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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
 
Final Report Year 2023

Final Report Abstract

Thrombo-inflammatory gestational vascular complications (TIGVCs) such as preeclampsia (PE) are associated with maternal and fetal morbidity and mortality. 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 underlying in utero mechanisms and the mechanisms perpetuating the consequences into postnatal life remain under-studied. We have previously 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, accumulation of activated platelets within the placenta, NLRP3 inflammasome activation 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. In the current proposal we were able to identify a new function of placental thrombomodulin (TM), a coagulation regulator in PE and suggested that soluble TM limits thromboinflammatory pregnancy complications. Furthermore, we identified a crucial role of EV-induced placental thrombo-inflammation on altering trophoblast differentiation and suggested platelet activation or inflammasome activation as a therapeutic target in order to achieve successful placentation. In follow-up studies we show that lowmolecular weight heparin (LMWH), a safe anticoagulant used during pregnancy is able to prevent inflammasome activation and restores trophoblast function. While LMWH is not indicated for preeclampsia, its potential anti-inflammatory effects suggest that further studies are required to explore its potential beneficial effects. Finally, we identified that EVs do not only induce a PE-like phenotype, but are causatively linked with re-programming of embryonic tissues such as heart, kidney and brain, which predisposes the mice to complications in adult life. Importantly, we observed that such offspring are biased towards an inflammatory state and more severe disease courses (e.g. in renal diseases) later in life. Further studies focusing on identifying the potential of resident immune-cell programming are required to outline mechanisms in detail.

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