Work Package One

in vitro Placenta modelling​

Work Package Two

integrative Placenta modelling​

Work Package Three

imaging Placenta​

in vitro 3D placenta modelling

- mimic the placenta ​in vitro

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in vitro Placenta modelling:

​The overall objective is to develop state-of-the-art  models to mimic the placenta in vitro. The placenta rapidly develops structurally and functionally throughout gestation and is a unique organ having blood supply from two organisms. The placenta is made up of maternal and fetal vessels, with numerous highly branched villi lined with trophoblasts (syncytio) facilitating gaseous, nutrient and waste exchange. 
Currently, tissue culture using explants from delivered placenta offer the only routine method to study the whole multicellular placenta ex vivo.  This restricts our ability to understand the dynamic cellular interaction in normal and diseased placenta, since the explants are from delivered term placenta and are no longer under the same haemodynamic forces. ​
Mimetas will utilise their unique OrganoPlates® platform to permit advanced organ-on-a-chip technology to be used in any lab setting, providing in vitro modelling of complex multicellular organs.  Mimetas has successfully developed human perfusable 3D vasculature, CNS, gut and kidney. Organ-on-a-chip technology offers functionality not possible with conventional 2D or 3D culture; it is a rapidly advancing technology with the ability to better replicate complex organs. 
Extracellular vesicles (EVs) are involved in cell-to-cell communication network and actively transfer various molecules including proteins and RNA, for targeted cell phenotype modulation via transcriptional and stable epigenetic changes. During pregnancy, placental-derived EVs may provide a natural placental derived biopsy available in the maternal blood to determine placenta wellbeing. ​
Gene editing technology will be used to encapsulate the complex pathophysiological disease conditions.
ESR1 Design and development of placenta-on-a-chip model mimicking normal and diseased placenta characteristics
​Dr Henriette Lanz and Dr Chee Ping Ng, Mimetas, Leiden, The Netherlands
ESR2 Development of assays to measure translational markers to characterize placental vascular on-a-chip model
Dr Chee Ping Ng and Dr Henriette Lanz , Mimetas, Leiden, The Netherlands
​ESR3​ Identification of placental derived angiomodulatory extracellular vesicles 
Dr Benedetta Bussolatti, University of Torino, Torino,  Italy
ESR4  Design and generation of in vitro models of diseased placenta to mimic the  pathophysiology  of  preeclampsia  and intra  uterine growth restriction
Dr Colin Murdoch, University of Dundee, Dundee, UK

integrative placenta modelling

- Making sense of multi-omics data using systems biology

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integrative Placenta modelling:

Making sense of multi-omics data using systems biology.
Integrating multi-dimensional, multi-omics data generated from in WP2 derived from placental tissues establish an evidence-based cause and effect relationship for early/late onset preeclampsia (PE) and intra-uterine growth restriction (IUGR), (WP3) and from placental-derived extracellular vesicles (WP1) with reference to the clinical phenotypes observed. The genetic factors underlying PE and IUGR susceptibility comprise of both maternal and fetal genetic components leading to placental pathophysiology. 
Genome-wide technologies and genotyping can identify fetal/placental variants. Epigenetic regulation has gained importance in recent years, playing a large part in normal placental development as well as for specific dysregulations observed in pathological situations, where the placenta plays a central role, such as PE and IUGR. Epigenetic regulation of gene expression (defined as heritable and non-associated with DNA mutations) relies upon three major molecular mechanisms: DNA methylation/demethylation, alterations of post-translational marks apposed on the histones, and the load of non-coding RNA (in particular miRNAs).   Establishing the full transcriptomic outcome and regulatory mechanisms will enrich the omics datasets in physiological and pathophysiological outcomes and consequently influences the proteome and metabolome. Our aim is to to full coverage of the ‘omics’ in relation to early and late onset  preeclampsia and intrauterine growth restriction. 
ESR5  ​Transcriptomic, placental   blueprint   from   human   and   mouse   preeclampsia   or   growth restriction   and   circulating miRNAs/lncRNAs
Prof Leon De Windt, Maastricht University, Maastricht, Netherlands
ESR6 ​Genome-wide investigation in patients with early/late-onset preeclampsia 
Dr Daniel Vaiman and Dr Céline Méhats, INSERM, Paris, France
ESR7 Axis of Placental Aging in Adverse Pregnancy Outcomes: Telomeres and Mitochondria
Dr Fergus McCarthy and Dr Cathal McCarthy, University College Cork, Cork, Republic of Ireland
ESR8 Epigenetic  genome-wide  investigation  in  patients  with  early/late-onset  preeclampsia 
Dr Daniel Vaiman and Dr Céline Méhats, INSERM, Paris, France
ESR9 Integrative   placenta:   a   systems   biology   approach   towards   phenotype-specific interactomes for placental function.
Prof  Olaf Wolkenhauer and Dr Shailendra Gupta, ​University of Rostock, Rostock, Germany

imaging placenta 

- improving pre-clinical and clinical imaging 

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imaging Placenta:
​The overall objective is to characterise and validate new methodologies for in vivo placenta modelling and clinical prediction of early/late onset preeclampsia (PE) and intra-uterine growth restriction (IUGR). Early prediction of pregnancies at risk from PE or IUGR will not only allow stratification of resources, it will provide insight into pathological mechanisms or identification of a window or target for therapeutic intervention. 
Animal models have proven to be essential tools furthering our understanding of cardiovascular disease as proof-of-concept, due to the wide availability of different transgenic mouse strains, high level of temporally and cellular genetic control, and the well-documented embryotic development. Yet, animal models investigating PE and IUGR have been restricted by questions of reproducibility and relevance to clinical phenotype. Standardising protocols for in vivo models and characterisation in relation to clinical assessment is essential to prevent duplication of results and discrepancy between scientific findings. Adaptation of tools is key to provide the ability to assess similar clinical parameters in animal models. ​​Adapation of LSI to allow minimally invasive visualisation of organ perfusion such as the placenta to assess perfusion as a surrogate of oxygenation. 
Moor Instruments develops commercial devices for the measurement of tissue blood flow (Laser Doppler imaging (LDI), fibre optic LD, Laser Speckle contrast imager (LSI)); endothelial function (iontophoresis); and absolute assessment of deep tissue oxygenation (Spatially-resolved NIRS) for a wide range of clinical and research applications.   
The ability to evaluate in real time human placental structure and function by using new advances in ultrasound or magnetic resonance imaging (MRI) in early gestation will help determine the clinical trajectory of a patient toward the development of placental disorders like PE and IUGR - potentially allowing physicians to intervene early and possibly effect/limit the severity of these diseases. All physiological data will be layered onto omics data generating advance disease platform for interrogation​.​
ESR 10  ​Development of endoscopic laser speckle imaging probe and miniaturise iontophoresis  for  assessment  of  placenta  perfusion  and  endothelial function in murine pregnancy models
Dr Colin Murdoch, Prof Faisel Khan, University of Dundee, Dundee, UK & Dr Rodney Gush, Moor Instruments, UK
ESR 11 ​Enhancing imaging of the placenta in murine models of PE and standardisation of PE models    
Prof Asif Ahmed and Dr Keqing Wang, Aston University, Birmingham, UK
ESR 12 ​Consequences of intra-uterine growth restriction on feto-maternal hemodynamics and brain development in the rabbit model
Prof Jan Deprest, Katholieke Universiteit Leuven, Leuven, Belgium
ESR 13 ​Application  of  novel  ultrasound  technology  for  improving  diagnostic capability of complicated pregnancies
Prof Asma Khalil and Prof Basky Thilaganathan, St George's, University of London, UK
ESR 14 ​Development    of    epigenetic    markers    of    abnormal    fetal    intrauterine neurodevelopment, correlation with fetal Doppler ultrasound
Dr Jose Morales Rosello,  Fundacion para la Investigacion del Hospital Universitario La Fe de la Comunidad Valenciana (HULAFE), Valencia, Spain
ESR 15 ​Development   of   novel   ultrasound   tools   for   maternal   and   fetal cardiovascular assessment
​Prof Basky Thilaganathan and Prof Asma Khalil, ​St George's, University of London, UK