cellj.2018.5221
Local and systemic factors and implantation: what is the evidence?
Fertil Steril. 2016 Apr;105(4):873-84. doi: 10.1016/j.fertnstert.2016.02.018. Epub 2016 Mar 3.
Fox C1, Morin S2, Jeong JW3, Scott RT Jr2, Lessey BA4.
Significant progress has been made in the understanding of embryonic competence and endometrial receptivity since the inception of assisted reproductive technology. The endometrium is a highly dynamic tissue that plays a crucial role in the establishment and maintenance of normal pregnancy. In response to steroid sex hormones, the endometrium undergoes marked changes during the menstrual cycle that are critical for acceptance of the nascent embryo. There is also a wide body of literature on systemic factors that impact assisted reproductive technology outcomes. Patient prognosis is impacted by an array of factors that tip the scales in her favor or against success. Recognizing the local and systemic factors will allow clinicians to better understand and optimize the maternal environment at the time of implantation. This review will address the current literature on endometrial and systemic factors related to impaired implantation and highlight recent advances in this area of reproductive medicine. Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved. KEYWORDS: Endometrium; IVF; immune factors; implantation; thyroid; vitamin D
The role of CX3CL1 in fetal-maternal interaction during human gestation
Cell Adh Migr. 2016 Jan 8:0. [Epub ahead of print]
Demirci EK1, Salamonsen LA2,3, Gauster M4.
Embryo implantation and subsequent placentation require a fine balanced fetal-maternal cross-talk of hormones, cytokines and chemokines. Amongst the group of chemokines, CX3CL1 (also known as fractalkine) has recently attracted attention in the field of reproductive research. It exists both as membrane-bound and soluble isoforms. On the basis of current experimental evidence, fractalkine is suggested to regulate adhesion and migration processes in fetal-maternal interaction at different stages of human pregnancy. Expressed by uterine glandular epithelial cells, predominantly during the mid-secretory phase of the menstrual cycle, fractalkine appears to prime the blastocyst for forthcoming implantation. After implantation, fractalkine is suggested to regulate invasion of extravillous trophoblasts by altering their expression profile of adhesion molecules. With onset of perfusion of the intervillous space at the end of first trimester, fractalkine present at the apical microvillous plasma membrane of the syncytiotrophoblast may mediate close interaction of placental villi with circulating maternal blood cells. KEYWORDS: Fractalkine; fetal-maternal cross-talk; implantation; invasion; trophoblast
The adherens junction is lost during normal pregnancy but not during ovarian hyper stimulated pregnancy
Acta Histochem. 2015 Dec 28. pii: S0065-1281(15)30033-7. doi: 10.1016/j.acthis.2015.12.004. [Epub ahead of print]
Dowland SN1, Madawala RJ2, Lindsay LA2, Murphy CR2.
During early pregnancy in the rat, the luminal uterine epithelial cells (UECs) must transform to a receptive state to permit blastocyst attachment and implantation. The implantation process involves penetration of the epithelial barrier, so it is expected that the transformation of UECs includes alterations in the lateral junctional complex. Previous studies have demonstrated a deepening of the tight junction (zonula occludens) and a reduction in the number of desmosomes (macula adherens) in UECs at the time of implantation. However, the adherens junction (zonula adherens), which is primarily responsible for cell-cell adhesion, has been little studied during early pregnancy. This study investigated the adherens junction in rat UECs during the early stages of normal pregnancy and ovarian hyperstimulated (OH) pregnancy using transmission electron microscopy. The adherens junction is present in UECs at the time of fertilisation, but is lost at the time of blastocyst implantation during normal pregnancy. Interestingly, at the time of implantation after OH, adherens junctions are retained and may impede blastocyst penetration of the epithelium. The adherens junction anchors the actin-based terminal web, which is known to be disrupted in UECs during early pregnancy. However, artificial disruption of the terminal web, using cytochalasin D, did not cause removal of the adherens junction in UECs. This study revealed that adherens junction disassembly occurs during early pregnancy, but that this process does not occur during OH pregnancy. Such disassembly does not appear to depend on the disruption of the terminal web. Copyright © 2015 Elsevier GmbH. All rights reserved. KEYWORDS: Adherens junction; Epithelium; Implantation; Ovarian hyperstimulation; Pregnancy; Uterine receptivity PMID 26738975
Cellular Regulation of the Uterine Microenvironment That Enables Embryo Implantation
Front Immunol. 2015 Jun 17;6:321. doi: 10.3389/fimmu.2015.00321. eCollection 2015.
Zenclussen AC1, Hämmerling GJ2.
Implantation of the fertilized egg into the maternal uterus is a crucial step in pregnancy establishment. Increasing evidence suggests that its success depends on various cell types of the innate immune system and on the fine balance between inflammatory and anti-inflammatory processes. In addition, it has recently been established that regulatory T cells play a superordinate role in dictating the quality of uterine environment required for successful pregnancy. Here, we discuss the cellular regulation of uterine receptivity with emphasis on the function and regulation of cells from the innate and adaptive immune system. KEYWORDS: Treg cells; implantation; macrophages; mast cells; neutrophils; uterine DCs; uterine NK cells; uterine environment
http://journal.frontiersin.org/article/10.3389/fimmu.2015.00321/full © 2015 Zenclussen and Hämmerling. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Where and when should natural killer cells be tested in women with repeated implantation failure?
J Reprod Immunol. 2015 Feb 4. pii: S0165-0378(15)00019-4. doi: 10.1016/j.jri.2014.12.009. [Epub ahead of print]
Santillán I1, Lozano I2, Illán J3, Verdú V2, Coca S4, Bajo-Arenas JM5, Martinez F6.
The aim of this study was to identify the candidates for natural killer (NK) testing and to define the best methodology. For this purpose a prospective study was performed on 73 women with repeated implantation failure (RIF). RIF was considered to exist in patients not achieving clinical pregnancy after three transfers with at least one good-quality embryo. Idiopathic RIF was considered to exist in patients in whom thrombophilia, hysteroscopy and endometrial culture were normal, and no chromosomal factor was suspected. Thirty-two of the 73 patients were considered to have idiopathic RIF, and 17 fertile women with children were taken as controls. Immunohistochemical staining for endometrial CD56+ and blood CD56+ or CD16+ NK cells measured using flow cytometry were compared during the mid-luteal phase in both patients and controls. Seventeen out of the 32 patients with idiopathic RIF and only one of the controls had >250 CD56 cells per high power field 400× in endometrial biopsy (p<0.001). The percentage of blood NK cells out of the total lymphocyte population was higher in women with idiopathic RIF (13.4±1.2%; range, 2.63-29.01) than in controls (8.4±0.7%; range, 5.72-13.28; p=0.026). There was a positive correlation between blood and endometrial CD56 cells (ρ=0.707; p<0.001). No significant differences were found between patients with other types of RIF and controls. This study suggested that testing for NK cells might be useful in women with idiopathic RIF during the mid-luteal phase. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved. KEYWORDS: CD56; Endometrium; Immunohistochemistry; Implantation; Natural killer cells
Expression Patterns of MicroRNAs in Porcine Endometrium and Their Potential Roles in Embryo Implantation and Placentation
PLoS One. 2014 Feb 5;9(2):e87867. doi: 10.1371/journal.pone.0087867. eCollection 2014.
Su L, Liu R, Cheng W, Zhu M, Li X, Zhao S, Yu M. Author information
Implantation and placentation are critical steps for successful pregnancy. The pig has a non-invasive placenta and the uterine luminal epithelium is intact throughout pregnancy. To better understand the regulation mechanisms in functions of endometrium at three certain gestational stages that are critical for embryo/fetal loss in pigs, we characterized microRNA (miRNA) expression profiles in the endometrium on days 15 (implantation period), 26 (placentation period) and 50 (mid-gestation period) of gestation. The differentially expressed miRNAs across gestational days were detected and of which, 65 miRNAs were grouped into 4 distinct categories according to the similarities in their temporal expression patterns: (1) categories A and B contain majority of miRNAs (51 miRNAs, such as the miR-181 family) that were down- or up-regulated between gestational days 15 and 26, respectively; (2) categories C and D (14 miRNAs) consist miRNAs that were down- or up-regulated between gestational days 26 and 50, respectively. The expression patterns represented by eleven miRNAs were validated by qPCR. The majority of miRNAs were in categories A and B, suggesting that these miRNAs were involved in regulation of embryo implantation and placentation. The pathway analysis revealed that the predicted targets were involved in several pathways, such as focal adhesion, cell proliferation and tissue remolding. Furthermore, we identified that genes well-known to affect embryo implantation in pigs, namely SPP1, ITGB3 and ESR1, contain the miR-181a or miR-181c binding sites using the luciferase reporter system. The present study revealed distinctive miRNA expression patterns in the porcine endometrium during the implantation, placentation or mid-gestation periods. Additionally, our results suggested that miR-181a and miR-181c likely play important roles in the regulation of genes and pathways that are known to be involved in embryo implantation and placentation in pigs.
MiR-98 is involved in rat embryo implantation by targeting Bcl-xl
FEBS Lett. 2014 Jan 17. pii: S0014-5793(14)00023-4. doi: 10.1016/j.febslet.2013.12.026. [Epub ahead of print]
Xia HF1, Jin XH2, Cao ZF2, Shi T3, Ma X4. Author information
Abstract In a previous study, via microRNA microarray analysis we found that miR-98 is differentially expressed in rat uteri during the peri-implantation period (unpublished data). However, the role of miR-98 in rat embryo implantation remains elusive. Here, we found that the level of miR-98 is lower on day 5 and 6 of gestation (g.d. 5-6) than that on g.d.3-4 and g.d.7-8 in rat. MiR-98 expression is significantly decreased by delayed implantation. Down-regulation of miR-98 promotes ESC proliferation and inhibits apoptosis. Up-regulation of miR-98 displays opposite effects. Further investigation revealed that miR-98 can bind to the 3'-UTR of Bcl-xl to inhibit Bcl-xl translation. Collectively, down-regulation of miR-98 in rat uterus during the receptive phase is linked to the increase of cell proliferation via targeting Bcl-xl. Copyright © 2014. Published by Elsevier B.V. KEYWORDS: 3′-UTR, 3′-untranslated region, 5-bromo-4-chloro-3-indolyl phosphate, B-cell lymphoma-extra large, BCIP, Bcl-xl, DIG, ESCs, Embryo implantation, FITC, HRP, MicroRNAs, NBT, PFA, PI, Rat, Uterus, digoxigenin, endometrial stromal cells, fluorescein isothiocyanate, horseradish peroxidase, miR-98, miRNAs, p-nitroblue tetrazolium chloride, paraformaldehyde, phosphatidylinositol
The role of the osteopontin-integrin αvβ3 interaction at implantation: functional analysis using three different in vitro models
Hum Reprod. 2014 Jan 17.
Kang YJ, Forbes K, Carver J, Aplin JD. Author information
Abstract STUDY QUESTION: Does the interaction between integrin and its ligand osteopontin (OPN) mediate embryonic attachment to endometrial epithelium at implantation? SUMMARY ANSWER: OPN of epithelial origin binds the receptor integrin αvβ3 at the maternal surface to support adhesion during the early stages of implantation. WHAT IS KNOWN ALREADY: Integrin αvβ3 and OPN are both present in the endometrial luminal epithelium in the mid-secretory phase. STUDY DESIGN, SIZE, DURATION: Microscopy of attachment sites of blastocysts (mouse, n = 151, human, n = 8) and OPN- or BSA-coated beads (n = 488) interacting with Ishikawa cell monolayers at 24 and 48 h. Levels of epithelial OPN or integrin αvβ3 were altered by siRNA-mediated targeting and the results compared with non-targeting siRNA or mock-transfected controls. PARTICIPANTS/MATERIALS, SETTING, METHODS: In vitro modelling of early implantation with human endometrial cells (Ishikawa) and mouse or human embryos or ligand-coated beads. Immunolocalization of antigen around attached embryos was measured by image analysis with multiple repeats (n > 3), allowing a gradient of relative intensity to be detected. Attachment was quantified using a stability scale and protein expression documented by indirect immunofluorescence. Protein associations were probed by pulldown assays. MAIN RESULTS AND THE ROLE OF CHANCE: Integrin and OPN levels were increased in epithelial cells near to attached embryos. The pulldown assay confirmed OPN-integrin αvβ3 binding (n > 3). Decreased attachment stability of mouse embryos observed after siRNA knock-down of integrin αvβ3 or OPN itself, or OPN-coated beads after knock-down of integrin αvβ3, was tested for significance using Kruskal-Wallis with Dunn's post hoc tests. LIMITATIONS, REASONS FOR CAUTION: In vitro model. Attachment data using human embryos is limited by embryo availability. Mouse embryo attachment to human cells involves a species crossover so must be interpreted with caution. Ligand-coated beads allow specific molecular interactions mediating attachment to be probed, but obviously lack the adhesion and signaling repertoire of a live embryo. WIDER IMPLICATIONS OF THE FINDINGS: Some of the literature identifies reduced integrin αvβ3 expression in infertile endometrium; these findings predict that embryo attachment stability will be reduced in vivo if integrin levels are low. We suggest that the robustness of the initial attachment of the embryo affects its ability to progress to the post-epithelial phase of implantation; some poorly attached embryos will be lost. STUDY FUNDING/COMPETING INTEREST(S): No external funds were used for this study, which was supported by funds from the Universities of Manchester and Oxford. None of the authors has any conflict of interest to declare. TRIAL REGISTRATION NUMBER: N/A. KEYWORDS: endometrium, implantation, integrin αvβ3, osteopontin
Degradation of estrogen receptor α in activated blastocysts is associated with implantation in the delayed-implantation mouse model
Mol Hum Reprod. 2014 Jan 16. [Epub ahead of print]
Saito K, Furukawa E, Kobayashi M, Fukui E, Yoshizawa M, Matsumoto H. Author information
Abstract Implantation of a blastocyst into a receptive uterus involves a series of highly coordinated cellular and molecular events directed by ovarian estrogen and progesterone (P4). In particular, estrogen is essential for on-time uterine receptivity and blastocyst activation in mice. Although estrogen receptor α (ERα) is expressed in blastocysts, its targeted disruption leaves embryonic development and implantation unaffected. Therefore, the role of ERα in implanting blastocysts remains unclear. Using a delayed implantation model in mice, we showed increased expression of ERα in implantation-induced (activated) blastocysts; however, this ERα expression in activated blastocysts decreased within 6-h culture. In contrast, Breast cancer 1 (Brca1) was maintained in the blastocysts during the culture. Treatment of activated blastocysts with the proteasome inhibitor MG132 demonstrated that proteolysis is associated with downregulation of ERα expression in activated blastocysts. Embryo transfer of MG132-treated activated blastocysts into recipient mice on the morning of day 4 of pseudopregnancy (day 1=vaginal plug) showed a decreased implantation rate, whereas combined treatment with MG132 and the estrogen receptor antagonist, ICI 182,780, resulted in recovery of the rate of implantation. This study has revealed that downregulation of ERα in activated blastocyst is associated with completion of blastocyst implantation after embryo transfer on the morning of day 4 of pseudopregnancy. Our results also suggest that selective protein turnover, such as that of ERα, occurs in activated blastocysts, while expression of other proteins, including Brca1, is maintained at the same stage. KEYWORDS: blastocyst, estrogen receptor α, implantation, pregnancy, proteolysis
Physiological and molecular determinants of embryo implantation
Mol Aspects Med. 2013 Oct;34(5):939-80. doi: 10.1016/j.mam.2012.12.011. Epub 2013 Jan 2.
Zhang S1, Lin H, Kong S, Wang S, Wang H, Wang H, Armant DR.
Embryo implantation involves the intimate interaction between an implantation-competent blastocyst and a receptive uterus, which occurs in a limited time period known as the window of implantation. Emerging evidence shows that defects originating during embryo implantation induce ripple effects with adverse consequences on later gestation events, highlighting the significance of this event for pregnancy success. Although a multitude of cellular events and molecular pathways involved in embryo-uterine crosstalk during implantation have been identified through gene expression studies and genetically engineered mouse models, a comprehensive understanding of the nature of embryo implantation is still missing. This review focuses on recent progress with particular attention to physiological and molecular determinants of blastocyst activation, uterine receptivity, blastocyst attachment and uterine decidualization. A better understanding of underlying mechanisms governing embryo implantation should generate new strategies to rectify implantation failure and improve pregnancy rates in women. Copyright © 2012 Elsevier Ltd. All rights reserved. KEYWORDS: Blastocyst activation; Blastocyst attachment; Decidualization; Embryo implantation; Uterine receptivity PMID 23290997
Mucins help to avoid alloreactivity at the maternal feral interface
Clin Dev Immunol. 2013;2013:542152. doi: 10.1155/2013/542152. Epub 2013 Jun 20.
Redzovic A1, Laskarin G, Dominovic M, Haller H, Rukavina D. Author information
During gestation, many different mechanisms act to render the maternal immune system tolerant to semi-allogeneic trophoblast cells of foetal origin, including those mediated via mucins that are expressed during the peri-implantation period in the uterus. Tumour- associated glycoprotein-72 (TAG-72) enhances the already established tolerogenic features of decidual dendritic cells with the inability to progress towards Th1 immune orientation due to lowered interferon (IFN)- γ and interleukin (IL)-15 expression. Mucine 1 (Muc 1) supports alternative activation of decidual macrophages, restricts the proliferation of decidual regulatory CD56(+) bright natural killer (NK) cells, and downregulates their cytotoxic potential, including cytotoxic mediator protein expression. Removing TAG-72 and Muc 1 from the eutopic implantation site likely contributes to better control of trophoblast invasion by T cells and NK cells and appears to have important immunologic advantages for successful implantation, in addition to mechanical advantages. However, these processes may lead to uncontrolled trophoblast growth after implantation, inefficient defence against infection or tumours, and elimination of unwanted immunocompetent cells at the maternal-foetal interface. The use of mucins by tumour cells to affect the local microenvironment in order to avoid the host immune response and to promote local tumour growth, invasion, and metastasis confirms this postulation.
Differential expression and regulation of Cryab in mouse uterus during pre-implantation period
Reproduction. 2013 Apr 11. [Epub ahead of print]
Tian XC, Wang QY, Li DD, Wang ST, Yang ZQ, Guo B, Yue ZP. Source X Tian, College of Veterinary Medicine, Jilin University, Changchun, China.
The aim of this study was to examine the expression and regulation of crystallin, alpha B (Cryab) gene in mouse uterus during the peri-implantation period by in situ hybridization and real-time PCR. There was no detectable Cryab mRNA signal on days 1-4 of pregnancy. On day 5 of pregnancy when embryo implanted, a high level of Cryab mRNA signal was found in the subluminal stroma surrounding the implanting blastocyst. On days 6-8, Cryab mRNA was strongly expressed in the primary decidua. By real-time PCR, a high level of Cryab expression was detected on days 7 and 8 of pregnancy, although Cryab expression was seen through days 1-8. Under in vivo and in vitro artificial decidualization, Cryab expression was significantly elevated. Compared with the progesterone-primed delayed implantation uterus, a high level of Cryab mRNA expression was observed in estrogen-activated implantation uterus. In the uterine stromal cells, cAMP, estrogen and progesterone could induce the expression of Cryab gene. In the ovariectomized mouse uterus, estrogen could also induce the expression of Cryab while progesterone inhibited its expression. Our data suggest that Cryab may play an important role during mouse embryo implantation and decidualization and that estrogen and progesterone can regulate the expression of Cryab gene.
Does the presence of a Caesarean section scar affect implantation site and early pregnancy outcome in women attending an early pregnancy assessment unit?
Hum Reprod. 2013 Apr 12. [Epub ahead of print]
Naji O, Wynants L, Smith A, Abdallah Y, Saso S, Stalder C, Van Huffel S, Ghaem-Maghami S, Van Calster B, Timmerman D, Bourne T. Source Obstetrics and Gynaecology Unit, Queen Charlottes and Chelsea Hospital, Imperial College, London, UK. Abstract STUDY QUESTION: Are there any differences in the location and distance to the internal cervical ostium of the implantation site of the intrauterine gestation sacs, early pregnancy symptoms and pregnancy outcome at 12 weeks gestation between women with and without a previous Caesarean section (CS)? SUMMARY ANSWER: The presence of a CS scar affects the site of implantation, and the distance between implantation site and the scar is related to the risk of spontaneous abortion. WHAT IS KNOWN ALREADY?: Little is known about the impact of a CS scar on implantation other than the risk of Caesarean scar pregnancy (CSP). Furthermore, there is a paucity of information on how the proximity of implantation to the scar impacts on pregnancy outcome in the first trimester. STUDY DESIGN, SIZE, AND DURATION: A prospective cohort study conducted over 15 months in the early pregnancy unit of a London Teaching Hospital. Three hundred and eighty women underwent a transvaginal scan at 6-11 weeks of gestation. A total of 170 women had undergone ≥1 CS, and 210 women had no history of CS. PARTICIPANTS/MATERIALS, SETTING, METHODS: The 380 women were recruited as consecutive non-selected cases. The relationship between the implanted sac and the CS scar was assessed by quantifiable measures and by subjective impression. Logistic regression analysis was used to determine the influence of the presence of a CS scar on pregnancy outcome. The final outcome of the study was the viability of the pregnancy at 12 weeks. MAIN RESULTS AND THE ROLE OF CHANCE: Implantation was most frequently posterior (53%) in the CS group and fundal in the non-CS group (42%). Gestation sac implantation was 8.7 mm lower in the CS group (95% confidence interval (CI) 6.7-10.7, P < 0.0001). Presenting complaints differed in women with and without a previous CS (P = 0.0009). More frequent vaginal bleeding [73 versus 55%, difference -18, 95% CI (-27 to -8%] yet no clearly increased spontaneous abortion rates were noted in the CS group compared with the non-CS group (adjusted odds ratio = 1.1, 95% CI 0.6-1.9, P = 0.74). Subjective impression showed that in eight cases the implantation site crossed the scar, seven of which resulted in spontaneous abortion, while the remaining case survived to term complicated by placenta praevia and post-partum haemorrhage. The subjective impression of the examiner was supported by the measurements of distance between implantation site and CS scar. LIMITATIONS, REASONS FOR CAUTION: A weakness of the study is the lack of a reference technique to verify the location of implantation. WIDER IMPLICATIONS OF THE FINDINGS: This study adds further support to the hypothesis that the presence of a CS on the uterus impacts on the implantation site of a future pregnancy. The possibility that the CS scar has an impact on the risk of spontaneous abortion should be further studied. Caution must be exercised when implantation occurs near to, and crosses, a CS scar as this is not always associated with the diagnosis of CSP. A potential limitation of the study is that we did not examine scar dimensions and morphology. STUDY FUNDING/COMPETING INTEREST(S): The authors have no competing interests to declare. The study was not supported by an external grant.
Mechanisms of implantation: strategies for successful pregnancy
Nat Med. 2012 Dec;18(12):1754-67. doi: 10.1038/nm.3012.
Cha J, Sun X, Dey SK. Source Division of Reproductive Sciences, Perinatal Institute, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
Physiological and molecular processes initiated during implantation for pregnancy success are complex but highly organized. This review primarily highlights adverse ripple effects arising from defects during the peri-implantation period that perpetuate throughout pregnancy. These defects are reflected in aberrations in embryo spacing, decidualization, placentation and intrauterine embryonic growth, manifesting in preeclampsia, miscarriages and/or preterm birth. Understanding molecular signaling networks that coordinate strategies for successful implantation and decidualization may lead to approaches to improve the outcome of natural pregnancy and pregnancy conceived from in vitro fertilization.
Mouse estrous cycle (~4 d)
- pre-receptive (days 1–3), no implantation, requires priming with progesterone (P4) superimposed with estrogen
- receptive (day 4)
- blastocysts implant with their inner cell mass (ICM) oriented toward the lumen
- non-receptive or refractory (day 5 onward)
Humans menstrual cycle (~28–30 d)
- pre-receptive phase spans first 7 d after ovulation (early luteal phase)
- receptive mid-luteal phase (~7–10 d after ovulation)
- ** blastocysts implant with their inner cell mass (ICM) oriented toward the epithelium
- non-receptive phase remainder of the cycle (late luteal phase)
Human placentation from nidation to 5 weeks of gestation. Part II: Tools to model the crucial first days
Placenta. 2012 May;33(5):335-42. Epub 2012 Feb 25.
James JL, Carter AM, Chamley LW. Source Department of Obstetrics and Gynecology, University of Auckland, 85 Park Rd, Grafton, Auckland, New Zealand. firstname.lastname@example.org
Human pregnancy is unusual with respect to monthly spontaneous decidualisation as well as the degree of placental invasion and interaction with the decidualised endometrial stroma. This review covers in vivo animal models and in vitro cell culture models that have been used to study the earliest stages of human implantation and placentation from nidation to 5 weeks of gestation. The field has expanded rapidly in recent years due to the generation of human embryonic stem cell lines and the ability of some scientists to culture human blastocysts. These models have enabled researchers to begin to elucidate the interactions involved in human blastocyst apposition, adhesion and implantation. However, we still understand very little about the differentiation processes involved in the formation of the placenta. Continued improvements to current models, including the potential isolation of a human trophoblast stem cell, will significantly enhance our ability to define the molecular and structural events occurring during human implantation and early placental development. Copyright © 2012 Elsevier Ltd. All rights reserved.
Uterine NK Cells Are Critical in Shaping DC Immunogenic Functions Compatible with Pregnancy Progression
PLoS One. 2012;7(10):e46755. doi: 10.1371/journal.pone.0046755. Epub 2012 Oct 8.
González IT, Barrientos G, Freitag N, Otto T, Thijssen VL, Moschansky P, von Kwiatkowski P, Klapp BF, Winterhager E, Bauersachs S, Blois SM. Source Medicine University of Berlin, Charité Centre 12 Internal Medicine and Dermatology, Laboratory of Reproductive Medicine, Berlin, Germany.
Dendritic cell (DC) and natural killer (NK) cell interactions are important for the regulation of innate and adaptive immunity, but their relevance during early pregnancy remains elusive. Using two different strategies to manipulate the frequency of NK cells and DC during gestation, we investigated their relative impact on the decidualization process and on angiogenic responses that characterize murine implantation. Manipulation of the frequency of NK cells, DC or both lead to a defective decidual response characterized by decreased proliferation and differentiation of stromal cells. Whereas no detrimental effects were evident upon expansion of DC, NK cell ablation in such expanded DC mice severely compromised decidual development and led to early pregnancy loss. Pregnancy failure in these mice was associated with an unbalanced production of anti-angiogenic signals and most notably, with increased expression of genes related to inflammation and immunogenic activation of DC. Thus, NK cells appear to play an important role counteracting potential anomalies raised by DC expansion and overactivity in the decidua, becoming critical for normal pregnancy progression.
Chemokine gene silencing in decidual stromal cells limits T cell access to the maternal-fetal interface
Science. 2012 Jun 8;336(6086):1317-21.
Nancy P, Tagliani E, Tay CS, Asp P, Levy DE, Erlebacher A. Source Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
The chemokine-mediated recruitment of effector T cells to sites of inflammation is a central feature of the immune response. The extent to which chemokine expression levels are limited by the intrinsic developmental characteristics of a tissue has remained unexplored. We show in mice that effector T cells cannot accumulate within the decidua, the specialized stromal tissue encapsulating the fetus and placenta. Impaired accumulation was in part attributable to the epigenetic silencing of key T cell-attracting inflammatory chemokine genes in decidual stromal cells, as evidenced by promoter accrual of repressive histone marks. These findings give insight into mechanisms of fetomaternal immune tolerance, as well as reveal the epigenetic modification of tissue stromal cells as a modality for limiting effector T cell trafficking.
Inhibition of histone deacetylase activity in human endometrial stromal cells promotes extracellular matrix remodelling and limits embryo invasion
PLoS One. 2012;7(1):e30508. Epub 2012 Jan 26.
Estella C, Herrer I, Atkinson SP, Quiñonero A, Martínez S, Pellicer A, Simón C. Source Fundación Instituto Valenciano de Infertilidad, Valencia University, and Instituto Universitario IVI/INCLIVA, Valencia, Spain.
Invasion of the trophoblast into the maternal decidua is regulated by both the trophoectoderm and the endometrial stroma, and entails the action of tissue remodeling enzymes. Trophoblast invasion requires the action of metalloproteinases (MMPs) to degrade extracellular matrix (ECM) proteins and in turn, decidual cells express tissue inhibitors of MMPs (TIMPs). The balance between these promoting and restraining factors is a key event for the successful outcome of pregnancy. Gene expression is post-transcriptionally regulated by histone deacetylases (HDACs) that unpacks condensed chromatin activating gene expression. In this study we analyze the effect of histone acetylation on the expression of tissue remodeling enzymes and activity of human endometrial stromal cells (hESCs) related to trophoblast invasion control. Treatment of hESCs with the HDAC inhibitor trichostatin A (TSA) increased the expression of TIMP-1 and TIMP-3 while decreased MMP-2, MMP-9 and uPA and have an inhibitory effect on trophoblast invasion. Moreover, histone acetylation is detected at the promoters of TIMP-1 and TIMP-3 genes in TSA-treated. In addition, in an in vitro decidualized hESCs model, the increase of TIMP-1 and TIMP-3 expression is associated with histone acetylation at the promoters of these genes. Our results demonstrate that histone acetylation disrupt the balance of ECM modulators provoking a restrain of trophoblast invasion. These findings are important as an epigenetic mechanism that can be used to control trophoblast invasion.
PMID 22291969 [PubMed - indexed for MEDLINE] PMCID: PMC3266920
A balancing act: mechanisms by which the fetus avoids rejection by the maternal immune system
Reproduction. 2011 Jun;141(6):715-24. Epub 2011 Mar 9.
Warning JC, McCracken SA, Morris JM. Source Department of Perinatal Research, Kolling Institute of Medical Research, University of Sydney at Royal North Shore Hospital, Sydney, New South Wales 2065, Australia.
Abstract Successful pregnancy requires strict temporal regulation of maternal immune function to accommodate the growing fetus. Early implantation is facilitated by inflammatory processes that ensure adequate vascular remodeling and placental invasion. To prevent rejection of the fetus, this inflammation must be curtailed; reproductive immunologists are discovering that this process is orchestrated by the fetal unit and, in particular, the extravillous trophoblast. Soluble and particulate factors produced by the trophoblast regulate maternal immune cells within the decidua, as well as in the periphery. The aim of this review is to discuss the action of recently discovered immunomodulatory factors and mechanisms, and the potential effects of dysregulation of such mechanisms on the maternal immune response that may result in pregnancy loss or preeclampsia.
Hormonal induction of endometrial receptivity
Fertil Steril. 2011 Sep;96(3):530-5.
Paulson RJ. Source Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA. RPaulson@USC.edu
OBJECTIVE: To review and synthesize information from the scientific literature pertaining to the hormonal induction of endometrial receptivity before ET. DESIGN: Critical review of selected scientific literature, synthesis and formulation of opinion. SETTING: Not applicable. PATIENT(S): Prospective recipients of oocyte donation or candidates for frozen embryo transfer. INTERVENTION(S): Hormonal treatment for the purpose of induction of endometrial receptivity. MAIN OUTCOME MEASURE(S): Successful induction of endometrial receptivity, as substantiated by live birth rates, pregnancy rates, implantation rates or by measuring putative markers of endometrial receptivity. RESULT(S): The practice of assisted reproductive technology, particularly third-party parenting, in which the source of oocytes is separated from the endometrium, has allowed a separate assessment of embryo and endometrial development. Endometrial receptivity can be induced by exogenously administered E(2) and P in a variety of regimens. The degree of synchrony between embryo and endometrium influences the probability of embryo implantation and may be controlled by initiating P stimulation at different times relative to the stage of embryo development. Many substances have been investigated as adjuncts to E(2) and P in the induction of endometrial receptivity, but at the present time, their value is unproven. CONCLUSION(S): Estrogen and P are the only hormones necessary to prepare the endometrium for implantation. Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.
Human Fallopian tube epithelium constitutively expresses integrin endometrial receptivity markers: no evidence for a tubal implantation window
Mol Hum Reprod. 2011 Oct 16. [Epub ahead of print]
Brown JK, Shaw JL, Critchley HO, Horne AW. Source MRC Centre for Reproductive Health, The University of Edinburgh, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
Understanding of ectopic implantation within Fallopian tube (FT) is limited. In the human uterus, the putative 'window of implantation' in the mid-luteal phase of the menstrual cycle is accompanied by increased endometrial epithelial expression of the integrins α(1)β(1), α(4)β(1), and α(v)β(3) and its ligand osteopontin. Similar cyclical changes in FT integrin expression have been proposed to contribute to ectopic implantation, but supporting data are limited. In the current study, we present quantitative data on human Fallopian tube transcription and translation of the integrin subunits α(1), α(4), α(V), β(1) and β(3) during the follicular and mid-luteal phases of the menstrual cycle, together with a supporting immuocytochemical analysis of their spatial distribution within the Fallopian tube, and that of osteopontin. In contrast to previous studies, our data indicate that all five integrin receptivity markers are constitutively transcribed and translated in the Fallopian tube, with no evidence for changes in their expression or distribution during the window of implantation in the mid-luteal phase of the cycle. Furthermore, we could find no evidence for cyclic redistribution of the integrin α(v)β(3) ligand osteopontin within the Fallopian tube. Although we do not rule out the involvement of integrin endometrial receptivity markers in the establishment of ectopic pregnancy, our findings do not support their differential expression during a tubal implantation window.
Prokineticin 1 induces Dickkopf 1 expression and regulates cell proliferation and decidualization in the human endometrium
Mol Hum Reprod. 2011 Oct;17(10):626-36. doi: 10.1093/molehr/gar031. Epub 2011 May 5.
Macdonald LJ, Sales KJ, Grant V, Brown P, Jabbour HN, Catalano RD. Source MRC Human Reproductive Sciences Unit, The Queen's Medical Research Institute, Edinburgh, UK.
Prokineticin 1 (PROK1) signalling via prokineticin receptor 1 (PROKR1) regulates the expression of several genes with important roles in endometrial receptivity and implantation. This study investigated PROK1 regulation of Dickkopf 1 (DKK1) expression, a negative regulator of canonical Wnt signalling, and its function in the non-pregnant endometrium and first trimester decidua. DKK1 mRNA expression is elevated during the mid-secretory phase of the menstrual cycle and expression increases further in first trimester decidua. DKK1 protein expression is localized to glandular epithelial and stromal cells during the proliferative, early- and mid-secretory phases, whereas expression is confined to the stroma in the late-secretory phase and first trimester decidua. PROK1 induces the expression of DKK1 in endometrial epithelial cells stably expressing PROKR1 and in first trimester decidua explants, via a Gq-calcium-calcineurin-nuclear factor of activated T-cells-mediated pathway. Endometrial epithelial cell proliferation is negatively regulated by PROK1-PROKR1 signalling. We demonstrate that this effect on cell proliferation occurs via DKK1 expression, as siRNA targeted against DKK1 reduces the PROK1-induced decrease in proliferation. Furthermore, decidualization of primary human endometrial stromal cells with progesterone and cyclic adenosine monophosphate is inhibited by miRNA knock down of PROK1 or DKK1. These data demonstrate important roles for PROK1 and DKK1 during endometrial receptivity and early pregnancy, which include regulation of endometrial cell proliferation and decidualization.
Human endometrial CD98 is essential for blastocyst adhesion
PLoS One. 2010 Oct 15;5(10):e13380.
Domínguez F, Simón C, Quiñonero A, Ramírez MÁ, González-Muñoz E, Burghardt H, Cervero A, Martínez S, Pellicer A, Palacín M, Sánchez-Madrid F, Yáñez-Mó M. Source Fundación IVI, Instituto Universitario IVI, Universidad de Valencia, Valencia, Spain.
BACKGROUND: Understanding the molecular basis of embryonic implantation is of great clinical and biological relevance. Little is currently known about the adhesion receptors that determine endometrial receptivity for embryonic implantation in humans. METHODS AND PRINCIPAL FINDINGS: Using two human endometrial cell lines characterized by low and high receptivity, we identified the membrane receptor CD98 as a novel molecule selectively and significantly associated with the receptive phenotype. In human endometrial samples, CD98 was the only molecule studied whose expression was restricted to the implantation window in human endometrial tissue. CD98 expression was restricted to the apical surface and included in tetraspanin-enriched microdomains of primary endometrial epithelial cells, as demonstrated by the biochemical association between CD98 and tetraspanin CD9. CD98 expression was induced in vitro by treatment of primary endometrial epithelial cells with human chorionic gonadotropin, 17-β-estradiol, LIF or EGF. Endometrial overexpression of CD98 or tetraspanin CD9 greatly enhanced mouse blastocyst adhesion, while their siRNA-mediated depletion reduced the blastocyst adhesion rate. CONCLUSIONS: These results indicate that CD98, a component of tetraspanin-enriched microdomains, appears to be an important determinant of human endometrial receptivity during the implantation window.
Early stages of implantation as revealed by an in vitro model
Reproduction. 2010 May;139(5):905-14. Epub 2010 Feb 23.
Singh H, Nardo L, Kimber SJ, Aplin JD. Source Maternal and Fetal Health Research, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, M13 9WL, UK.
Our limited understanding of the processes underlying steroid hormonal control of human endometrial receptivity is largely due to the lack of a relevant model system. To overcome scarcity of material, we have developed a model in which mouse embryos attach to human Ishikawa cells, which express functional steroid hormone receptors. Blastocysts flushed from day 4 pregnant superovulated mice were transferred to confluent Ishikawa cell monolayers. After 48 h of co-culture, 85% of the blastocysts had attached loosely, but only 40% attached stably to the epithelial cell surface. In contrast, 95% of the embryos attached stably to tissue culture plastic. Thus, weak attachment of a majority of the embryos was followed by stronger adhesion of a smaller proportion. Seventeen percent of the transferred blastocysts modified the epithelial cell surface with loss of MUC1 at the attachment site, extending variably to adjacent epithelial cells. Initially, stable attachment occurred without disruption to the integrity of the epithelial monolayer, but at later stages after the embryo had spread laterally, displacement of subjacent cells was observed. A modest increase in stable attachment, but no changes to MUC1 clearance, was observed after assisted hatching. After 24 h priming of Ishikawa cells by 17beta-oestradiol (OE(2)) followed by 72-h incubation with medroxyprogesterone acetate and OE(2), stable attachment increased from 40 to 70%. Initial attachment is efficient either in the presence or in the absence of hormone; steroid treatment increased the incidence of stable attachment. Implantation failure is predicted to occur in this model when embryos fail to progress from initial to stable attachment.
PMID: 20179188 http://www.ncbi.nlm.nih.gov/pubmed/20179188
Local regulation of implantation at the human fetal-maternal interface
Int J Dev Biol. 2010;54(2-3):313-22. Dimitriadis E, Nie G, Hannan NJ, Paiva P, Salamonsen LA.
Prince Henrys Institute of Medical Research, Clayton, Victoria, Australia.
Abstract Embryo implantation and formation of a functional placenta are complex processes that require a plethora of regulatory molecules. In recent years, many of these mediators have been identified, often from studies in experimental animals. Furthermore, their expression patterns at the embryo-maternal interface in women have been characterized and provide clues to their potential actions. What has been missing in most cases is any experimental demonstration of their function. Proteases, cytokines and chemokines are among the molecules identified at the embryo-maternal interface. Functional studies of the protease, proprotein convertase (PC)6, the gp130 cytokines, leukemia inhibitory factor (LIF) and interleukin (IL)11 and the chemokines, CX3CL1 and CCL14 demonstrate potential actions within the uterine cavity. These actions include: enhancing blastocyst development, modifying adhesive properties of the blastocyst and the uterine epithelial surface, and providing chemotactic guidance to the blastocyst. As implantation proceeds, PC6 and IL-11 also act to drive decidualization. The products (proteases, chemokines and cytokines) produced by these decidual cells provide a unique environment. This is important for both directing and restraining trophoblast invasion and for leukocyte trafficking into the decidua until the placenta is fully established.
Lymphatics in the human endometrium disappear during decidualization
Volchek M, Girling JE, Lash GE, Cann L, Kumar B, Robson SC, Bulmer JN, Rogers PA. Hum Reprod. 2010 Oct;25(10):2455-64. Epub 2010 Aug 21.
BACKGROUND: The mammalian placenta plays a central role in maternal tolerance of the semi-allogeneic fetus and fluid balance between the maternal and fetal compartments. The lymphatics play a role in both these function. The aim of this study was to describe the distribution of lymphatic vessels in human decidua, with particular focus on the lymphatics that surround remodelling spiral arteries during decidualization and trophoblast invasion.
METHODS: Placental bed and non-placental bed (decidua parietalis) biopsies were obtained from 41 women undergoing elective termination of pregnancy at 6-18 weeks gestational age as well as placental bed biopsies from 5 women undergoing elective Caesarean section at term. In addition to routine haematoxylin and eosin staining, double immunohistochemical labelling was performed on serial 3-µm sections to identify lymphatic vessels in conjunction with one of the following: blood vessels, smooth muscle, epithelial and trophoblast cells or proliferating cells. Representative photomicrographs of all sections were obtained from a total of 273 areas (46 samples, average 6 range 3-15 areas per sample). Descriptive findings of the organization of lymphatics in human placental bed and decidua parietalis were made from a total of 1638 images.
RESULTS: Lymphatic vessels positive for podoplanin were abundant in non-decidualized hypersecretory endometrium at all stages of gestation. By contrast, the decidua was nearly always devoid of lymphatics. In some samples, structures that appeared to be regressing lymphatics could be observed at the boundary between non-decidualized hypersecretory and decidualized endometrium. Lymphatic vessels were notably absent from the vicinity of spiral arteries that were surrounded by decidualized stromal cells. Lymphatic vessels in non-decidualized hypersecretory endometrium appeared larger and more elongated as gestation progressed. Proliferating lymphatic vascular endothelial cells were identified in both large vessels, and in streaks of D2-40 positive cells that could have been newly forming lymphatic vessels. Placental bed lymphatics exhibited limited and variable staining with LYVE-1 at all stages of pregnancy apart from term.
CONCLUSIONS: We have made novel observations on lymphatics in the placental bed and their relationship with other structures throughout pregnancy. Endometrial stromal cell decidualization results in a loss of lymphatics, with this phenomenon being particularly apparent around the spiral arteries.
The transcription factor C/EBPbeta is a marker of uterine receptivity and expressed at the implantation site in the primate
Reprod Sci. 2010 May;17(5):434-43. Epub 2010 Mar 11.
Kannan A, Fazleabas AT, Bagchi IC, Bagchi MK.
Department of Vet. Biosciences University of Illinois at Chicago, Chicago, IL, USA. Abstract During early pregnancy, the endometrium undergoes pronounced hormone-dependent functional changes in preparation for embryo implantation. Local autocrine-paracrine signaling at the fetal-maternal interface is crucial for the establishment of pregnancy. We previously reported that the transcription factor C/ EBPbeta, which is expressed at the implantation sites (ISs) in pregnant mice, acts as a key mediator of steroid hormone responsiveness in the endometrium. Mice lacking C/EBPbeta fail to support implantation due to defects in epithelial proliferation and stromal cell differentiation. In the current study, C/EBPbeta expression was dramatically stimulated in the endometrium of baboons (Papio anubis) during the window of uterine receptivity in response to a local infusion of chorionic gonadotropin, an embryonic signal. A robust induction of C/EBPbeta expression was also seen at the IS in the baboon and the human. Collectively, our results indicate that C/EBPbeta is a biomarker of endometrial receptivity and plays a conserved functional role during implantation in the primate.
Immune surveillance of the maternal/fetal interface: controversies and implications
Trends Endocrinol Metab. 2010 Jul;21(7):428-34. Epub 2010 Mar 19.
Erlebacher A. Source
New York University School of Medicine, New York, NY, USA. Adrian.Erlebacher@nyumc.org Abstract How the fetal 'allograft' avoids rejection during pregnancy remains a major unresolved immunological paradox. Recent work has suggested that fetomaternal tolerance is in fact maintained by a number of redundant mechanisms, but their relative importance has remained poorly defined. In this paper, I discuss an emerging controversy regarding the ability of maternal T cells to mediate fetal rejection at a time when they appear to be ignorant of fetal and placental antigens. This paradox within a paradox highlights two major research directions in the field of reproductive immunology that, when ultimately reconciled, promise to give significant insight into mechanisms of impaired fertility and compromised fetal and maternal health. Copyright 2010 Elsevier Ltd. All rights reserved.
Immune regulation of conception and embryo implantation-all about quality control?
J Reprod Immunol. 2010 May;85(1):51-7. Epub 2010 Mar 27.
Research Centre for Reproductive Health, Discipline of Obstetrics and Gynaecology, University of Adelaide, Adelaide, SA 5005 Australia. email@example.com Abstract Medawar's hypotheses for explaining maternal immune tolerance of the semi-allogeneic fetus are now proven incorrect or insufficient. The mother's immune response is not passive, suppressed, indolent or physically constrained in pregnancy. Instead, her immune system is centrally engaged with all steps of the reproductive process from conception to embryo implantation and placental development. Emerging studies show that immune cells are positioned and equipped to sense antigens and other signals originating in seminal fluid, the embryo and placental trophoblast. The immune response appears competent to utilise this information to discriminate the reproductive fitness and compatibility of the male partner and the integrity and developmental competence of the conceptus tissue. Since the immune response is modulated by the individual's infectious, inflammatory, stress, nutritional and metabolic status, immune influence on progression or disruption of pregnancy may be further influenced by environmental stressors and resource availability. This opinion paper advances the view that the immune system operates in pregnancy to integrate these signals and to exert executive quality control to either accommodate or reject the conceptus. It is argued that 'immune-mediated quality control' would facilitate optimal female reproductive investment and maximise offspring fitness, and thereby explain the evolutionary advantage of maternal immune awareness of the conceptus tissue.
Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.
Regional development of uterine decidualization: molecular signaling by Hoxa-10
Mol Reprod Dev. 2010 May;77(5):387-96.
Reproductive Sciences, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039, USA. firstname.lastname@example.org Abstract Uterine decidualization, a key event in implantation, is critically controlled by stromal cell proliferation and differentiation. Although the molecular mechanism that controls this event is not well understood, the general consensus is that the factors derived locally at the site of implantation influence aspects of decidualization. Hoxa-10, a developmentally regulated homeobox transcription factor, is highly expressed in decidualizing stromal cells, and targeted deletion of Hoxa-10 in mice shows severe decidualization defects, primarily due to the reduced stromal cell responsiveness to progesterone (P(4)). While the increased stromal cell proliferation is considered to be an initiator of decidualization, the establishment of a full-grown functional decidua appears to depend on the aspects of regional proliferation and differentiation. In this regard, this article provides an overview of potential signaling mechanisms mediated by Hoxa-10 that can influence a host of genes and cell functions necessary for propagating regional decidual development.
Natural selection of human embryos: impaired decidualization of endometrium disables embryo-maternal interactions and causes recurrent pregnancy loss
PLoS One. 2010 Apr 21;5(4):e10287.
Salker M, Teklenburg G, Molokhia M, Lavery S, Trew G, Aojanepong T, Mardon HJ, Lokugamage AU, Rai R, Landles C, Roelen BA, Quenby S, Kuijk EW, Kavelaars A, Heijnen CJ, Regan L, Macklon NS, Brosens JJ.
Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Hospital, London, United Kingdom. Abstract BACKGROUND: Recurrent pregnancy loss (RPL), defined as 3 or more consecutive miscarriages, is widely attributed either to repeated chromosomal instability in the conceptus or to uterine factors that are poorly defined. We tested the hypothesis that abnormal cyclic differentiation of endometrial stromal cells (ESCs) into specialized decidual cells predisposes to RPL, based on the observation that this process may not only be indispensable for placenta formation in pregnancy but also for embryo recognition and selection at time of implantation.
METHODOLOGY/PRINCIPAL FINDINGS: Analysis of mid-secretory endometrial biopsies demonstrated that RPL is associated with decreased expression of the decidual marker prolactin (PRL) but increased levels of prokineticin-1 (PROK1), a cytokine that promotes implantation. These in vivo findings were entirely recapitulated when ESCs were purified from patients with and without a history of RPL and decidualized in culture. In addition to attenuated PRL production and prolonged and enhanced PROK1 expression, RPL was further associated with a complete dysregulation of both markers upon treatment of ESC cultures with human chorionic gonadotropin, a glycoprotein hormone abundantly expressed by the implanting embryo. We postulated that impaired embryo recognition and selection would clinically be associated with increased fecundity, defined by short time-to-pregnancy (TTP) intervals. Woman-based analysis of the mean and mode TTP in a cohort of 560 RPL patients showed that 40% can be considered "superfertile", defined by a mean TTP of 3 months or less.
CONCLUSIONS: Impaired cyclic decidualization of the endometrium facilitates implantation yet predisposes to subsequent pregnancy failure by disabling natural embryo selection and by disrupting the maternal responses to embryonic signals. These findings suggest a novel pathological pathway that unifies maternal and embryonic causes of RPL.
Temporal and spatial expression of muc1 during implantation in sows
Int J Mol Sci. 2010 May 27;11(6):2322-35.
Ren Q, Guan S, Fu J, Wang A.
College of Animal Science and Technology, China Agricultural University, Beijing 100193, China; E-Mails: email@example.com (Q.R.); firstname.lastname@example.org (S.G.). Abstract Recent evidence points to an important role for Muc1 in embryo implantation. In this study, Real-time PCR and immunohistochemistry were used to study mRNA and protein levels at, and between, the attachment sites of the endometrium of Day 13, 18 and 24 pregnant sows. The results indicate that Muc1 mRNA expression was higher between attachment sites than at attachment sites during implantation and this effect was significant on Day 13 (P < 0.01) and 24 (P < 0.01). Intense Muc1 immunostaining was observed in luminal epithelium and stroma and the staining between attachment sites was stronger than at attachment sites on Days 13 and 18. Collectively, these results suggest the crucial role of Muc1 in successful implantation and embryo survival.
- Porcine embryos begin to attach to the uterus on Days 13–14 of pregnancy
Endometrial decidualization: of mice and men
Ramathal CY, Bagchi IC, Taylor RN, Bagchi MK. Semin Reprod Med. 2010 Jan;28(1):17-26. Epub 2010 Jan 26. Review. PMID 20104425
Endometrial pinopodes indicate a shift in the window of receptivity in IVF cycles
Pinopodes are small, finger-like protrusions from the endometrium.
The formation of endometrial pinopodes detected by scanning electron microscopy may be a specific marker for uterine receptivity. Aiming to assess the effects of ovarian stimulation on pinopode formation, we examined sequential endometrial biopsies from 17 oocyte donors. Seven normally menstruating women served as controls. Up to four samples were taken from each woman at 24–72 h intervals between days 14 and 24, giving a total of 69 samples. The day of oocyte retrieval was designated day 14 in ovarian stimulation cycles and the day of luteinizing hormone surge was designated day 13 in natural cycles. Endometrial morphology and pinopode numbers were similar in both groups. Fully developed pinopodes appeared in only one sample per cycle, indicating their short life span. However, the cycle day these structures appeared varied up to 5 days between women and the distribution was as follows: day 18 (n=2), day 19 (n=7), day 20 (n=4), day 21 (n=3), day 22 (n=1) in ovarian stimulation cycles, and day 20 (n=2), day 21 (n=2), day 22 (n=3) in natural cycles. Furthermore, accelerated pinopode formation in ovarian stimulation cycles was positively correlated with day 13 progesterone. Our findings show that ovarian stimulation does not affect endometrial pinopode formation in terms of quantity and life span. The cycle days when pinopodes form are specific to the individual, being on average 1–2 days earlier in ovarian stimulation than in natural cycles. These changes in pinopode expression may reflect shifts in the window of receptivity, resulting in ovo-endometrial asynchrony and limiting implantation success in in-vitro fertilization.
Modulation of the maternal immune system by the pre-implantation embryo
BMC Genomics. 2010 Aug 13;11:474.
Walker CG, Meier S, Littlejohn MD, Lehnert K, Roche JR, Mitchell MD.
DairyNZ Ltd,, Hamilton, New Zealand. Caroline.Walker@dairynz.co.nz Abstract BACKGROUND: A large proportion of pregnancy losses occur during the pre-implantation period, when the developing embryo is elongating rapidly and signalling its presence to the maternal system. The molecular mechanisms that prevent luteolysis and support embryo survival within the maternal environment are not well understood. To gain a more complete picture of these molecular events, genome-wide transcriptional profiles of reproductive day 17 endometrial tissue were determined in pregnant and cyclic Holstein-Friesian dairy cattle.
RESULTS: Microarray analyses revealed 1,839 and 1,189 differentially expressed transcripts between pregnant and cyclic animals (with > or = 1.5 fold change in expression; P-value < 0.05, MTC Benjamini-Hochberg) in caruncular and intercaruncular endometrium respectively. Gene ontology and biological pathway analysis of differentially expressed genes revealed enrichment for genes involved in interferon signalling and modulation of the immune response in pregnant animals.
CONCLUSION: The maternal immune system actively surveys the uterine environment during early pregnancy. The embryo modulates this response inducing the expression of endometrial molecules that suppress the immune response and promote maternal tolerance to the embryo. During this period of local immune suppression, genes of the innate immune response (in particular, antimicrobial genes) may function to protect the uterus against infection.
Special Issue - The Intra-uterine Environment and Placentation
July 2009 Volume 215, Issue 1 Pages 1–90
- Issue content
- Adhesion molecules in endometrial epithelium: tissue integrity and embryo implantation
- You have free access to this contentTrophoblast-mediated spiral artery remodelling: a role for apoptosis
- Insulin and the IGF system in the human placenta of normal and diabetic pregnancies
- A stereological perspective on placental morphology in normal and complicated pregnancies
Secreted phosphoprotein 1 (SPP1, osteopontin) binds to integrin alpha v beta 6 on porcine trophectoderm cells and integrin alpha v beta 3 on uterine luminal epithelial cells, and promotes trophectoderm cell adhesion and migration
Biol Reprod. 2009 Nov;81(5):814-25. Epub 2009 Jul 1.
Erikson DW, Burghardt RC, Bayless KJ, Johnson GA.
Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas 77843, USA. Abstract Conceptus implantation involves pregnancy-specific alterations in extracellular matrix at the conceptus-maternal interface. Secreted phosphoprotein 1 (SPP1, osteopontin) is induced just before implantation and is present at the conceptus-maternal interface in mammals. In the present study, we investigated mechanisms by which SPP1 facilitates porcine conceptus and uterine luminal epithelial cell attachment. Native bovine milk and wild-type rat recombinant SPP1 stimulated trophectoderm cell migration. Bovine milk SPP1, ovine uterine SPP1, and recombinant wild-type, but not mutated, rat SPP1 promoted dose- and cation-dependent attachment of porcine trophectoderm and uterine luminal epithelial cells, which was markedly reduced in the presence of a linear Arg-Gly-Asp integrin-blocking peptide. Affinity chromatography and immunoprecipitation experiments revealed direct binding of alpha v beta 6 trophectoderm and alpha v beta 3 uterine epithelial cell integrins to SPP1. Immunofluorescence microscopy using SPP1-coated microspheres revealed colocalization of the alpha v integrin subunit and talin at focal adhesions as well as at the apical domain of trophectoderm cells. Similarly, immunofluorescence staining of implantation sites in frozen gravid uterine cross sections localized SPP1 and alpha v integrin to the apical surfaces of trophectoderm and luminal epithelium and beta 3 integrin to the apical surface of luminal epithelium. To our knowledge, the present study is the first to demonstrate functionally that SPP1 directly binds specific integrins to promote trophectoderm cell migration and attachment to luminal epithelium that may be critical to conceptus elongation and implantation.
The expression of receptivity markers in the fallopian tube epithelium
Histochem Cell Biol. 2009 Aug;132(2):159-67. Epub 2009 Apr 23.
Makrigiannakis A, Karamouti M, Petsas G, Makris N, Nikas G, Antsaklis A.
In Vitro Fertilization Unit, Department of Obstetrics and Gynaecology, Medical School, University of Crete, Heraklion, 71003, Greece. email@example.com
Abstract Pinopodes represent the morphological and integrins, the biomolecular markers of endometrial receptivity. We studied using scanning electron microscopy, the expression of pinopodes on tubal samples and their corresponding endometria, from 21 women of reproductive age (7 from proliferative phase, 7 from day LH +5 and 7 from day LH +7). In addition, we examined the immunohistochemical staining of integrins alpha v beta 3, alpha v beta 5 and their ligands, fibronectin (FN) and osteopontin (OPN) in the same tubal epithelium samples. Pinopodes were detected on the tubal epithelium exclusively during day LH +7, coincident with their formation in the endometrium and synchronous to alpha v beta 3 sharp increase in the oviduct epithelium, suggesting a regulation similar to the endometrium. In contrast, alpha v beta 5, FN and OPN remained unchanged during the cycle. These results show for the first time the formation of pinopodes in the tubal epithelium at the time of endometrial receptivity and correlate it with the upregulation of the intact dimmer alpha v beta 3 in the tubes.
An integrated view of L-selectin and trophinin function in human embryo implantation
J Obstet Gynaecol Res. 2008 Apr;34(2):129-36.
Fukuda MN, Sugihara K. Source Glycobiology Unit, Tumor Microenvironment Program, NCI Cancer Center, Burnham Institute for Medical Research, La Jolla, California 92037, USA. firstname.lastname@example.org
Determining molecular mechanisms of human embryo implantation is an extremely challenging task due to the limitation of materials and significant differences underlying this process among mammalian species. Recently, L-selectin and its ligand carbohydrate have been proposed as a system that mediates initial adhesion of human blastocysts to the uterine epithelia. We have also identified trophinin as a unique apical cell adhesion molecule potentially involved in the initial adhesion of trophectoderm of the human blastocyst to endometrial surface epithelia. In the mouse, the binding between ErbB4 on the blastocyst and heparin-binding epidermal growth factor-like growth factor on the endometrial surface enables the initial step of the blastocyst implantation. The evidence suggests that L-selectin and trophinin are included in human embryo implantation. This review summarizes findings relevant to the functions of L-selectin and trophinin in human embryo implantation, and proposes a model that reconciles these cell adhesion mechanisms.
Proposed role of L-selectin and trophinin in human embryo implantation
(a) A human blastocyst entering the uterine cavity is prevented from adhering to endometrial surface epithelia by heavily glycosylated MUC1, except for epithelia that express L-selectin ligand (T). The human blastocyst expresses L-selectin (L), and ‘rolls’ on the endometrial surface covered by glycocalyx (cell surface layer shown by grey color).
(b) The blastocyst weakly interacts on the glycocalyx. During this interaction, human chorionic gonadotropin (hCG) secreted from the blastocyst acts locally on endometrial surface epithelia to induce trophinin expression in the endometrial epithelial cells.
(c) Trophinin expressed by endometrial epithelia is enriched in the pinopodes, the structure extended above the glycocalyx.42 MUC1, which is the major component of endometrial glycocalyx and carries L-selectin ligand, is down-regulated from the endometrial surface epithelia underneath the blastocyst,31 allowing direct contact of blastocyst trophectoderm cells and pinopodes. Trophectoderm cells and pinopodes then bind strongly together by trophinin-trophinin binding.
Time of implantation of the conceptus and loss of pregnancy
N Engl J Med. 1999 Jun 10;340(23):1796-9.
Wilcox AJ, Baird DD, Weinberg CR.
Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA. Abstract BACKGROUND: Implantation of the conceptus is a key step in pregnancy, but little is known about the time of implantation or the relation between the time of implantation and the outcome of pregnancy.
METHODS: We collected daily urine samples for up to six months from 221 women attempting to conceive after ceasing to use contraception. Ovulation was identified on the basis of the ratio of urinary estrogen metabolites to progesterone metabolites, which changes rapidly with luteinization of the ovarian follicle. The time of implantation was defined by the appearance of chorionic gonadotropin in maternal urine.
RESULTS: There were 199 conceptions, for 95 percent of which (189) we had sufficient data for analysis. Of these 189 pregnancies, 141 (75 percent) lasted at least six weeks past the last menstrual period, and the remaining 48 pregnancies (25 percent) ended in early loss. Among the pregnancies that lasted six weeks or more, the first appearance of chorionic gonadotropin occurred 6 to 12 days after ovulation; 118 women (84 percent) had implantation on day 8, 9, or 10. The risk of early pregnancy loss increased with later implantation (P<0.001). Among the 102 conceptuses that implanted by the ninth day, 13 percent ended in early loss. This proportion rose to 26 percent with implantation on day 10, to 52 percent on day 11, and to 82 percent after day 11.
CONCLUSIONS: In most successful human pregnancies, the conceptus implants 8 to 10 days after ovulation. The risk of early pregnancy loss increases with later implantation.
In most successful human pregnancies, the conceptus implants 8 to 10 days after ovulation. The risk of early pregnancy loss increases with later implantation.
The HOXA10 homeobox gene controls embryonic uterine development and adult endometrial receptivity. The three-amino-acid loop extension (TALE) family homeobox genes like myeloid ecotropic viral integration site 1 (MEIS) provide enhanced target gene activation and specificity in HOX-regulated cellular processes by acting as HOX cofactors.
Embryo-induced alterations in the molecular phenotype of primate endometrium
J Reprod Immunol. 2009 Dec;83(1-2):65-71. Epub 2009 Oct 31.
Nimbkar-Joshi S, Rosario G, Katkam RR, Manjramkar DD, Metkari SM, Puri CP, Sachdeva G.
Primate Biology Division, National Institute for Research in Reproductive Health, Mumbai, India.
endometrial expression of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNFalpha), as well as expression of immunosuppressive factors such as transforming growth factor beta-2 (TGFbeta2), interleukin-6 (IL-6) and placental protein-14 (PP-14), even before the embryo starts invading the endometrium.
Pinopodes: a questionable role in endometrial receptivity
Hum Reprod Update. 2009 Mar-Apr;15(2):229-36.
Quinn CE, Casper RF. Source Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Institute of Medical Sciences, University of Toronto, ON, Canada. Abstract BACKGROUND: A better understanding of endometrial receptivity is crucial to the creation and optimization of tests to assess the window of implantation in a clinical setting. Testing endometrial receptivity via scanning electron microscopy of endometrial samples reveals that pinopodes are a very good marker of endometrial receptivity in the rat. There is still disagreement in the literature as to their usefulness as a receptivity marker in both mice and humans.
METHODS: Publications related to the discovery, study and usefulness of pinopodes as a marker of endometrial preparation for implantation in both rodents and humans were identified through MEDLINE and other bibliographic databases.
RESULTS: There is substantial evidence that pinopodes are good markers of endometrial receptivity in the rat. Pinopodes are not useful in the mouse or human as consistent markers of endometrial receptivity for implantation. In the human, pinopodes have a prolonged (>5 days) presence in the luteal phase and fail to delineate the brief (24-48 h) window of receptivity.
CONCLUSIONS: While there are many publications arising from one group supporting the use of pinopodes as a reliable marker of human endometrial receptivity, few independent groups have been able to confirm these results. The clinical usefulness of pinopodes to delineate a period of endometrial receptivity seems unlikely following recent findings that pinopodes are present throughout the luteal phase of the menstrual cycle.
Expression of Wilms' tumor suppressor gene (WT1) in human endometrium: regulation through decidual differentiation
J Clin Endocrinol Metab. 2001 Dec;86(12):5964-72. Makrigiannakis A, Coukos G, Mantani A, Prokopakis P, Trew G, Margara R, Winston R, White J.
Department of Reproductive Science and Medicine, Imperial College School of Medicine, Hammersmith Hospital, W12 ONN OHS, London, United Kingdom. email@example.com Abstract The Wilms' tumor suppressor gene (WT1) encodes a zinc-finger containing transcription factor that is selectively expressed in the developing urogenital tract and functions as a tissue-specific developmental regulator. In addition to its gene-regulatory function through DNA binding properties, WT-1 also regulates transcription by formation of protein-protein complexes. These properties place WT-1 as a major regulator of cell growth and differentiation. In view of these observations, we studied WT1 mRNA and protein in human endometrial extracts and in endometrial stromal cells (ESCs) differentiating into decidual cells in vitro, by RT-PCR and Western blotting, respectively. WT1 protein expression was also studied in situ in the proliferative and the secretory phase of the menstrual cycle in the early pregnant state. Analysis by PCR of total RNA prepared from human ESCs demonstrated the presence of WT1 mRNA and four WT1 mRNA splice variants. Western blot analysis of nuclear protein extracts from ESCs yielded one immunoreactive protein of the expected size (approximately 52-54 kDa) recognized by the WT1 antibody. Immunohistochemical staining showed that WT1 protein is localized only to nuclei of human endometrial stromal cells. It remains constant in the proliferative and the secretory phase of the menstrual cycle and is increased remarkably during decidualization in early pregnancy. ESCs decidualized in vitro were investigated for WT-1 expression, which confirmed that decidualizing stimuli (E2, medroxy-progesterone-acetate, and relaxin for 12 d or cAMP and progesterone for 1-4 d) induced WT-1 mRNA (P < 0.05) and increased protein levels (P < 0.05). These data indicate that in humans the WT1 gene is expressed in ESCs and its mRNA and protein levels remain constant in the proliferative and the secretory phase of the menstrual cycle and that WT1 mRNA and protein expression increases significantly in ESCs when these cells differentiate into decidual cells.
Potential roles of decidual prolactin in early pregnancy
Reproduction. 2001 Feb;121(2):197-205.
Jabbour HN, Critchley HO.
MRC Human Reproductive Sciences Unit and Obstetrics and Gynaecology, Department of Reproductive and Development Sciences, Centre for Reproductive Biology, 37 Chalmers Street, Edinburgh EH3 9ET, UK. firstname.lastname@example.org Abstract Successful establishment of pregnancy is dependent on uterine receptivity at the time of trophoblast invasion and implantation. The endometrium undergoes morphological and functional differentiation during the mid- to late secretory phase of the menstrual cycle in preparation for such an event. These changes are orchestrated by ovarian steroid hormones. However, local autocrine-paracrine signalling at the deciduo-placental interface is crucial for successful establishment of pregnancy. One key cytokine that may regulate many functions in implantation is prolactin. Prolactin is secreted by the decidualized endometrium at the time of predicted conception and, in the event of pregnancy, local expression and secretion of prolactin persists until term. Prolactin mediates its effect on target cells through interaction with single-pass transmembrane receptors. Localization of the sites of expression of the prolactin receptor indicates that the cytokine may regulate an array of functions in the pregnant uterus that are crucial in im-plantation and early pregnancy.
Immunohistochemical evaluation of human placental implantation: an initial study
Am J Obstet Gynecol. 1985 Oct 1;153(3):239-44.
Tuttle SE, O'Toole RV, O'Shaughnessy RW, Zuspan FP.
Immunohistochemical staining for human chorionic gonadotropin and factor VIII-related antigen with the avidin-biotin complex immunoperoxidase technique was used as a marker for syncytiotrophoblast and endothelial cells, respectively, in the human placental bed. Material from placental implantation sites at varying stages of gestation (8 weeks to term) was studied. Trophoblastic invasion of the uterine stroma and blood vessels were evaluated. Syncytiotrophoblasts lining placental villi and anchoring villi were positive for human chorionic gonadotropin at all stages of gestation studied. Endothelial cells lining maternal uterine blood vessels were positive for factor VIII-related antigen. At early stages of intrauterine placentation (8 and 11 weeks) trophoblastic invasion of uterine blood vessels and trophoblastic incorporation in the walls of dilated vessels were present. An unexpected finding, however, was the large number of giant cells in the superficial placental bed which had morphology suggestive of syncytiotrophoblast but which were negative for human chorionic gonadotropin. In addition, many enlarged, rather pleomorphic cells lining superficial blood vessels were found to be positive for factor VIII-related antigen, which identified them as endothelial cells and not migrating trophoblastic elements. This study demonstrates that human chorionic gonadotropin and factor VIII-related antigen immunoperoxidase staining is a helpful adjunct in evaluating human placentation and suggests extension of the technique with use of other antibodies to evaluate components of the placental bed.
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