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    ABSTRACT: Trophoblast stem cells (TSCs) are a self-renewing stem cell population derived from the early trophoblast lineage, analogous to embryonic stem cells (ESCs) that can be generated from the inner cell mass (ICM) of the mouse blastocyst. In that sense TSCs and ESCs reflect the earliest lineage differentiation event after fertilization. TSCs are characterized by an indefinite proliferation potential and by multipotency, i.e. the ability to differentiate into all the various trophoblast cell types of the placenta. These properties are driven by specific signalling pathways orchestrating characteristic transcriptional outputs. Here we review the recent advances in studying the signalling cascades and the transcriptional regulatory networks that define specification and maintenance of TSCs, and provide a future outlook of TSC research.
    Placenta 11/2013; DOI:10.1016/j.placenta.2013.10.013
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    ABSTRACT: A report on the UK Genome Science Meeting, held at the University of Nottingham, UK, 2-4 September 2013.
    Genome biology 10/2013; 14(10):312. DOI:10.1186/gb4135
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    ABSTRACT: During development, a fetus and its placenta must respond to a changing maternal environment to ensure normal growth is achieved and survival is maintained. The mechanisms behind developmental programming involve complex interactions between epigenetic and physiological processes, which are not well understood. Importantly, when programming goes awry, it puts the fetus at risk for disease later in life and may, in some instances, affect subsequent generations via epigenetic processes including DNA methylation. The one-carbon metabolism, which includes the folate, methionine and choline pathways, provides methyl groups necessary for DNA methylation and a normal epigenetic landscape. Accordingly, disruptions in this pathway affect placental development and function leading to altered fetal programming. Remarkably, recent studies have revealed that abnormal folate metabolism causes transgenerational effects probably through epigenetic inheritance. The epigenetic mechanisms behind this phenomenon are not well understood but they have important implications for the influence of the metabolic environment on epigenetic stability and non-genetic inheritance of disease. Importantly, there are increasing concerns that assisted reproductive technologies cause aberrant epigenetic profiles in embryos leading to abnormal fetal programming. How the negative epigenetic consequences of assisted reproduction treatment affect subsequent generations requires further investigation. It is well established that the food we eat and the environment that we are exposed to as a baby in our mother's womb, after birth and into adulthood affect our susceptibility to disease. Remarkably, evidence indicates that the effects of these environmental stressors may also be detrimental to the development of our children and our grandchildren, even when they are not exposed to the stressor. Research is ongoing to understand how these abnormalities are transmitted between generations through non-genetic means. Epigenetic mechanisms likely cause this phenomenon. Epigenetic control of gene expression involves molecules that bind to DNA and regulate whether a gene is 'on' or 'off'. The specific combination of these epigenetic marks throughout the genome determines what group of genes is expressed and, therefore, a cell's identity. Between each generation, these epigenetic signatures are 'wiped clean' or reprogrammed in the spermatozoa and eggs. If these epigenetic marks are dysregulated and/or reprogramming goes awry, abnormal epigenetic patterns might be inherited by the next generation. One study in mice has found that a defect in the metabolism of folate (folic acid), a vitamin important for normal fetal development, causes detrimental effects on development of its grandchildren and even great grandchildren, which may be attributed to inheritance of defective epigenetic marks. Importantly, some embryos generated by assisted reproduction treatment also have abnormal epigenetic profiles. Therefore, care must be taken to ensure that proper programming occurs so aberrant epigenetic changes are not inherited by subsequent generations, ultimately affecting their disease susceptibility.
    Reproductive biomedicine online 09/2013; 27(6). DOI:10.1016/j.rbmo.2013.09.008
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    ABSTRACT: The importance of maternal folate consumption for normal development is well established, yet the molecular mechanism linking folate metabolism to development remains poorly understood. The enzyme methionine synthase reductase (Mtrr) is necessary for utilization of methyl groups from the folate cycle. We found that a hypomorphic mutation of the mouse Mtrr gene results in intrauterine growth restriction, developmental delay, and congenital malformations, including neural tube, heart, and placental defects. Importantly, these defects were dependent upon the Mtrr genotypes of the maternal grandparents. Furthermore, we observed widespread epigenetic instability associated with altered gene expression in the placentas of wild-type grandprogeny of Mtrr-deficient maternal grandparents. Embryo transfer experiments revealed that Mtrr deficiency in mice lead to two distinct, separable phenotypes: adverse effects on their wild-type daughters' uterine environment, leading to growth defects in wild-type grandprogeny, and the appearance of congenital malformations independent of maternal environment that persist for five generations, likely through transgenerational epigenetic inheritance. PAPERFLICK:
    Cell 09/2013; 155(1):81-93. DOI:10.1016/j.cell.2013.09.002
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    ABSTRACT: Although embryo implantation is essential for human survival, it remains an enigmatic biological phenomenon. Following fertilization, the resulting blastocyst must signal its presence to the mother, attach to the luminal epithelium of the endometrium and embed into the decidualising stroma. Failure to do so results in infertility, which affects around 9% of women. Subsequent placental development requires remodelling of maternal blood vessels by trophoblast cells from the placenta, that invade deep into the decidua. Failure in these very early stages can compromise fetal development, resulting in diseases of pregnancy such as intrauterine growth restriction or pre-eclampsia which can also impact on health in adulthood. Abnormal implantation therefore constitutes a significant disease burden in humans. Although we have known for many years that successful implantation requires an embryo that is competent to implant and an endometrium that is receptive, the molecular basis of these processes remains poorly understood. Our inability to identify implantation-competent embryos or to diagnose/treat the non-receptive endometrium therefore limits our ability to intervene through assisted reproduction techniques. This Implantation Symposium aims to review recent exciting developments in our understanding of the biology of early implantation and to highlight the rapid progress being made to translate these into improved diagnosis and treatment.
    Reproductive biomedicine online 09/2013; 27(5). DOI:10.1016/j.rbmo.2013.08.005
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    ABSTRACT: Megalin and cubilin are multifunctional endocytic receptors associated with many transporting epithelia. They play an essential role in transport of nutrients through the visceral yolk sac of rodents during embryogenesis. Here, we immunolocalise them to the endodermal layer of the human yolk sac, and to the syncytiotrophoblast and cytotrophoblast cells of placental villi. In villi, the protein level of both receptors increased with gestation. The mRNA for megalin remained constant, while that encoding cubilin increased with gestation. These results suggest megalin and cubilin may be important in human maternal-fetal transfer, and that they increase across gestation to facilitate this function.
    Placenta 08/2013; 34(11). DOI:10.1016/j.placenta.2013.08.003
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    ABSTRACT: In developed societies, high-sugar and high-fat (HSHF) diets are now the norm and are increasing the rates of maternal obesity during pregnancy. In pregnant rodents, these diets lead to cardiovascular and metabolic dysfunction in their adult offspring, but the intrauterine mechanisms involved remain unknown. This study shows that, relative to standard chow, HSHF feeding throughout mouse pregnancy increases maternal adiposity (+30%, P<0.05) and reduces fetoplacental growth at d 16 (-10%, P<0.001). At d 19, however, HSHF diet group pup weight had normalized, despite the HSHF diet group placenta remaining small and morphologically compromised. This altered fetal growth trajectory was associated with enhanced placental glucose and amino acid transfer (+35%, P<0.001) and expression of their transporters (+40%, P<0.024). HSHF feeding also up-regulated placental expression of fatty acid transporter protein, metabolic signaling pathways (phosphoinositol 3-kinase and mitogen-activated protein kinase), and several growth regulatory imprinted genes (Igf2, Dlk1, Snrpn, Grb10, and H19) independently of changes in DNA methylation. Obesogenic diets during pregnancy, therefore, alter maternal nutrient partitioning, partly through changes in the placental phenotype, which helps to meet fetal nutrient demands for growth near term. However, by altering provision of specific nutrients, dietary-induced placental adaptations have important roles in programming development with health implications for the offspring in later life.-Sferruzzi-Perri, A. N., Vaughan, O. R., Haro, M., Cooper, W. N., Musial, B., Charalambous, M., Pestana, D., Ayyar, S., Ferguson-Smith, A. C., Burton, G. J., Constancia, M., Fowden, A. L. An obesogenic diet during mouse pregnancy modifies maternal nutrient partitioning and the fetal growth trajectory.
    The FASEB Journal 06/2013; 27(10). DOI:10.1096/fj.13-234823
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    ABSTRACT: Syncytiotrophoblast is the multinucleated epithelium of the placenta. Although many nuclei are dispersed within the syncytioplasm, others are aggregated into specializations, referred to as true and false syncytial knots and syncytial sprouts. Nuclei within true knots display highly condensed chromatin and are thought to be aged and effete. True knots increase in frequency with gestational age. Excessive formation (Tenney-Parker change) is associated with placental pathology, and a knotting index is used to assess severity. However, this index is potentially confounded by the creation of artifactual appearances (false knots) through tangential sectioning. In addition, knots must be distinguished from syncytial sprouts, which are markers of trophoblast proliferation. Here, we distinguish among sprouts, true knots, and false knots using serial sections and perform IHC for proliferating cell nuclear antigen, upstream binding factor, RNA polymerase II, and 8-oxo-deoxyguanosine as markers of recent incorporation, transcriptional activity, and oxidative damage. Villous explants were exposed to hydrogen peroxide to test the relationship between transcriptional activity and oxidative damage. Sprouts and false knots were found to contain recently incorporated and transcriptionally active nuclei. By contrast, most nuclei within true knots are negative for transcriptional markers but positive for 8-oxo-deoxyguanosine. In vitro, we observed a negative correlation between transcriptional activity and oxidative damage. These findings demonstrate that true knots contain effete damaged nuclei and provide IHC markers for their identification.
    American Journal Of Pathology 05/2013; DOI:10.1016/j.ajpath.2013.03.016
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    Reproductive biomedicine online 04/2013; 26(4):303-4. DOI:10.1016/j.rbmo.2013.02.010
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    ABSTRACT: Viviparity has many evolutionary advantages but brings with it the problem of the semi-allogeneic foetus having to coexist with the mother for the duration of pregnancy. In species with haemochorial placentation this problem is particularly evident as foetal trophoblast cells are extensively intermingled with maternal tissue and are directly exposed to maternal blood. Fascinating adaptations on both the foetal and maternal side have allowed for this interaction to be re-directed away from an immune rejection response not only towards immunotolerance, but in fact towards actively supporting reproductive success. Recent data have shown that some of these remarkable adaptations are conserved between mice and humans. Thus, a subset of trophoblast cells that is directly exposed to the maternal uterine environment shares the feature of expressing an unusual antigen repertoire on their surface. Paternal antigens can be recognized by maternal immune cells, in particular uterine natural killer cells that express cognate receptors, to regulate the extensive remodelling events that take place at the implantation site. Detailed genetic dissection experiments in the mouse have further demonstrated the direct impact of antigenic dissimilarity on foetal growth. With the availability of inbred strains, in vitro culture systems of trophoblast stem cells, and in-depth genetic, genomic and epigenomic data the mouse will be a valuable model system to study the intricate immune crosstalk at the foeto-maternal boundary. These insights will pave the way towards unravelling the mutual and synergistic interactions between trophoblast and its surrounding maternal environment, and in doing so help understand pregnancy pathologies.
    Journal of Reproductive Immunology 03/2013; 97(1):36-42. DOI:10.1016/j.jri.2012.10.006
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