Periodic Reporting for period 2 - iPLACENTA (Innovation in modelling Placenta for Maternal and Fetal Health)
Période du rapport: 2020-01-01 au 2022-05-31
iPlacenta is an EU Horizon2020 ITN which trained 15 PhD early stage researchers to model and image the placenta for maternal and fetal health. The consortium was developed and coordinated by Dr Colin Murdoch at the University of Dundee.
Two of the most common complications during pregnancy, preeclampsia (PE) and intrauterine growth restriction (IUGR) are thought to stem from abnormal development and function of the placenta. The WHO reported PE and IUGR as one of the least funded areas of medical research, and there has been comparatively little progress in developing diagnostic tests and therapies. Yet, PE and IUGR cause a great personal, societal and economic impact. PE claims the lives of 76,000 mothers and 500,000 babies annually worldwide. IUGR affects 60,000 births across the EU per year and is the most common factor for stillborn babies. Yet the prediction rate is woefully poor, placing a heavy burden on the healthcare system. For those that survive both PE and IUGR, there are life-long serious cardiovascular and neurological consequences.
iPLACENTA aims to use advancements in technology in a multidisciplinary network to enhance our ability to model, visualise and assess the placenta at different levels (in vitro, in silico and in vivo), as well as its interaction with the maternal cardiovascular system, with a view to improving diagnosis and eventual treatment of major placental diseases.
Two of the most common complications during pregnancy, preeclampsia (PE) and intrauterine growth restriction (IUGR) are thought to stem from abnormal development and function of the placenta. The WHO reported PE and IUGR as one of the least funded areas of medical research, and there has been comparatively little progress in developing diagnostic tests and therapies. Yet, PE and IUGR cause a great personal, societal and economic impact. PE claims the lives of 76,000 mothers and 500,000 babies annually worldwide. IUGR affects 60,000 births across the EU per year and is the most common factor for stillborn babies. Yet the prediction rate is woefully poor, placing a heavy burden on the healthcare system. For those that survive both PE and IUGR, there are life-long serious cardiovascular and neurological consequences.
iPLACENTA aims to use advancements in technology in a multidisciplinary network to enhance our ability to model, visualise and assess the placenta at different levels (in vitro, in silico and in vivo), as well as its interaction with the maternal cardiovascular system, with a view to improving diagnosis and eventual treatment of major placental diseases.
In addition to receiving excellent training in their own research fields, ESRs have benefited from intersectoral and multidisciplinary training gaining transferable skills in project management, open science, public engagement and entrepreneurship. Whilst being exposed to different sectors. The consortium was coordinated by Colin Murdoch University of Dundee and all ESRs are on track to complete their post-graduate training.
Work Package (WP) 1 developed state-of-the-art model to mimic the placenta in vitro. ESRs from Mimetas and University of Dundee utilised Mimetas’ unique OrganoPlates® platform to create a placenta-on-a-chip model to emulate the clinical disease situation, as well as the integration of functional characteristics. This model mimics the interplay of the placenta barrier with vascular system, providing a miniaturised effective tool for mechanistic studies or drug development. University of Dundee developed a method to differentiate human stem cells into trophoblast cells and integrated them into the 3D placenta on a chip model. University of Torino isolated and characterised extracellular vesicles (EV) from amniotic fluid and maternal plasma. During pregnancy, placental-derived EVs may provide a natural placental derived biopsy available in the maternal blood to determine placenta wellbeing.
In WP2 iPlacenta established a modularized molecular interaction network maps in the context ‘omics’ data of preeclampsia and Intrauterine growth restriction. Studies at INSERM identified changes in genomic methylation and alternative splicing sites and expression quantitative trait loci (eQTL) in PE And IUGR. University College Cork elucidate molecular signalling networks mediating premature placental aging in PE and IUGR at a cellular and placental level. Maastricht University generated a transcriptomic blueprint of the diseased placenta performing RNAseq analysis of human control and PE/IUGR placentas. University of Rostock has constructed NaviCenta (www.sbi.uni-rostock.de/minerva/index.xhtml?id=NaviCenta) a placenta-specific disease map, which is accessible from all in the research community
The objective of WP3 is to characterise and validate new methodologies for in vivo placenta modelling and clinical prediction of early/late onset PE and IUGR..
University of Dundee (Murdoch/ Krstajiic) in collaboration with Moor validated a miniature chip-on-tip camera for laser speckle imaging of blood perfusion. The validation and characterisation of this miniature camera paves the way for incorporation into an endoscopic probe that can benefit pre-clinical animal models or endoscopic surgery. In addition the project refined animal studies as part of the 3R’s developing a smaller lighter and flexible iontophoresis chamber for in vivo endothelial assessment in small animals.
KU Leuven developed and characterized a rabbit model of IUGR, both by deepening the current knowledge and by additionally analysing other organs and at different time points.
HULAFE identified epigenetic markers of abnormal fetal neurodevelopment with a focus on miRNAs showing association of those miRNAs with molecular pathways involved in the pathophysiology of growth restriction.
St Georges focused on analysing the correlation between hypertensive disorders of pregnancy (HDP) and development of cardiovascular disease (CVD) later in life conducting maternal echocardiography in the peripartum and postpartum period. The important results show that around two thirds of HDP patients had persistent cardiovascular impairment within one year postpartum suggesting that close follow-up of pregnant women with HDP might be an important first step to control CVD later in life. Also, St Georges and Dundee demonstrated that ophthalmic artery doppler correlated with uterine artery doppler and aortic stiffness in HDP and IUGR pregnancies, suggesting that . ophthalmic artery doppler could be a useful to monitor HDP, especially in low resource settings with limited technical equipment.
Work Package (WP) 1 developed state-of-the-art model to mimic the placenta in vitro. ESRs from Mimetas and University of Dundee utilised Mimetas’ unique OrganoPlates® platform to create a placenta-on-a-chip model to emulate the clinical disease situation, as well as the integration of functional characteristics. This model mimics the interplay of the placenta barrier with vascular system, providing a miniaturised effective tool for mechanistic studies or drug development. University of Dundee developed a method to differentiate human stem cells into trophoblast cells and integrated them into the 3D placenta on a chip model. University of Torino isolated and characterised extracellular vesicles (EV) from amniotic fluid and maternal plasma. During pregnancy, placental-derived EVs may provide a natural placental derived biopsy available in the maternal blood to determine placenta wellbeing.
In WP2 iPlacenta established a modularized molecular interaction network maps in the context ‘omics’ data of preeclampsia and Intrauterine growth restriction. Studies at INSERM identified changes in genomic methylation and alternative splicing sites and expression quantitative trait loci (eQTL) in PE And IUGR. University College Cork elucidate molecular signalling networks mediating premature placental aging in PE and IUGR at a cellular and placental level. Maastricht University generated a transcriptomic blueprint of the diseased placenta performing RNAseq analysis of human control and PE/IUGR placentas. University of Rostock has constructed NaviCenta (www.sbi.uni-rostock.de/minerva/index.xhtml?id=NaviCenta) a placenta-specific disease map, which is accessible from all in the research community
The objective of WP3 is to characterise and validate new methodologies for in vivo placenta modelling and clinical prediction of early/late onset PE and IUGR..
University of Dundee (Murdoch/ Krstajiic) in collaboration with Moor validated a miniature chip-on-tip camera for laser speckle imaging of blood perfusion. The validation and characterisation of this miniature camera paves the way for incorporation into an endoscopic probe that can benefit pre-clinical animal models or endoscopic surgery. In addition the project refined animal studies as part of the 3R’s developing a smaller lighter and flexible iontophoresis chamber for in vivo endothelial assessment in small animals.
KU Leuven developed and characterized a rabbit model of IUGR, both by deepening the current knowledge and by additionally analysing other organs and at different time points.
HULAFE identified epigenetic markers of abnormal fetal neurodevelopment with a focus on miRNAs showing association of those miRNAs with molecular pathways involved in the pathophysiology of growth restriction.
St Georges focused on analysing the correlation between hypertensive disorders of pregnancy (HDP) and development of cardiovascular disease (CVD) later in life conducting maternal echocardiography in the peripartum and postpartum period. The important results show that around two thirds of HDP patients had persistent cardiovascular impairment within one year postpartum suggesting that close follow-up of pregnant women with HDP might be an important first step to control CVD later in life. Also, St Georges and Dundee demonstrated that ophthalmic artery doppler correlated with uterine artery doppler and aortic stiffness in HDP and IUGR pregnancies, suggesting that . ophthalmic artery doppler could be a useful to monitor HDP, especially in low resource settings with limited technical equipment.
The ESRs are expected to become a key asset to the EU to lead translational research and deliver high-impact technological approaches. iPLACENTA broadened the scope of the participating institutions’ research capacities by bringing together a network and expanding academia collaboration with companies.
A major achievement of iPlacenta was linking academic research to industrial exploitation, the organ-on-a-chip company Mimetas, with the University of Dundee have developed and extensively characterised a placenta-on-a-chip model that is commercially available. A validated in vitro placenta model for high throughput screening using industry standardised readily available OrganoPlates® platform is expected to have a great impact on placental field.
In the setting of pre-clinical models, the collaboration between Dundee (Murdoch/Krstajiic) with the UK-based medical imaging device company Moor Instruments has led to two potential devices for commercial benefit. First a new flexible, smaller iontophoresis chamber, and a laser speckle imaging for flexible endoscopic imaging of organ perfusion.
The development of NaviCenta an open access placenta model to help integrate large omic data sets into the placenta function by University of Rostock will help the placenta field make sense of large omic data sets.
At the clinical level, St Georges London have identified that women who suffer from HDP are at risk of development of cardiovascular disease and may inform policy changes to ensuring that close follow-up of HDP post pregnancy.
A major achievement of iPlacenta was linking academic research to industrial exploitation, the organ-on-a-chip company Mimetas, with the University of Dundee have developed and extensively characterised a placenta-on-a-chip model that is commercially available. A validated in vitro placenta model for high throughput screening using industry standardised readily available OrganoPlates® platform is expected to have a great impact on placental field.
In the setting of pre-clinical models, the collaboration between Dundee (Murdoch/Krstajiic) with the UK-based medical imaging device company Moor Instruments has led to two potential devices for commercial benefit. First a new flexible, smaller iontophoresis chamber, and a laser speckle imaging for flexible endoscopic imaging of organ perfusion.
The development of NaviCenta an open access placenta model to help integrate large omic data sets into the placenta function by University of Rostock will help the placenta field make sense of large omic data sets.
At the clinical level, St Georges London have identified that women who suffer from HDP are at risk of development of cardiovascular disease and may inform policy changes to ensuring that close follow-up of HDP post pregnancy.