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Scientific Milestones 2008 to 2016

Scientific Milestones 2008 to 2016

 

2016

What Is Trophoblast? A Combination of Criteria Define Human First-Trimester Trophoblast

Research performed at the Centre identified 4 key criteria that for the first time rigorously define ‘trophoblast’. A team led by Ashley Moffett showed that a set of protein markers combined with the HLA class I profile, methylation status of ELF-5, and expression of microRNAs from the chromosome 19 miRNA cluster reliably identifies human early trophoblast cells. These criteria should clarify the nature of many transformed and induced ‘trophoblast’ cell lines, and aid in interpretation of experimental data arising from their use. 

 

Self-organization of the human embryo in the absence of maternal tissues

Magda Zernicka-Goetz and colleagues provided new insights into the mechanisms by which the bilaminar human early embryo organises from the inner cell mass and how the amnion forms through their novel in vitro culture system involving artificial matrices. They demonstrate for the first time that amnion formation occurs through the formation of cell rosettes, and is independent of any maternal signalling. Their work continues to advance our understanding of the separation between the embryonic and extraembryonic lineages.

 

 

Computational modeling of the structure-function relationship in human placental terminal villi

Romina Plitman developed a computational model of blood flow though, and oxygen exchange across, terminal villi in the mature human placenta. Her model demonstrated the importance of the geometry of the fetal capillaries in terms of localised variations their calibre for delivering fetal blood to specialised areas for diffusional exchange, and allowing adequate time for transfer of oxygen to occur. This paves the way for more complex models integrating maternal and fetal blood flows that will shed light on how the 3D architecture of a placental lobule develops.

 

Dino Giussani, Amanda Sferruzzi-Perri and Abby Fowden edited a special issue of the Journal of Physiology dedicated to the memory of Sir Joseph Barcroft as part of the centennial celebrations of the Physiological Laboratory. The issue focused on the effects of hypoxia on placental and fetal development, and contained nine contributions from members of the Centre. (link to J Physiol)

 

2015

Screening for fetal growth restriction with universal third trimester ultrasonography in nulliparous women in the Pregnancy Outcome Prediction (POP) study: a prospective cohort study

Gordon Smith, Ulla Sovio and colleagues demonstrated from the POP study that screening of nulliparous women with universal third trimester fetal biometry roughly tripled detection of small-for-gestational age infants. Combining ultrasound analyses of fetal biometry and fetal growth velocity they were able to identify a subset of SGA fetuses that were at increased risk of neonatal morbidity. Their influential paper, published in the Lancet, will hopefully lead through a change in clinical practice to a reduction in the risk of stillbirth.

 

Fgf and Esrrb integrate epigenetic and transcriptional networks that regulate self-renewal of trophoblast stem cells

Paulina Latos and Myriam Hemberger identified the transcriptional networks that regulate self-renewal of murine trophoblast stem cells. The network centres around Elf-5 and downstream target genes, and their findings increase our understanding of early placental development.

 

2014

Differential activation of placental unfolded protein response pathways implies heterogeneity in causation of early- and late-onset pre-eclampsia.

The first molecular evidence demonstrating heterogeneity of placental pathology in cases of pre-eclampsia. Placental stress responses pathways are strongly activated in cases of early-onset pre-eclampsia, whereas placentas from late-onset cases (>34 weeks) are almost indistinguishable from normal controls. These data indicate a contrasting role of the placenta in causation of the two forms of the syndrome.

 

Magda Zernicka-Goetz creates a major breakthrough by developing an in vitro system enabling implantation of the blastocyst to be visualized and recorded in real time. The technique opens possibilities or understanding morphogenetic aspects of blastocyst development during implantation, and interactions with extracellular matrices. Link

 

Correction: Corrigendum: MHC-dependent inhibition of uterine NK cells impedes fetal growth and decidual vascular remodeling

Jens Kieckbusch and Louise Gaynor, working with Francesco Colucci and Ashley Moffett, provide compelling evidence that uterine Natural Killer cells play a key role in establishing the blood supply to the placenta. Inhibition of these cells during implantation in the mouse leads to compromised remodeling of the uterine spiral artery supplying the placenta and reduced fetal growth.

 

2013

Another first!..some compelling evidence of a role for the placenta in programming of adult life. Increased reactivity to anxiety-provoking stimuli is manifest later in life only in those animals where there is a mismatch between placental supply and fetal demand for nutrients during gestation. These findings further distinguish placental dysfunction from IUGR, and reveal a novel role for the placenta on long term programming of emotional behaviour. Link

 

The first demonstration that endoplasmic reticulum stress can lead to reduced energy levels through impairment of mitochondrial function. Inhibition of protein synthesis by stress-response pathways is associated with reduced levels and activities of complexes in the electron transport chain. These effects are seen in placentas from pregnancies at high altitude, and may contribute to the accompanying growth restriction. Link

 

Hydrogen sulphide and the placenta; first demonstration that hydrogen sulphide is a potent vasodilator of the fetal circulation in the human placenta, and that the enzyme responsible for its production in the smooth muscle around stem villus arteries is reduced in pathological placentas associated with increased umbilical vascular resistance. Link

 

 

2012

First experimental evidence that endoplasmic reticulum stress can lead to placental dysmorphogenesis, and that this is associated with loss of multipotency of trophoblast stem cells secondary to reduced bioactivity of key growth factors. This may be one mechanism by which placental stress results in growth restriction of the fetus. Link

 

First identification that oxidative stress in the fetal cardiovascular system is the mechanism through which developmental hypoxia programmes both cardiac and vascular disease in later life, providing not only an insight to mechanism but also possible targets for clinical intervention. Link

 

2011

First identification that interactions between paternal antigens on the invading trophoblast cells and receptors on the maternal immune cells (uterine Natural Killer cells) affect the blood flow to the fetus, and hence pup weight, in the mouse. This study confirmed the importance of immunological crosstalk for normal physiological function of the placenta, and the importance of immunological interactions for the developmental programming of adult Link

 

Demonstration that a low protein maternal diet influences gene expression in the pancreas of the rat fetus in utero, predisposing to type 2 diabetes in later life. This study identified a fundamental mechanism by which poor fetal nutrition, during critical periods of development, interacts with the genome to influence long-term health, and has major relevance for the current epidemic of diabetes. Link

 

First direct evidence of developmental mechanisms that limit total demand for maternal nutrients during fetal overgrowth. Prior to this study nothing was known about the relationship between the placenta and the fetus in the situation of genetically determined overgrowth. This work shows that feto-placental signals are in operation to avoid excess drainage of maternal resources that might otherwise compromise fetal viability and future maternal reproductive success. This work has important implications to our understanding of fetal overgrowth, as large-for-gestation age infants are becoming more common in many parts of the world. Link

 

2010

Publication of 'The Human Placenta and Developmental Programming'. This is the first text to explore the association between placental development and function, and the risk of developing chronic disease in later adult life. Link

 

First direct evidence that adverse maternal-fetal immunological interactions are associated with complications of human pregnancy, such as miscarriage, intrauterine growth restriction and pre-eclampsia. This study identified that certain combinations of antigens on the invading trophoblast cells and receptors on the uterine Natural Killer cells appear to place the pregnancy at risk. Link

 

First identification of an epigenetically regulated trophoblast stem cell compartment in the human early placenta. This study demonstrated the presence of a population of highly proliferative cytotrophoblast cells positive for the transcription factor ELF5 over the villous surface and at the proximal end of the cytotrophoblast cell columns. Link

 

2009

First demonstration that some nuclei within the syncytiotrophoblast are transcriptionally active, shedding new insight into how this critical tissue is able to adapt rapidly to changes in the intrauterine environment. Link

 

2008

First identification of the molecular mechanism underlying the differentiation of trophoblast cells in the mouse. This study demonstrated that the transcription factor, ELF5, creates a positive-feedback loop with trophoblast stem cell determinants, but is repressed by methylation in the cells of the embryo. Link

 

First demonstration of endoplasmic reticulum stress as a major component of the placental pathology in complications of pregnancy associated with intrauterine growth restriction and low birth weight. This study provides a molecular mechanism for the reduced cell proliferation seen in these pregnancies, opening new avenues for therapies. Link

 

Publication of 'Comparative placentation; structures, functions and evolution', a monograph providing details on placental structures from sharks and fishes through to higher primates and man. Link