43
159.80
3.72
79

Publication History View all

  • [Show abstract] [Hide abstract]
    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
  • Source
    [Show abstract] [Hide abstract]
    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
  • Source
    [Show abstract] [Hide abstract]
    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; DOI:10.1016/j.rbmo.2013.09.008
  • [Show abstract] [Hide abstract]
    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
  • Source
    [Show abstract] [Hide abstract]
    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
  • Source
    Reproductive biomedicine online 04/2013; 26(4):303-4. DOI:10.1016/j.rbmo.2013.02.010
  • [Show abstract] [Hide abstract]
    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
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Early mammalian development consists of two distinct phases separated by the event of implantation. Whereas much has been discovered about developmental mechanisms prior to implantation, the inability to culture and follow in real time cell behaviour over the period of implantation means that the second phase has not been explored in as much detail. Recently, a novel in-vitro culture system was described that permits continuous culture and time-lapse observations through the peri- and early post-implantation stages. This system has already delivered detailed information on the cellular processes accompanying early morphogenesis and allowed direct connections to be established between events occurring at the two developmental phases. This review discusses the potential of this novel technology and its possible applications that could have not only impact on basic science but also practical implications for human medicine. Early mammalian development consists of two distinct phases separated by the event of implantation (preimplantation and post-implantation). Whereas much has been discovered about developmental mechanisms prior to implantation, the inability to culture and follow in real time cell behaviour over the period of implantation has resulted in the second phase remaining explored in much less detail. Recently, a novel in-vitro culture system was described that permits continuous culture and time-lapse observations through the peri- and early post-implantation stages. This system has already delivered detailed information on the cellular processes accompanying early morphogenesis and allowed direct connections to be established between events occurring at the two developmental phases. This review discusses the potential of this novel technology and its possible applications that could have not only impact on basic science but also practical implications for human medicine.
    Reproductive biomedicine online 02/2013; 26(6). DOI:10.1016/j.rbmo.2013.02.009
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Fetal growth is critically dependent on energy metabolism in the placenta, which drives active exchange of nutrients. Placental oxygen levels are therefore vital, and chronic hypoxia during pregnancy impairs fetal growth. Here we tested the hypothesis that placental hypoxia alters mitochondrial electron transport chain (ETS) function, and sought to identify underlying mechanisms. We cultured human placental cells under different oxygen concentrations. Mitochondrial respiration was measured, alongside levels of ETS complexes. Additionally, we studied placentas from sea-level and high-altitude pregnancies. After 4 d at 1% O(2) (1.01 KPa), complex I-supported respiration was 57% and 37% lower, in trophoblast-like JEG3 cells and fibroblasts, respectively, compared with controls cultured at 21% O(2) (21.24 KPa); complex IV-supported respiration was 22% and 30% lower. Correspondingly, complex I levels were 45% lower in placentas from high-altitude pregnancies than those from sea-level pregnancies. Expression of HIF-responsive microRNA-210 was increased in hypoxic fibroblasts and high-altitude placentas, whilst expression of its targets, iron-sulfur cluster scaffold (ISCU) and cytochrome c oxidase assembly protein (COX10), decreased. Moreover, protein synthesis inhibition, a feature of the high-altitude placenta, also suppressed ETS complex protein levels. Our results demonstrate that mitochondrial function is altered in hypoxic human placentas, with specific suppression of complexes I and IV compromising energy metabolism and potentially contributing to impaired fetal growth.
    PLoS ONE 01/2013; 8(1):e55194. DOI:10.1371/journal.pone.0055194
  • [Show abstract] [Hide abstract]
    ABSTRACT: PURPOSE OF REVIEW: Size at birth is critical in determining life expectancy with both small and large neonates at risk of shortened life spans. This review examines the hormonal and nutritional drivers of intrauterine growth with emphasis on the role of foetal hormones as nutritional signals in utero. RECENT FINDINGS: Nutrients drive intrauterine growth by providing substrate for tissue accretion, whereas hormones regulate nutrient distribution between foetal oxidative metabolism and mass accumulation. The main hormonal drivers of intrauterine growth are insulin, insulin-like growth factors and thyroid hormones. Together with leptin and cortisol, these hormones control cellular nutrient uptake and the balance between accretion and differentiation in regulating tissue growth. They also act indirectly via the placenta to alter the materno-foetal supply of nutrients and oxygen. By responding to nutrient and oxygen availability, foetal hormones optimize the survival and growth of the foetus with respect to its genetic potential, particularly during adverse conditions. However, changes in the intrauterine growth of individual tissues may alter their function permanently. SUMMARY: In both normal and compromised pregnancies, intrauterine growth is determined by multiple hormonal and nutritional drivers which interact to produce a specific pattern of intrauterine development with potential lifelong consequences for health.
    01/2013; DOI:10.1097/MCO.0b013e32835e3643
Information provided on this web page is aggregated encyclopedic and bibliographical information relating to the named institution. Information provided is not approved by the institution itself. The institution’s logo (and/or other graphical identification, such as a coat of arms) is used only to identify the institution in a nominal way. Under certain jurisdictions it may be property of the institution.
View all

Top publications last week

 
Journal of the Society for Gynecologic Investigation 10/2004; 11(6):342-52. DOI:10.1016/j.jsgi.2004.03.003
15 Downloads
 
Journal of Clinical Endocrinology &amp Metabolism 07/2002; 87(6):2954-9. DOI:10.1210/jcem.87.6.8563
7 Downloads