Preeclampsia is a hypertensive disorder of pregnancy associated with important maternal and perinatal mortality and morbidity. It complicates 2 to 7% of pregnancies and causes more than 70 000 maternal deaths each year worldwide. Although symptomatic management has improved there is currently no curative treatment, and only childbirth and delivery of the placenta, usually prematurely, alleviate the mother’s symptoms. The management of extremely preterm infants is a major societal challenge in medical, ethical and economic terms. Substantial advances in neonatology are enabling the intensive care of increasingly preterm infants (from 5.5 months of gestation), without really ensuring a neurologic and pulmonary outcome free of long-term handicap. These small for gestational age infants remain in a hospital setting until they attain a weight of approximately 2500 g. The cost of their care is considerable. A study in the United Kingdom put the annual cost of care of such children, up to the age of 18 years, at over one billion euros. Therefore the development of therapeutic strategies for preeclampsia is one of the highest priorities in perinatal medicine. Placental insufficiency plays a central role in the pathophysiology of preeclampsia. Abnormal placentation during the first trimester leads to defective remodeling of the uterine vascularization. This results progressively in placental hypoperfusion, which induces trophoblast dysfunction and the release in maternal circulation of trophoblastic factors leading to an excessive inflammatory response, endothelial dysfunction and glomerular damage. Among these factors, the most important is sFlt-1, which is a soluble form of the VEGF and PlGF receptor. sFlt-1 binds to free VEGF and PlGF in the maternal circulation, thus reducing their bioavailability for their membrane receptor. The result is inhibition of the effects of VEGF and PlGF on maternal endothelial cells and podocytes. The sFlt-1/PlGF ratio reflects the circulating angiogenic balance and is correlated with severity of the disease. Targeting the sFLT-1 pathway is one of the most promising strategies for the development of new treatments for preeclampsia. As sFlt-1 results from alternative splicing, its peptide sequence is identical to that of the extracellular part of the membrane receptor. The development of drugs that act specifically on the soluble form and not on the membrane form is therefore particularly complex. The alternative is to eliminate from the maternal circulation the placenta-derived sFlt-1 produced in excess. We therefore aim to develop a specific apheresis system to reduce circulating sFlt-1 and to increase free PlGF in order to restore the physiologic angiogenic balance that maintains a healthy endothelial function and normal glomerular stage. To shift the equilibrium of sFlt-1/PlGF binding, we envisage grafting the capture surface of magnetic beads with molecules that behave as a competitive antagonist of PlGF in its binding to sFlt-1 and have a greater affinity than PlGF for sFlt-1 (VEGF the natural ligand, synthetic peptides and peptidomimetic ligands are potential candidates). This competitive biomimetic binding approach will capture the circulating sFlt-1 while releasing PlGF from its soluble receptor and will modulate the sFlt-1/PlGF ratio more effectively, thereby increasing the bioavailability of PlGF and potentiating its effects on maternal endothelial function. For this proof of concept, we will also use a new approach based on fluidized bed. This microfluidic technology enhances mass transfer between the solid and liquid phases and should therefore improve the restoration of the physiological sflt1/PlGF ratio compared to conventional apheresis systems.

Exposure to environmental chemical contaminants may lead to adverse effects on human pregnancy and fetal development. The toxics under suspicion may act directly on the fetus but also via their effects on the placenta which is the interface structure between mother and fetus whose exchange functions, as well as endocrine function play a physiological crucial role in the success of pregnancy and fetal development. However, the nature of the deleterious effects of environmental contaminants on the placenta and genetic targets as well as molecular and cellular mechanisms involved are poorly known. The placental key cell is the trophoblast. These cells differentiate spontaneously in vitro into syncytiotrophoblast cells which are the site of all exchange and hormonal functions of the placenta. Primary cultures of trophoblast cells at different terms of pregnancy represent a unique source of human placental material that can be exposed in vitro to environmental pollutants and thus enabling to characterize the placental response to these contaminants throughout pregnancy in human species. Using cultures of placental cells in the first and last trimesters of pregnancy is an approach to analyze the response of placental tissues from exposure to environmental contaminants throughout pregnancy. Therefore the aim of our project is to establish the molecular basis of placental toxicology using two pollutants, benzo(a)pyrene and MEHP, a metabolite of DEHP phthalate. The project will be carried out on 1) in vitro models with cultures of first trimester (early and end late-term) and cultures of term placenta which will take into account the complexity of the human placenta for its development and its physiology throughout pregnancy and on 2) a dynamic model reproducing the physiological conditions of placenta at term. This project concerning placental toxicology will use biological techniques specific to the human placental physiology and analytical techniques of mass spectrometry. This entirely innovative project is based on the internationally recognized expertise of placental physiology for partner 1 and on approaches to experimental toxicology and analysis by mass spectrometry of proteins and metabolites for partner 2. The feasibility of this project is provided by 1 / specific equipment to Institut Universitaire «Médicament, Toxicologie, Chimie et Environnement» (IMTCE) 2 / technological expertise of involved teams in the Faculty of Pharmacy 3 / Foundation PremUp (www.premup.org) that allows access to placental biological samples whatever the term of pregnancy. This project will establish close links between both teams in the IMTCE of Paris-Descartes, whose objective is to animate interfaces between chemistry, biology and pharmaco-toxicology that are at the heart of this project. These data can be integrated in the long term in a multidisciplinary frame, involving cellular and molecular toxicology, medical practice (monitoring of pregnancy and child development) and epidemiology. Based on scientific considerations and on a multidisciplinary approach, the objective is to provide recommendations on the environment of the pregnant woman.

In the human placenta, organ responsible for fetal growth and development, the multinucleated cellular layer, named syncytiotrophoblast (ST) plays a major role. Indeed ST bathing in maternal blood is the site of nutrient exchange and hormone synthesis. ST expands and regenerates all along pregnancy via the recruitment by fusion of underlying mononucleated cytotrophoblast cells. The apical membrane of ST is formed of microvilli which can brake away in the intervillous space. In addition, large ST pieces, called sprouts, are also released in the maternal blood all along pregnancy. Preeclampsia one of the main causes of severe premature births and Intra-Uterine Growth Retardation (IUGR) are two major pregnancy pathologies from placental origin with major socio-economical and human costs. They are associated with a large release of membrane trophoblast necrotic material as well as an abnormal regeneration of the ST. These ST fragments are inflammatory for the maternal endothelial cells. Therefore extensive membrane ruptures occur in physiological and pathological conditions, and must be compensated by efficient processes of membrane repair. Our current understanding of the mechanisms of membrane repair of the human placenta is very poor. Recently, Partner-1 (A. Brisson) has elucidated the function of Annexin-A5 in membrane repair. Annexin-A5 discovered originally in the placenta is the prototype member of the annexins, a family of soluble proteins that share the property of binding to negatively-charged lipid membranes, principally those containing phosphatidylserine (PS) in a Ca2+-dependant manner. According to J. Rand’s hypothesis, proposed fifteen years ago, PS molecules are exposed at the ST membrane surface and Annexin-A5 forms a layer covering the ST surface, which prevents blood coagulation in the intervillous space. Despite its potential interest, this hypothesis is weakly supported by low-resolution immune-histological data. The recent finding that Annexin-A5 occupies a central place in the machinery of membrane repair, which is of vital importance in cell’s life, constitutes a major breakthrough in Annexin-A5 research. This study concludes that Annexin-A5 promotes membrane repair via the formation of 2D arrays at the level of damaged membranes, which prevents the expansion of membrane wound and facilitates the final step of membrane resealing. In view of 1) the role of Annexin-A5 in membrane repair, 2) the extensive membrane damages occurring at the placenta ST membrane and 3) the high Annexin-A5 content of the placenta, we postulate that Annexin-A5 is involved in membrane repair of the ST membrane. The overall aim of the PlacentA5 project is thus to elucidate whether Annexin-A5 is involved in membrane repair of placental ST, and what is its exact role in normal and pathological placentas. The strength of this project is the task force joining two leader teams with unique complementary expertise. Partner 1 (A. Brisson) is a leader in imaging and structure-function studies of Annexin-A5 assemblies. Partner 2 (D. Evain-Brion) is an international reference team in the field of human placenta physiology and human trophoblast differentiation, with a unique expertise in setting in vitro models of human trophoblast differentiation. This project is developed within the RTRS PremUp allowing normal and patholigical placenta collections.

DAIOR (Distributed Artificial Intelligence for the OR) aims to develop AI-driven technologies to improve outcomes of patients undergoing surgery, by integrating and analysing massive multimodal data generated in the operating room (OR) in real time through a distributed approach. We envision a future where interconnected ORs continuously receive, send and process knowledge using interoperable artificial intelligence models to promote value-based healthcare. Towards this ambition, this German-French project proposes to prototype and validate the next generation interoperable AI-empowered OR in Europe. DIAOR is centred on two use cases: 1) build and validate a novel surgical environment to leverage OR-based AI Federated Learning (FL) expertise existing in Mannheim & Strasbourg ORs, to ultimately improve patient outcomes; 2) implement an AI solution to enable cross-border robotic telesurgery between interoperable connected operating rooms.