FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2085996922> ?p ?o ?g. }

• W2085996922 endingPage "5" @default.
• W2085996922 startingPage "1" @default.
• W2085996922 abstract "It may have involved only 23 good-quality human embryos, and the findings were published as a technical report in Nature Medicine, but the study of Vanneste and colleagues deserves a closer look1. Using a new array-based approach that allows combined screening of genome-wide copy number and loss of heterozygosity in single blastomeres, these investigators examined the incidence of gross chromosomal errors in cleavage-stage embryos from young fertile women. The incidence was staggering. In fact, only two out of the 23 cleavage-stage in-vitro fertilization (IVF) embryos were found to have a normal karyotype in all blastomeres, approximately half of the embryos had no normal cells at all and the remainder were mosaic for large-scale structural chromosomal imbalances, caused predominantly by mitotic non-disjunction1. Whether or not spontaneously conceived pre-implantation human embryos display similar frequency and complexity of gross chromosomal errors remains untested, although there are few, if any, reasons to doubt it. If confirmed, the data imply that the number of ‘healthy’ live births far outstrips the number of ‘normal’ human embryos at the time of implantation. While the study of Vanneste and coworkers sheds new light on some key issues in reproductive medicine, it simultaneously raises some difficult new questions. For example, the mitotic error rate in cleavage-stage embryos was found to be much higher than the meiotic aneuploidy rate. Consequently, the genome of one or two blastomeres is unlikely to be representative of the whole embryo, which explains the failure of pre-implantation genetic screening to improve IVF outcome2. The remarkable prevalence of gross chromosomal instability in human embryos, irrespective of maternal age, is likely to be a major factor in the low monthly conception rates, averaging approximately 20%, which compares unfavorably with many other species. However, if a transient period of chromosomal instability in human embryonic development is the norm, rather than the exception, what could be the possible biological advantages? What are the mechanisms that subsequently restore chromosomal order, especially in the inner cell mass? And how can the mother prevent investment in compromised pregnancies and safely dispose of grossly abnormal human embryos, which from a genetic viewpoint have been compared to cancer cells? As implantation sites are pretty much inaccessible in humans, our understanding of early pregnancy events is invariably based on animal models, and more specifically, the mouse3. Here, implantation is viewed as a harmonious and cooperative process, with the developmentally competent embryo engaging in molecular ‘cross-talk’ with a receptive endometrium. The result of this dialogue allows the embryo to make loose and then stable contact with the luminal endometrial epithelial cells. The embryo then invades the underlying stroma and triggers a maternal decidual response, characterized by local edema, influx of immune cells and differentiation of stromal fibroblasts into specialist secretory decidual cells4. This model of embryo implantation has been uncritically transposed to the human situation. Consequently, the Holy Grail in reproductive medicine, especially within the context of IVF, has been the search for markers predictive, on the one hand, of endometrial receptivity (e.g. αvβ3 integrin, interleukin-11 or leukemia inhibitory factor)5-7 and, on the other hand, of embryonic competence (e.g. pre-implantation genetic screening). Despite tremendous efforts of numerous investigators, attempts to predict successful implantation, and thus improve subsequent take-home baby rates, have so far been futile, although the enthusiasm for this approach appears to be undiminished8. Furthermore, endeavors to improve IVF outcome by treating infertile patients with factors indispensable for implantation in the mouse, such as leukemia inhibitory factor, have so far only managed to achieve the opposite9. Superficially there seem to be few reasons to doubt that the murine model of implantation applies to human pregnancies, even if there are obvious interspecies differences. For example, gross embryonic chromosomal abnormalities are extremely rare in mice. However, this is thought to be irrelevant to the implantation model, as compromised human embryos are widely assumed to be biologically inert and unable to interact with maternal tissues (let alone implant), and whose ultimate fate is to ‘wither away’. In most mammals the endometrium transiently expresses a receptive phenotype, starting in the human approximately 6 days after the postovulatory progesterone surge and estimated to last between 2 and 4 days. The fact that the human ‘implantation window’ coincides with spontaneous decidualization of the stromal compartment, a process that in the absence of pregnancy triggers menstruation, is viewed as a quirky and rather unfortunate evolutionary variation, considering the high burden of menstrual disorders, but otherwise with little or no relevance to the implantation process6. Mouse, but not human, embryos are capable of temporarily suspending development while awaiting the correct maternal signals for implantation, a process termed embryonic ‘diapause’10. Moreover, the mouse strategy of reproductive success is obviously based on quantity, characterized by rapid breeding cycles, multiple synchronized implantation events, large litter size and natural selection of offspring after birth. But then again, why can these striking interspecies differences not be reconciled in a single implantation model? The answer to the above question is not ambiguous but simply that a single implantation model cannot accommodate the divergent reproductive strategies of mice and men. The differences are too profound. From an evolutionary perspective, pregnancy is far from being a harmonious encounter between mother and fetus but a continuously evolving challenge to accommodate the specific interests of both parties11, 12. Comparative genomic studies across many diverse taxa have consistently found that those genes related to reproduction and immune responses are among the most rapidly evolving in the genome13, suggesting that evolutionary changes in embryonic behavior and placenta formation are invariably opposed by maternal countermeasures. Human pre-implantation embryos are marred by chromosomal instability, cannot undergo diapause and give rise to deep invading placentae. Moreover, the notion that developmentally compromised embryos are somehow indolent and biologically silent is pertinently wrong. In fact, it is well established that arresting embryos are biologically extremely ‘noisy’ as the result of metabolic overdrive14. Thus, what are these maternal countermeasures that have evolved to deal with the unique human embryonic characteristics? The most striking innovation, confined to humans and a handful of other species with deep placentation, is spontaneous cyclic decidualization of the endometrium, which in the absence of pregnancy triggers menstruation15. Once the blastocyst has breached the luminal epithelium, it becomes quickly embedded in the uterine mucosa16. Extravillous trophoblast cells then emanate from the tips of the anchoring chorionic villi and invade the decidua as well as the inner third of the myometrium17. A subpopulation of these cells, the endovascular extravillous trophoblast cells, intravasates the terminal spiral arteries, plugging them for several weeks before destroying most of the musculoelastic vessel wall, thereby establishing high-flow, low-resistance uteroplacental circulation. Thus, human trophoblast seems to display such aggressive features that it has been compared to an invading and metastasizing tumor18. This widely held view invariably assigns the decidua the role of the defender whose job it is to control invasion by keeping the aggressive trophoblast in check. This concept of the ‘passive’ decidua and the ‘invasive’ embryo is being challenged by recent observations. In coculture models, hatched blastocysts placed onto a monolayer of decidualized endometrial stromal cells undergo expansion, a process that resembles embryo invasion19, 20. Interestingly, trophoblast outgrowth was found to be dependent on the migratory capacity of the decidual cells, as inhibition of pathways that regulate motility, cytoskeleton re-organization and focal adhesion in decidual cells severely compromised blastocyst expansion19, 20. Our own work has highlighted that the migratory and invasive capacities of endometrial stromal cells are markedly enhanced upon differentiation into decidual cells and then fully unleashed in response to trophoblast-derived signals21. These observations bear two novel messages for our understanding of human implantation: first, decidualization renders the endometrial stromal compartment more responsive to trophoblastic signals and, second, the role of the decidua in remodeling of the fetal–maternal interface is much more dynamic than hitherto recognized. In fact, the findings suggest that, rather than being invaded, the decidual cells actively engulf and encapsulate the embryo, a concept that fits well the appearance of early human implantation sites on high-resolution ultrasound or histological analysis (Figure 1)22, 23. Embryo invasion or decidual encapsulation? (a) High-resolution ultrasound image of an early implantation site. An abnormal amount of free fluid in the uterine lumen (dotted line) allowed clear visualization of the gestational sac bulging into the lumen cavity. The pregnancy went on to progress normally. (b) Drawing of an early human implantation site (Carnegie stage 6). The superficial uterine epithelium is discontinuous. The conceptus (blue) is about 2 mm in diameter. The embryo is visible and at the bilaminar disc stage, and the presumptive intervillous space can be seen within the trophoblast layer. The endometrium comprises a superficial compact layer within which the implantation cavity is located, and a deeper spongiosum. Approximately 7 days after attachment. (Reproduced from Aplin and Jones22 and Falkiner23 with permission). Why would decidualizing endometrial cells actively encapsulate the early conceptus? The answer may lie in the remarkable observations made by Teklenburg and colleagues24. These investigators used a human co-culture model, consisting of hatched blastocysts cultured on decidualizing endometrial stromal cells, in an attempt to identify key factors involved in the embryo–maternal cross-talk during early pregnancy. To do this, the co-culture supernatants were collected after 3 days, and the levels of a host of putative implantation cytokines, growth factors and chemokines were measured and compared with the levels produced by decidualizing endometrial stromal cells in the absence of an embryo. The experimental strategy was risky as individual blastocysts were cocultured with at least 50 000 decidualizing endometrial cells. Nonetheless, these investigators went ahead, hoping that the maternal response to a developing embryo would be sufficient to alter the accumulating levels of various secreted implantation mediators in the cocultures. They were wrong. Except for a modest decrease in interleukin-5 expression, developing human embryos had no detectable effects on the decidual secretions. However, and most fortuitously, a phenomenal response was noted when embryos became compromised during the coculture period. When the blastocyst appeared morphologically to be arresting, the decidualizing cells responded by shutting down the production of key implantation mediators and immunomodulators. Teklenburg and colleagues then went on to repeat the coculture experiments, but this time with endometrial stromal cells not first decidualized, and found that the blastocyst did not trigger a maternal response, irrespective of whether or not the embryonic development in culture was normal24. Thus, human endometrial stromal cells become biosensors of embryo quality, but only upon differentiation into decidual cells. Moreover, the magnitude of this response is impressive, which suggests that it is not confined to cells in the immediate vicinity of the embryo but propagated throughout the decidua. Put differently, the data suggest that cyclic decidualization enables the endometrium to rapidly encapsulate the implanting conceptus, to perform quality control, and to dispose of developmentally compromised embryos by triggering a menstruation-like event. The observation that cyclic decidualization of the endometrium may have emerged as a mechanism for rapid embryo encapsulation, recognition and selection, immediately raised the possibility that defects in this process could facilitate implantation of compromised embryos and result in early pregnancy loss. In truth, this concept of impaired embryo selection underpinning miscarriages is not entirely new. For example, a study of 221 women attempting to conceive demonstrated a dramatic increase in the risk of early miscarriage if pregnancy was established beyond the normal ‘implantation window’25. Similarly, another study found that women suffering recurrent spontaneous miscarriage express lower levels of mucin 1, an anti-adhesion molecule that contributes to the barrier function of luminal epithelium26. While these studies strongly hinted that inadequate embryo selection at the time of implantation is causal to pregnancy loss27, the role of the decidualizing stromal cells in this process had not yet been investigated. We therefore examined the expression of two marker genes in mid-secretory endometrial biopsies from women with and without a history of three or more consecutive pregnancy losses. The first marker, prokineticin-1, is a recently identified key regulator of endometrial receptivity28, and the second, prolactin, is expressed in the endometrium only by decidualizing cells4. Consistent with the concept of impaired embryo recognition and selection, we found that decidual prolactin expression was grossly impaired in women with recurrent pregnancy loss, whereas the prokineticin-1 levels were higher, especially in biopsy samples from patients suffering predominantly from preclinical (biochemical) miscarriages29. Remarkably, these in vivo findings were entirely recapitulated when endometrial stromal cells were purified from patients with and without recurrent miscarriages and decidualized in culture. In addition to attenuated prolactin production and prolonged and enhanced prokineticin-1 expression, recurrent pregnancy loss was further associated with a complete dysregulation of both markers in response to treatment of the cultures with human chorionic gonadotropin, a glycoprotein hormone abundantly expressed by the implanting embryo29. In sum, the data demonstrate that endometrial preparation for pregnancy in recurrent miscarriage patients is characterized by impaired decidualization of resident stromal cells, prolonged endometrial receptivity, lack of embryo recognition and a dysregulated response to embryonic signals. Reproduction in humans is unique in two major aspects. First, the incidence of chromosomally abnormal and developmentally compromised human pre-implantation embryos is exceptionally high and, second, the uterus decidualizes spontaneously each cycle, a process responsible for the menstrual shedding of the endometrium in the absence of a viable pregnancy. We propose that these reproductive peculiarities are in fact functionally linked, with the decidual process enabling the mother to limit investment in compromised pregnancies. The concept of natural embryo selection raises important, but as yet unanswered, questions. For example, the nature of the embryonic signals responsible for the decidual response remains elusive and we do not understand the mechanism that enables endometrial stromal cells to become biological sensors of embryo quality upon decidualization. Whether or not the decidual response is tailored to individual embryos, and contributes to ‘normalization’ of the implanting embryo, is also not known but is not beyond the realms of possibilities29. The natural embryo-selection paradigm sheds new light on many aspects of early pregnancy complications. For example, while the decidual process may be essential for embryo selection, it is also indispensable for placenta formation. In other words, a single pathological pathway may be responsible for both euploidic and aneuploidic pregnancy losses. In view of the excess of chromosomally abnormal pre-implantation human embryos, this unifying concept predicts that the likelihood of euploidic pregnancy failure increases with the number of miscarriages, which is indeed the case30. It also predicts that miscarriage is a risk factor for late obstetric complications in a subsequent ongoing pregnancy and explains why many patients suffering from recurrent pregnancy loss appear to be ‘superfertile’29, defined by consistent, very short time-to-pregnancy intervals. Above everything else, however, the natural embryo-selection paradigm infers that preconception markers exist that are predictive of subsequent pregnancy outcome. If correct, these markers could have far-reaching clinical implications by allowing identification and treatment of women at risk of pregnancy complication before pregnancy." @default.
• W2085996922 created "2016-06-24" @default.
• W2085996922 creator A5025845183 @default.
• W2085996922 creator A5091306061 @default.
• W2085996922 date "2010-06-25" @default.
• W2085996922 modified "2023-10-09" @default.
• W2085996922 title "Something new about early pregnancy: decidual biosensoring and natural embryo selection" @default.
• W2085996922 cites W108658453 @default.
• W2085996922 cites W1968846073 @default.
• W2085996922 cites W1975690978 @default.
• W2085996922 cites W1980151434 @default.
• W2085996922 cites W1993866784 @default.
• W2085996922 cites W2002059069 @default.
• W2085996922 cites W2004020866 @default.
• W2085996922 cites W2011809207 @default.
• W2085996922 cites W2013801759 @default.
• W2085996922 cites W2018217912 @default.
• W2085996922 cites W2035127972 @default.
• W2085996922 cites W2045461902 @default.
• W2085996922 cites W2049014099 @default.
• W2085996922 cites W2053701919 @default.
• W2085996922 cites W2065346340 @default.
• W2085996922 cites W2073882976 @default.
• W2085996922 cites W2074682657 @default.
• W2085996922 cites W2092182760 @default.
• W2085996922 cites W2100963977 @default.
• W2085996922 cites W2109657910 @default.
• W2085996922 cites W2112675387 @default.
• W2085996922 cites W2120403739 @default.
• W2085996922 cites W2131074211 @default.
• W2085996922 cites W2133381977 @default.
• W2085996922 cites W2133735092 @default.
• W2085996922 cites W2138256051 @default.
• W2085996922 cites W2158141040 @default.
• W2085996922 cites W2167383223 @default.
• W2085996922 cites W2325674170 @default.
• W2085996922 cites W605487361 @default.
• W2085996922 doi "https://doi.org/10.1002/uog.7714" @default.
• W2085996922 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/20582930" @default.
• W2085996922 hasPublicationYear "2010" @default.
• W2085996922 type Work @default.
• W2085996922 sameAs 2085996922 @default.
• W2085996922 citedByCount "38" @default.
• W2085996922 countsByYear W20859969222012 @default.
• W2085996922 countsByYear W20859969222013 @default.
• W2085996922 countsByYear W20859969222014 @default.
• W2085996922 countsByYear W20859969222015 @default.
• W2085996922 countsByYear W20859969222016 @default.
• W2085996922 countsByYear W20859969222017 @default.
• W2085996922 countsByYear W20859969222018 @default.
• W2085996922 countsByYear W20859969222019 @default.
• W2085996922 countsByYear W20859969222020 @default.
• W2085996922 countsByYear W20859969222021 @default.
• W2085996922 countsByYear W20859969222022 @default.
• W2085996922 crossrefType "journal-article" @default.
• W2085996922 hasAuthorship W2085996922A5025845183 @default.
• W2085996922 hasAuthorship W2085996922A5091306061 @default.
• W2085996922 hasConcept C131872663 @default.
• W2085996922 hasConcept C154945302 @default.
• W2085996922 hasConcept C16685009 @default.
• W2085996922 hasConcept C172680121 @default.
• W2085996922 hasConcept C196843134 @default.
• W2085996922 hasConcept C2776953305 @default.
• W2085996922 hasConcept C2779234561 @default.
• W2085996922 hasConcept C2780197806 @default.
• W2085996922 hasConcept C2908647359 @default.
• W2085996922 hasConcept C29456083 @default.
• W2085996922 hasConcept C41008148 @default.
• W2085996922 hasConcept C54355233 @default.
• W2085996922 hasConcept C71924100 @default.
• W2085996922 hasConcept C75268714 @default.
• W2085996922 hasConcept C81917197 @default.
• W2085996922 hasConcept C86803240 @default.
• W2085996922 hasConcept C95444343 @default.
• W2085996922 hasConcept C99454951 @default.
• W2085996922 hasConceptScore W2085996922C131872663 @default.
• W2085996922 hasConceptScore W2085996922C154945302 @default.
• W2085996922 hasConceptScore W2085996922C16685009 @default.
• W2085996922 hasConceptScore W2085996922C172680121 @default.
• W2085996922 hasConceptScore W2085996922C196843134 @default.
• W2085996922 hasConceptScore W2085996922C2776953305 @default.
• W2085996922 hasConceptScore W2085996922C2779234561 @default.
• W2085996922 hasConceptScore W2085996922C2780197806 @default.
• W2085996922 hasConceptScore W2085996922C2908647359 @default.
• W2085996922 hasConceptScore W2085996922C29456083 @default.
• W2085996922 hasConceptScore W2085996922C41008148 @default.
• W2085996922 hasConceptScore W2085996922C54355233 @default.
• W2085996922 hasConceptScore W2085996922C71924100 @default.
• W2085996922 hasConceptScore W2085996922C75268714 @default.
• W2085996922 hasConceptScore W2085996922C81917197 @default.
• W2085996922 hasConceptScore W2085996922C86803240 @default.
• W2085996922 hasConceptScore W2085996922C95444343 @default.
• W2085996922 hasConceptScore W2085996922C99454951 @default.
• W2085996922 hasIssue "1" @default.
• W2085996922 hasLocation W20859969221 @default.
• W2085996922 hasLocation W20859969222 @default.
• W2085996922 hasOpenAccess W2085996922 @default.
• W2085996922 hasPrimaryLocation W20859969221 @default.

• next