Maternal-embryonic cross-talk via platelets and EVs: a new mechanism of embryonic reprogramming

• Applicant: Dr. Shrey Kohli
• Subject Area: Public Health, Healthcare Research, Social and Occupational Medicine ; Gynaecology and Obstetrics
• Term: from 2018 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 396257148

Gestational vascular diseases such as preeclampsia (PE) are associated with maternal and fetal morbidity and mortality. The mechanisms underlying PE remain enigmatic and delivery of the placenta is the only known remedy. PE not only results in an inflammatory insult to maternal organs but also affects the embryos resulting in IUGR. This increases the risk for cardiovascular and metabolic diseases in the embryos later in life. The causes and mechanisms promoting reprogramming of fetus due to pregnancy complications remain unknown. We have recently shown that maternal extracellular vesicles (EVs) promote preeclampsia by triggering a thrombo-inflammatory pathway at the feto-maternal interface. In particular, EVs cause platelet-activation and accumulation of activated platelets within the placenta. ATP released from activated platelets induces NLRP3 inflammasome activation via purinergic signaling in embryonic trophoblast cells. It remains unresolved as to what promotes accumulation of activated platelets predominantly in the placenta. Besides, the effects of EVs and activated platelets on the embryo proper and its consequences later in life remain unknown. Based on our recently published data and further preliminary work we intend to address the following questions within the proposed research project:What factors/molecules promote adhesion of maternal platelets to embryonic trophoblast cells after EV injections and what is their mechanism?Do EVs carry cargo molecules that can be transported across the placenta into the embryo?What are the consequences of trans-placental transport of EVs and/or their cargos into the embryo?What are the long-term post-natal effects of EVs acting on the placenta and / or the embryo for chronic diseases?Answering these questions will provide new insights into the role of EVs in pregnancy complications. The documentation of a cross talk between the mother and the embryo via transplacental transport of EVs and / or their contents would constitute a novel pathway of feto-maternal communication during the pregnancy. This may lay ground for new therapeutic strategies to combat not only PE and IUGR, but also fetal re-programming towards chronic disease in adult life.

• DFG Programme: Research Grants