Timeline

First demonstration that mitochondrial capacity disrupted in the placenta at high altitude

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 F. Colleoni, N. Padmanabhan, H. Yung, E. D. Watson, I. Cetin, M. C. T. van Patot, G. J. Burton, A. J. Murray, Suppression of Mitochondrial Electron Transport Chain Function in the Hypoxic Human Placenta: A Role for miRNA-210 and Protein Synthesis Inhibition. PLOS ONE 8, e55194 (2013).

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Metformin and maternal obesity Maternal - but not fetoplacental - health improved by metformin in mouse model of obesity

A. Hufnagel, D. S. Fernandez-Twinn, H. L. Blackmore, T. J. Ashmore, R. A. Heaton, B. Jenkins, A. Koulman, I. P. Hargreaves, C. E. Aiken, S. E. Ozanne, Maternal but not fetoplacental health can be improved by metformin in a murine diet-induced model of maternal obesity and glucose intolerance. J. Physiol. 600, 903–919 (2022).

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Uterine ILC1 Molecular definition of group 1 innate lymphoid cells in the mouse uterus

I. Filipovic, L. Chiossone, P. Vacca, R. S. Hamilton, T. Ingegnere, J.-M. Doisne, D. A. Hawkes, M. C. Mingari, A. M. Sharkey, L. Moretta, F. Colucci, Molecular definition of group 1 innate lymphoid cells in the mouse uterus. Nat. Commun. 9, 4492 (2018).

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Human uterine NK cells regulate differentiation of extravillous trophoblast

Q. Li, A. Sharkey, M. Sheridan, E. Magistrati, A. Arutyunyan, O. Huhn, C. Sancho-Serra, H. Anderson, N. McGovern, L. Esposito, R. Fernando, L. Gardner, R. Vento-Tormo, M. Y. Turco, A. Moffett, Human uterine natural killer cells regulate differentiation of extravillous trophoblast early in pregnancy. Cell Stem Cell, doi: 10.1016/j.stem.2023.12.013 (2024).

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Stem cell derived model of the postimplanation human embryo

B. A. T. Weatherbee, C. W. Gantner, L. K. Iwamoto-Stohl, R. M. Daza, N. Hamazaki, J. Shendure, M. Zernicka-Goetz, A model of the post-implantation human embryo derived from pluripotent stem cells. Nature, 1–3 (2023).

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scNM&T-seq Multi-omic method advanced to include chromatin accessibility

S. J. Clark, R. Argelaguet, C.-A. Kapourani, T. M. Stubbs, H. J. Lee, C. Alda-Catalinas, F. Krueger, G. Sanguinetti, G. Kelsey, J. C. Marioni, O. Stegle, W. Reik, scNMT-seq enables joint profiling of chromatin accessibility DNA methylation and transcription in single cells. Nat. Commun. 9, 781 (2018).

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Mitochondrial respirometry Technique developed to allow mitochondrial respirometry on frozen samples

F. Colleoni, A. J. Morash, T. Ashmore, M. Monk, G. J. Burton, A. J. Murray, Cryopreservation of placental biopsies for mitochondrial respiratory analysis. Placenta 33, 122–123 (2012)

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Uterine NK cell education CD94/NKG2A pathway linked to human pregnancy and fetal brain outcomes

N. Shreeve, D. Depierreux, D. Hawkes, J. A. Traherne, U. Sovio, O. Huhn, J. Jayaraman, A. Horowitz, H. Ghadially, J. R. B. Perry, A. Moffett, J. G. Sled, A. M. Sharkey, F. Colucci, The CD94/NKG2A inhibitory receptor educates uterine NK cells to optimize pregnancy outcomes in humans and mice. Immunity 54, 1231-1244.e4 (2021).

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Folate metabolism Perturbation of folate metabolism shown to induce transgenerational epigenetic instability across generations

N. Padmanabhan, D. Jia, C. Geary-Joo, X. Wu, A. C. Ferguson-Smith, E. Fung, M. C. Bieda, F. F. Snyder, R. A. Gravel, J. C. Cross, E. D. Watson, Mutation in Folate Metabolism Causes Epigenetic Instability and Transgenerational Effects on Development. Cell 155, 81–93 (2013).

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Pregnancy Outcome Prediction Established a programme of diagnostic scans to predict fetal growth restriction

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. U. Sovio, I. R. White, A. Dacey, D. Pasupathy, G. C. S. Smith, Screening for fetal growth restriction with universal third trimester ultrasonography in nulliparous women in the Pregnancy Outcome Prediction (POP) study: a prospective cohort study. Lancet Lond. Engl. 386, 2089–2097 (2015)

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In utero effects on fertility Undernourishment shown to perturb the adult sperm methylome

E. J. Radford, M. Ito, H. Shi, J. A. Corish, K. Yamazawa, E. Isganaitis, S. Seisenberger, T. A. Hore, W. Reik, S. Erkek, A. H. F. M. Peters, M.-E. Patti, A. C. Ferguson-Smith, In utero undernourishment perturbs the adult sperm methylome and intergenerational metabolism. Science 345, 1255903 (2014).

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First evidence that human syncitiotrophoblast is transcriptionally active

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. P. M. Ellery, T. Cindrova-Davies, E. Jauniaux, A. C. Ferguson-Smith, G. J. Burton, Evidence for Transcriptional Activity in the Syncytiotrophoblast of the Human Placenta. Placenta 30, 329–334 (2009).

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First evidence of ER stress and translation inhibition in placental pathology

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. H. Yung, S. Calabrese, D. Hynx, B. A. Hemmings, I. Cetin, D. S. Charnock-Jones, G. J. Burton, Evidence of Placental Translation Inhibition and Endoplasmic Reticulum Stress in the Etiology of Human Intrauterine Growth Restriction. Am. J. Pathol. 173, 451–462 (2008).

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Sheep model of chronic hypoxia models features of preeclampsia

W. Tong, B. J. Allison, K. L. Brain, O. V. Patey, Y. Niu, K. J. Botting, S. G. Ford, T. A. Garrud, P. F. B. Wooding, C. J. Shaw, Q. Lyu, L. Zhang, J. Ma, T. Cindrova-Davies, H. W. Yung, G. J. Burton, D. A. Giussani, Chronic Hypoxia in Ovine Pregnancy Recapitulates Physiological and Molecular Markers of Preeclampsia in the Mother, Placenta, and Offspring. Hypertension 79, 1525–1535 (2022).

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Criteria defining the human 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. C. Q. E. Lee, L. Gardner, M. Turco, N. Zhao, M. J. Murray, N. Coleman, J. Rossant, M. Hemberger, A. Moffett, What Is Trophoblast? A Combination of Criteria Define Human First-Trimester Trophoblast. Stem Cell Rep. 6, 257–272 (2016).

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Spiral artery remodelling Showed that spiral artery remodelling impacts velocity of maternal inflow to the placenta, but not volume

G. J. Burton, A. W. Woods, E. Jauniaux, J. C. P. Kingdom, Rheological and Physiological Consequences of Conversion of the Maternal Spiral Arteries for Uteroplacental Blood Flow during Human Pregnancy. Placenta 30, 473–482 (2009).

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scM&T-seq First method for single-cell profiling of RNA and methylation

C. Angermueller, S. J. Clark, H. J. Lee, I. C. Macaulay, M. J. Teng, T. X. Hu, F. Krueger, S. A. Smallwood, C. P. Ponting, T. Voet, G. Kelsey, O. Stegle, W. Reik, Parallel single-cell sequencing links transcriptional and epigenetic heterogeneity. Nat. Methods 13, 229–232 (2016).

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Placental Group B Strep infection tied to neonatal unit admissions

F. Gaccioli, K. Stephens, U. Sovio, F. Jessop, H. S. Wong, S. Lager, E. Cook, M. C. de Goffau, K. Le Doare, S. J. Peacock, J. Parkhill, D. S. Charnock-Jones, G. C. S. Smith, Placental Streptococcus agalactiae DNA is associated with neonatal unit admission and foetal pro-inflammatory cytokines in term infants. Nat. Microbiol. 8, 2338–2348 (2023).

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Identification of Zfp57 A maternal-zygotic factor is identified as essential to establish and maintain imprints

X. Li, M. Ito, F. Zhou, N. Youngson, X. Zuo, P. Leder, A. C. Ferguson-Smith, A Maternal-Zygotic Effect Gene, Zfp57, Maintains Both Maternal and Paternal Imprints. Dev. Cell 15, 547–557 (2008).

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Demonstrated a conserved trophectoderm programme in human, cow and mouse

C. Gerri, A. McCarthy, G. Alanis-Lobato, A. Demtschenko, A. Bruneau, S. Loubersac, N. M. E. Fogarty, D. Hampshire, K. Elder, P. Snell, L. Christie, L. David, H. Van de Velde, A. A. Fouladi-Nashta, K. K. Niakan, Initiation of a conserved trophectoderm program in human, cow and mouse embryos. Nature 587, 443–447 (2020).

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Maternal DNA methylation regulates trophoblast development

M. R. Branco, M. King, V. Perez-Garcia, A. B. Bogutz, M. Caley, E. Fineberg, L. Lefebvre, S. J. Cook, W. Dean, M. Hemberger, W. Reik, Maternal DNA Methylation Regulates Early Trophoblast Development. Dev. Cell 36, 152–163 (2016).

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Embryo-scale single-cell multi-omics

Jenny Nichols, Wolf Reik and collaborators published the first molecular map at single-cell resolution of cellular differentiation from pluripotency towards all major embryonic lineages during gastrulation in the mouse. Lewis Wolpert famously said that gastrulation is “truly the most important time in one’s life”. This comprehensive delineation of mammalian cell differentiation trajectories in vivo represents a baseline for understanding the effects of gene mutations during development, as well as a roadmap for the optimization of in vitro differentiation protocols for regenerative medicine. B. Pijuan-Sala, J. A. Griffiths, C. Guibentif, T. W. Hiscock, W. Jawaid, F. J. Calero-Nieto, C. Mulas, X. Ibarra-Soria, R. C. V. Tyser, D. L. L. Ho, W. Reik, S. Srinivas, B. D. Simons, J. Nichols, J. C. Marioni, B. Göttgens, A single-cell molecular map of mouse gastrulation and early organogenesis. Nature 566, 490–495 (2019).

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R. Argelaguet, S. J. Clark, H. Mohammed, L. C. Stapel, C. Krueger, C.-A. Kapourani, I. Imaz-Rosshandler, T. Lohoff, Y. Xiang, C. W. Hanna, S. Smallwood, X. Ibarra-Soria, F. Buettner, G. Sanguinetti, W. Xie, F. Krueger, B. Göttgens, P. J. Rugg-Gunn, G. Kelsey, W. Dean, J. Nichols, O. Stegle, J. C. Marioni, W. Reik, Multi-omics profiling of mouse gastrulation at single cell resolution. Nature 576, 487–491 (2019).

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Preeclampsia subtypes Evidence of early-onset ‘placental’ and late-onset ‘maternal’ 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. H. W. Yung, D. Atkinson, T. Campion-Smith, M. Olovsson, D. S. Charnock-Jones, G. J. Burton, Differential activation of placental unfolded protein response pathways implies heterogeneity in causation of early- and late-onset pre-eclampsia. J. Pathol. 234, 262–276 (2014).

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First analysis of implantation stage aneuploidy human embryos

M. N. Shahbazi, T. Wang, X. Tao, B. A. T. Weatherbee, L. Sun, Y. Zhan, L. Keller, G. D. Smith, A. Pellicer, R. T. Scott, E. Seli, M. Zernicka-Goetz, Developmental potential of aneuploid human embryos cultured beyond implantation. Nat. Commun. 11, 3987 (2020).

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African KIR genetics Identified distinct KIR haplotype for preeclampsia risk in African women

A. Nakimuli, O. Chazara, S. E. Hiby, L. Farrell, S. Tukwasibwe, J. Jayaraman, J. A. Traherne, J. Trowsdale, F. Colucci, E. Lougee, R. W. Vaughan, A. M. Elliott, J. Byamugisha, P. Kaleebu, F. Mirembe, N. Nemat-Gorgani, P. Parham, P. J. Norman, A. Moffett, A KIR B centromeric region present in Africans but not Europeans protects pregnant women from pre-eclampsia. Proc. Natl. Acad. Sci. U. S. A. 112, 845–850 (2015).

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Non-genetic inheritance Genome-wide identification of the heritability of mouse epialleles

A. Kazachenka, T. M. Bertozzi, M. K. Sjoberg-Herrera, N. Walker, J. Gardner, R. Gunning, E. Pahita, S. Adams, D. Adams, A. C. Ferguson-Smith, Identification, Characterization, and Heritability of Murine Metastable Epialleles: Implications for Non-genetic Inheritance. Cell 175, 1717 (2018).

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In utero effects on fertility Undernourishment shown to perturb the adult sperm methylome

E. J. Radford, M. Ito, H. Shi, J. A. Corish, K. Yamazawa, E. Isganaitis, S. Seisenberger, T. A. Hore, W. Reik, S. Erkek, A. H. F. M. Peters, M.-E. Patti, A. C. Ferguson-Smith, In utero undernourishment perturbs the adult sperm methylome and intergenerational metabolism. Science 345, 1255903 (2014).

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Identification of H19 Identification of first imprinted lincRNA H19 (miR-675)

G. Smits, A. J. Mungall, S. Griffiths-Jones, P. Smith, D. Beury, L. Matthews, J. Rogers, A. J. Pask, G. Shaw, J. L. VandeBerg, J. R. McCarrey, M. B. Renfree, W. Reik, I. Dunham, Conservation of the H19 noncoding RNA and H19-IGF2 imprinting mechanism in therians. Nat. Genet. 40, 971–976 (2008).

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RNA-sequencing of the human yolk sac

In a landmark paper, Tereza Cindrova-Davies, Steve Charnock-Jones and colleagues presented RNA-Seq data for the human yolk sac. The data showed that far from being vestigial as commonly believed, the yolk sac expresses transcripts encoding a vast array of transporter proteins and secreted products. The yolk sac appears to be heavily involved in lipid handling and metabolism, and hence may provide an important pathway for the exchange of key nutrients during the first weeks of pregnancy. T. Cindrova-Davies, E. Jauniaux, M. G. Elliot, S. Gong, G. J. Burton, D. S. Charnock-Jones, RNA-seq reveals conservation of function among the yolk sacs of human, mouse, and chicken. Proc. Natl. Acad. Sci. 114, E4753–E4761 (2017).

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Derivation of human trophoblast organoids and stem cells

Margherita Turco, Lucy Gardner, Graham Burton, Ashley Moffett and colleagues derived trophoblast organoids from early placental tissues. These cultures are genetically stable in culture, can be maintained for over 1 year, frozen and biobanked, and show almost identical transciptomes and methylomes to first trimester trophoblast. They are functionally active, secreting an array of hormones and placental-specific glycoproteins. The cultures are the result of several decades of research, and will be transformative in the field. M. Y. Turco, L. Gardner, R. G. Kay, R. S. Hamilton, M. Prater, M. S. Hollinshead, A. McWhinnie, L. Esposito, R. Fernando, H. Skelton, F. Reimann, F. M. Gribble, A. Sharkey, S. G. E. Marsh, S. O’Rahilly, M. Hemberger, G. J. Burton, A. Moffett, Trophoblast organoids as a model for maternal–fetal interactions during human placentation. Nature 564, 263–267 (2018).

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scBS-seq First method capable of single-cell bisulfite sequencing for methylation

S. A. Smallwood, H. J. Lee, C. Angermueller, F. Krueger, H. Saadeh, J. Peat, S. R. Andrews, O. Stegle, W. Reik, G. Kelsey, Single-cell genome-wide bisulfite sequencing for assessing epigenetic heterogeneity. Nat. Methods 11, 817–820 (2014).

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Uterine NK cells First evidence that uterine NK cells promote fetal growth

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. J. Kieckbusch, L. M. Gaynor, A. Moffett, F. Colucci, MHC-dependent inhibition of uterine NK cells impedes fetal growth and decidual vascular remodelling. Nat. Commun. 5, 3359 (2014).

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Identified distinctive functions of innate lymphoid cells in human decidua

O. Huhn, M. A. Ivarsson, L. Gardner, M. Hollinshead, J. C. Stinchcombe, P. Chen, N. Shreeve, O. Chazara, L. E. Farrell, J. Theorell, H. Ghadially, P. Parham, G. Griffiths, A. Horowitz, A. Moffett, A. M. Sharkey, F. Colucci, Distinctive phenotypes and functions of innate lymphoid cells in human decidua during early pregnancy. Nat. Commun. 11, 381 (2020).

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Atlas of the temporal and spatial dynamics of the human endometrium

L. Garcia-Alonso, L.-F. Handfield, K. Roberts, K. Nikolakopoulou, R. C. Fernando, L. Gardner, B. Woodhams, A. Arutyunyan, K. Polanski, R. Hoo, C. Sancho-Serra, T. Li, K. Kwakwa, E. Tuck, V. Lorenzi, H. Massalha, M. Prete, V. Kleshchevnikov, A. Tarkowska, T. Porter, C. I. Mazzeo, S. van Dongen, M. Dabrowska, V. Vaskivskyi, K. T. Mahbubani, J. Park, M. Jimenez-Linan, L. Campos, V. Y. Kiselev, C. Lindskog, P. Ayuk, E. Prigmore, M. R. Stratton, K. Saeb-Parsy, A. Moffett, L. Moore, O. A. Bayraktar, S. A. Teichmann, M. Y. Turco, R. Vento-Tormo, Mapping the temporal and spatial dynamics of the human endometrium in vivo and in vitro. Nat. Genet. 53, 1698–1711 (2021).

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Midgestation development of mouse embryo models First demonstration of mouse ex utero development to headfold stages in embryo-models derived from stem cells

G. Amadei, C. E. Handford, C. Qiu, J. De Jonghe, H. Greenfeld, M. Tran, B. K. Martin, D.-Y. Chen, A. Aguilera-Castrejon, J. H. Hanna, M. B. Elowitz, F. Hollfelder, J. Shendure, D. M. Glover, M. Zernicka-Goetz, Embryo model completes gastrulation to neurulation and organogenesis. Nature 610, 143–153 (2022).

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K. Y. C. Lau, H. Rubinstein, C. W. Gantner, R. Hadas, G. Amadei, Y. Stelzer, M. Zernicka-Goetz, Mouse embryo model derived exclusively from embryonic stem cells undergoes neurulation and heart development. Cell Stem Cell 29, 1445-1458.e8 (2022).

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M. Bao, J. Cornwall-Scoones, E. Sanchez-Vasquez, A. L. Cox, D.-Y. Chen, J. De Jonghe, S. Shadkhoo, F. Hollfelder, M. Thomson, D. M. Glover, M. Zernicka-Goetz, Stem cell-derived synthetic embryos self-assemble by exploiting cadherin codes and cortical tension. Nat. Cell Biol. 24, 1341–1349 (2022).

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First genome editing in human embryos CRISPR-Cas9 used to knockout OCT4

N. M. E. Fogarty, A. McCarthy, K. E. Snijders, B. E. Powell, N. Kubikova, P. Blakeley, R. Lea, K. Elder, S. E. Wamaitha, D. Kim, V. Maciulyte, J. Kleinjung, J.-S. Kim, D. Wells, L. Vallier, A. Bertero, J. M. A. Turner, K. K. Niakan, Genome editing reveals a role for OCT4 in human embryogenesis. Nature 550, 67–73 (2017).

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Placental Igf2 axis First genetic evidence that the imprinted placental Igf2 axis responds to maternal nutrient supply and fetal demands

A. N. Sferruzzi-Perri, O. R. Vaughan, P. M. Coan, M. C. Suciu, R. Darbyshire, M. Constancia, G. J. Burton, A. L. Fowden, Placental-Specific Igf2 Deficiency Alters Developmental Adaptations to Undernutrition in Mice. Endocrinology 152, 3202–3212 (2011).

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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. E. Angiolini, P. M. Coan, I. Sandovici, O. H. Iwajomo, G. Peck, G. J. Burton, C. P. Sibley, W. Reik, A. L. Fowden, M. Constância, Developmental adaptations to increased fetal nutrient demand in mouse genetic models of Igf2-mediated overgrowth. FASEB J. 25, 1737–1745 (2011).

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HHV-6 and preeclampsia Fetal inheritance of integrated HHV-6 predisposes mothers to preeclampsia

F. Gaccioli, S. Lager, M. C. de Goffau, U. Sovio, J. Dopierala, S. Gong, E. Cook, A. Sharkey, A. Moffett, W. K. Lee, C. Delles, C. Venturini, J. Breuer, J. Parkhill, S. J. Peacock, D. S. Charnock-Jones, G. C. S. Smith, Fetal inheritance of chromosomally integrated human herpesvirus 6 predisposes the mother to pre-eclampsia. Nat. Microbiol. 5, 901–908 (2020).

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Ontogeny of human placental fetal macrophages throughout gestation

J. R. Thomas, A. Appios, E. F. Calderbank, N. Yoshida, X. Zhao, R. S. Hamilton, A. Moffett, A. Sharkey, E. Laurenti, C. W. Hanna, N. McGovern, Primitive haematopoiesis in the human placenta gives rise to macrophages with epigenetically silenced HLA-DR. Nat. Commun. 14, 1764 (2023).

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H19 placental function Demonstrated the physiological role of the imprinted H19 lncRNA in suppressing placental growth

A. Keniry, D. Oxley, P. Monnier, M. Kyba, L. Dandolo, G. Smits, W. Reik, The H19 lincRNA is a developmental reservoir of miR-675 that suppresses growth and Igf1r. Nat. Cell Biol. 14, 659–665 (2012).

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Obesogenic diet model Established a model for effect of maternal obesity on the placenta

A. N. Sferruzzi-Perri, O. R. Vaughan, M. Haro, W. N. Cooper, B. Musial, M. Charalambous, D. Pestana, S. Ayyar, A. C. Ferguson-Smith, G. J. Burton, M. Constancia, A. L. Fowden, An obesogenic diet during mouse pregnancy modifies maternal nutrient partitioning and the fetal growth trajectory. FASEB J. 27, 3928–3937 (2013).

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Placenta mitochondrial function impacts pregnancy complications

A. N. Sferruzzi-Perri, J. S. Higgins, O. R. Vaughan, A. J. Murray, A. L. Fowden, Placental mitochondria adapt developmentally and in response to hypoxia to support fetal growth. Proc. Natl. Acad. Sci. 116, 1621–1626 (2019).

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Billy Yung, Andrew Murray and colleagues provided some of the first evidence of activation of the mitochondrial unfolded protein response in mammalian cells, observing a reduction in mitochondrial oxidative phosphorylation in placentas from pregnancies complicated by early-onset pre-eclampsia. Understanding mitochondrial stress provides new insights into the pathophysiology of early-onset preeclampsia and other placentally-related complications of pregnancy. H. W. Yung, F. Colleoni, E. Dommett, T. Cindrova-Davies, J. Kingdom, A. J. Murray, G. J. Burton, Noncanonical mitochondrial unfolded protein response impairs placental oxidative phosphorylation in early-onset preeclampsia. Proc. Natl. Acad. Sci. 116, 18109–18118 (2019).

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Human placenta has no microbiome but can contain potential pathogens

Gordon Smith, Steve Charnock-Jones and the POPs team published a definitive study showing that placentas from normal pregnancies and those from cases of pre-eclampsia, pre-term delivery and small-for-gestational age babies do not have a microbiome. Almost all the bacterial signals detected arose either by acquisition during the birth process or through contamination of laboratory reagents. This large and highly stringent study lays to rest the idea that the placenta harbour pathogens and that they may be the cause of common complications of pregnancy. M. C. de Goffau, S. Lager, U. Sovio, F. Gaccioli, E. Cook, S. J. Peacock, J. Parkhill, D. S. Charnock-Jones, G. C. S. Smith, Human placenta has no microbiome but can contain potential pathogens. Nature 572, 329–334 (2019)

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Self-organisation of the human embryo First system capable of human embryo ex vivo up to 14 days

Magda Zernicka-Goetz, Marta Shahbazi, Kathy Niakan 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. M. N. Shahbazi, A. Jedrusik, S. Vuoristo, G. Recher, A. Hupalowska, V. Bolton, N. M. E. Fogarty, A. Campbell, L. G. Devito, D. Ilic, Y. Khalaf, K. K. Niakan, S. Fishel, M. Zernicka-Goetz, Self-organization of the human embryo in the absence of maternal tissues. Nat. Cell Biol. 18, 700–708 (2016).

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Genome-wide DNA methylation erasure Global demethylation of the mammalian genome provides evidence against trans generational epigenetic inheritance

C. Popp, W. Dean, S. Feng, S. J. Cokus, S. Andrews, M. Pellegrini, S. E. Jacobsen, W. Reik, Genome-wide erasure of DNA methylation in mouse primordial germ cells is affected by AID deficiency. Nature 463, 1101–1105 (2010).

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Elf5 methylation First demonstration of epigenetic mechanisms underlying trophoblast differentation

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. R. K. Ng, W. Dean, C. Dawson, D. Lucifero, Z. Madeja, W. Reik, M. Hemberger, Epigenetic restriction of embryonic cell lineage fate by methylation of Elf5. Nat. Cell Biol. 10, 1280–1290 (2008).

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Postnatal role of Dlk1/Dio3 First demonstration that Dlk1/Dio3 imprinted gene dosage is required for postnatal survival

S. R. Ferrón, M. Charalambous, E. Radford, K. McEwen, H. Wildner, E. Hind, J. M. Morante-Redolat, J. Laborda, F. Guillemot, S. R. Bauer, I. Fariñas, A. C. Ferguson-Smith, Postnatal loss of Dlk1 imprinting in stem cells and niche astrocytes regulates neurogenesis. Nature 475, 381–385 (2011).

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M. Charalambous, S. R. Ferron, S. T. da Rocha, A. J. Murray, T. Rowland, M. Ito, K. Schuster-Gossler, A. Hernandez, A. C. Ferguson-Smith, Imprinted Gene Dosage Is Critical for the Transition to Independent Life. Cell Metab. 15, 209–221 (2012).

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Placental Dlk1 axis First fetal signal shown to alter maternal metabolism

M. A. M. Cleaton, C. L. Dent, M. Howard, J. A. Corish, I. Gutteridge, U. Sovio, F. Gaccioli, N. Takahashi, S. R. Bauer, D. S. Charnock-Jones, T. L. Powell, G. C. S. Smith, A. C. Ferguson-Smith, M. Charalambous, Fetus-derived DLK1 is required for maternal metabolic adaptations to pregnancy and is associated with fetal growth restriction. Nat. Genet. 48, 1473–1480 (2016).

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First method capable of sequencing mRNA from single cells

F. Tang, C. Barbacioru, Y. Wang, E. Nordman, C. Lee, N. Xu, X. Wang, J. Bodeau, B. B. Tuch, A. Siddiqui, K. Lao, M. A. Surani, mRNA-Seq whole-transcriptome analysis of a single cell. Nat. Methods 6, 377–382 (2009).

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Embryonic lethality is often associated with severe placental malformation

Vicente Perez Garcia, Myriam Hemberger and colleagues published the placental data arising from the Deciphering the Mechanisms of Developmental Disorders programme, showing that a high proportion (~70%) of knockout lines that are lethal display placental dysmorphogenesis. This study raises the profile of the placenta, and emphasises the importance of assessing both the extra-embryonic and embryonic lineages in mutant lines. V. Perez-Garcia, E. Fineberg, R. Wilson, A. Murray, C. I. Mazzeo, C. Tudor, A. Sienerth, J. K. White, E. Tuck, E. J. Ryder, D. Gleeson, E. Siragher, H. Wardle-Jones, N. Staudt, N. Wali, J. Collins, S. Geyer, E. M. Busch-Nentwich, A. Galli, J. C. Smith, E. Robertson, D. J. Adams, W. J. Weninger, T. Mohun, M. Hemberger, Placentation defects are highly prevalent in embryonic lethal mouse mutants. Nature 555, 463–468 (2018).

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Human epiblast is competent to give rise to trophoblast

G. Guo, G. G. Stirparo, S. E. Strawbridge, D. Spindlow, J. Yang, J. Clarke, A. Dattani, A. Yanagida, M. A. Li, S. Myers, B. N. Özel, J. Nichols, A. Smith, Human naive epiblast cells possess unrestricted lineage potential. Cell Stem Cell 28, 1040-1056.e6 (2021).

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Spatial multi-omics map of trophoblast development in early pregnancy

A. Arutyunyan, K. Roberts, K. Troulé, F. C. K. Wong, M. A. Sheridan, I. Kats, L. Garcia-Alonso, B. Velten, R. Hoo, E. R. Ruiz-Morales, C. Sancho-Serra, J. Shilts, L.-F. Handfield, L. Marconato, E. Tuck, L. Gardner, C. I. Mazzeo, Q. Li, I. Kelava, G. J. Wright, E. Prigmore, S. A. Teichmann, O. A. Bayraktar, A. Moffett, O. Stegle, M. Y. Turco, R. Vento-Tormo, Spatial multiomics map of trophoblast development in early pregnancy. Nature 616, 143–151 (2023).

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‘Blastoid’ models of human development

A. Yanagida, D. Spindlow, J. Nichols, A. Dattani, A. Smith, G. Guo, Naive stem cell blastocyst model captures human embryo lineage segregation. Cell Stem Cell 28, 1016-1022.e4 (2021).

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B. Sozen, V. Jorgensen, B. A. T. Weatherbee, S. Chen, M. Zhu, M. Zernicka-Goetz, Reconstructing aspects of human embryogenesis with pluripotent stem cells. Nat. Commun. 12, 5550 (2021).

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Embryos exposed to hypoxia are 'Programmed' for Heart Disease

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 D. A. Giussani, E. J. Camm, Y. Niu, H. G. Richter, C. E. Blanco, R. Gottschalk, E. Z. Blake, K. A. Horder, A. S. Thakor, J. A. Hansell, A. D. Kane, F. B. P. Wooding, C. M. Cross, E. A. Herrera, Developmental Programming of Cardiovascular Dysfunction by Prenatal Hypoxia and Oxidative Stress. PLoS ONE 7, e31017 (2012).

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Human endometrial organoids First demonstration of long-term, hormone-responsive organoid cultures of human endometrium

Margherita Turco made a major breakthrough by generating organoids of human endometrial glands, with the expert help of Lucy Gardner. These organoids are stable in long-term culture, faithfully replicate the glands at the transcriptome level, and their secretome responds to early pregnancy hormones. The organoids can be frozen and biobanked, and are likely to prove a powerful tool for investigating the trophoblast-endometrial dialogue the stimulates early placental development. M. Y. Turco, L. Gardner, J. Hughes, T. Cindrova-Davies, M. J. Gomez, L. Farrell, M. Hollinshead, S. G. E. Marsh, J. J. Brosens, H. O. Critchley, B. D. Simons, M. Hemberger, B.-K. Koo, A. Moffett, G. J. Burton, Long-term, hormone-responsive organoid cultures of human endometrium in a chemically-defined medium. Nat. Cell Biol. 19, 568–577 (2017).

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HLA-KIR interactions First association of maternal-fetal immune interactions with birthweight

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. S. E. Hiby, R. Apps, A. M. Sharkey, L. E. Farrell, L. Gardner, A. Mulder, F. H. Claas, J. J. Walker, C. C. Redman, L. Morgan, C. Tower, L. Regan, G. E. Moore, M. Carrington, A. Moffett, Maternal activating KIRs protect against human reproductive failure mediated by fetal HLA-C2. J. Clin. Invest. 120, 4102–4110 (2010).

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Single-cell reconstruction of the maternal-fetal interface

Roser Vento, Margherita Turco, Ashley Moffett and colleagues reported the results of single-cell sequencing of the decidua during the first trimester based on analysis of 70,000 cells. They identified three major subsets of decidual natural killer cells that have distinctive immunomodulatory and chemokine profiles. They have also developed a repository of ligand–receptor complexes and a statistical tool to predict the cell-type specificity of cell–cell communication via these molecular interactions. These data provide an unprecedented insight into the cellular interactions during early placentation. R. Vento-Tormo, M. Efremova, R. A. Botting, M. Y. Turco, M. Vento-Tormo, K. B. Meyer, J.-E. Park, E. Stephenson, K. Polański, A. Goncalves, L. Gardner, S. Holmqvist, J. Henriksson, A. Zou, A. M. Sharkey, B. Millar, B. Innes, L. Wood, A. Wilbrey-Clark, R. P. Payne, M. A. Ivarsson, S. Lisgo, A. Filby, D. H. Rowitch, J. N. Bulmer, G. J. Wright, M. J. T. Stubbington, M. Haniffa, A. Moffett, S. A. Teichmann, Single-cell reconstruction of the early maternal–fetal interface in humans. Nature 563, 347–353 (2018).

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oxBS-Seq First method capable of quantitative 5hmc sequencing at single-base resolution

M. J. Booth, M. R. Branco, G. Ficz, D. Oxley, F. Krueger, W. Reik, S. Balasubramanian, Quantitative sequencing of 5-methylcytosine and 5-hydroxymethylcytosine at single-base resolution. Science 336, 934–937 (2012).

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Stem cell model of mouse embryogenesis First mouse embryo model of embryo-trophoblast interactions

S. E. Harrison, B. Sozen, N. Christodoulou, C. Kyprianou, M. Zernicka-Goetz, Assembly of embryonic and extraembryonic stem cells to mimic embryogenesis in vitro. Science 356, eaal1810 (2017).

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Imprinted genes in placental function First direct evidence that a paternally-expressed imprinted gene (IGF2) drives maternal physiological changes

J. Lopez-Tello, H. E. J. Yong, I. Sandovici, G. K. C. Dowsett, E. R. Christoforou, E. Salazar-Petres, R. Boyland, T. Napso, G. S. H. Yeo, B. Y. H. Lam, M. Constancia, A. N. Sferruzzi-Perri, Fetal manipulation of maternal metabolism is a critical function of the imprinted Igf2 gene. Cell Metab. 35, 1195-1208.e6 (2023).

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Retrotransposon methylation does not respond to environmental perturbations

T. M. Bertozzi, J. L. Becker, G. E. T. Blake, A. Bansal, D. K. Nguyen, D. S. Fernandez-Twinn, S. E. Ozanne, M. S. Bartolomei, R. A. Simmons, E. D. Watson, A. C. Ferguson-Smith, Variably methylated retrotransposons are refractory to a range of environmental perturbations. Nat. Genet. 53, 1233–1242 (2021).

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Cancer-like mutational profile in the placenta

T. H. H. Coorens, T. R. W. Oliver, R. Sanghvi, U. Sovio, E. Cook, R. Vento-Tormo, M. Haniffa, M. D. Young, R. Rahbari, N. Sebire, P. J. Campbell, D. S. Charnock-Jones, G. C. S. Smith, S. Behjati, Inherent mosaicism and extensive mutation of human placentas. Nature 592, 80–85 (2021).

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Unique function of DNA methylation editors in placental development

S. Andrews, C. Krueger, M. Mellado-Lopez, M. Hemberger, W. Dean, V. Perez-Garcia, C. W. Hanna, Mechanisms and function of de novo DNA methylation in placental development reveals an essential role for DNMT3B. Nat. Commun. 14, 371 (2023).

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The imprinted Igf2-Igf2r axis matches placental development to fetal demand

Sandovici, I., Georgopoulou, A., Pérez-García, V., Hufnagel, A., López-Tello, J., Lam, B. Y., ... & Constância, M. (2022). The imprinted Igf2-Igf2r axis is critical for matching placental microvasculature expansion to fetal growth. Developmental Cell, 57(1), 63-79.

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Severe nausea influenced by placenta released protein GDF15

M. Fejzo, N. Rocha, I. Cimino, S. M. Lockhart, C. J. Petry, R. G. Kay, K. Burling, P. Barker, A. L. George, N. Yasara, A. Premawardhena, S. Gong, E. Cook, D. Rimmington, K. Rainbow, D. J. Withers, V. Cortessis, P. M. Mullin, K. W. MacGibbon, E. Jin, A. Kam, A. Campbell, O. Polasek, G. Tzoneva, F. M. Gribble, G. S. H. Yeo, B. Y. H. Lam, V. Saudek, I. A. Hughes, K. K. Ong, J. R. B. Perry, A. Sutton Cole, M. Baumgarten, P. Welsh, N. Sattar, G. C. S. Smith, D. S. Charnock-Jones, A. P. Coll, C. L. Meek, S. Mettananda, C. Hayward, N. Mancuso, S. O’Rahilly, GDF15 linked to maternal risk of nausea and vomiting during pregnancy. Nature 625, 760–767 (2024).

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Spatial transciptomic profiling of nonhuman primate embryos in utero

S. Bergmann, C. A. Penfold, E. Slatery, D. Siriwardena, C. Drummer, S. Clark, S. E. Strawbridge, K. Kishimoto, A. Vickers, M. Tewary, T. N. Kohler, F. Hollfelder, W. Reik, E. Sasaki, R. Behr, T. E. Boroviak, Spatial profiling of early primate gastrulation in utero. Nature 609, 136–143 (2022).

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Maternal serum metabolite ratio for prediction of fetal growth restriction at term

U. Sovio, N. Goulding, N. McBride, E. Cook, F. Gaccioli, D. S. Charnock-Jones, D. A. Lawlor, G. C. S. Smith, A maternal serum metabolite ratio predicts fetal growth restriction at term. Nat. Med. 26, 348–353 (2020).

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FGF and estrogen Identified signalling roles in regulating 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. P. A. Latos, A. Goncalves, D. Oxley, H. Mohammed, E. Turro, M. Hemberger, Fgf and Esrrb integrate epigenetic and transcriptional networks that regulate self-renewal of trophoblast stem cells. Nat. Commun. 6, 7776 (2015).

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Role of maternal obesity in developmental programming of cardiovascular function

H. L. Blackmore, Y. Niu, D. S. Fernandez-Twinn, J. L. Tarry-Adkins, D. A. Giussani, S. E. Ozanne, Maternal Diet-induced Obesity Programs Cardiovascular Dysfunction in Adult Male Mouse Offspring Independent of Current Body Weight. Endocrinology 155, 3970–3980 (2014).

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