Title: Circulating placental extracellular vesicles as non-invasive placental biopsies and sources of diagnostic markers in fetal growth restriction
Funder: The Academy of Medical Sciences

Abstract: Fetal growth restriction (FGR) resulting from placental insufficiency is a serious and untreatable condition, affecting 8% of pregnancies. It can result in stillbirth or the need for extreme preterm delivery, with the associated neonatal and long-term morbidity. Investigating the pathophysiological mechanisms that underly placental insufficiency is made more challenging by the limited techniques for assessing placental function during on-going pregnancies. Extracellular vesicles (EVs) are small cell fragments containing RNA and protein cargo, released into the maternal circulation by maternal and placental cells. My hypothesis is that placental EVs (pEVs) can act as a non-invasive ‘biopsy’, reflecting the placental transcriptome/proteome. My preliminary data indicate that placental and maternal EVs isolated from maternal plasma can be separated using placental alkaline phosphatase antibodies bound to magnetic beads and that pEV protein content differs between pregnancies with appropriate-for-gestational-age (AGA) and FGR fetuses. The placental protein pregnancy associated plasma protein A (PAPP-A) was not detectable in maternal EVs and was higher in pEVs from AGA pregnancies than from FGR pregnancies. In this project I will (1) optimise pEV isolation (2) define the correlation between pEV cargo from plasma collected shortly before delivery and the placental transcriptome/proteome and (3) characterise pEVs from pregnancies with AGA and FGR fetuses between 20 and 27 weeks' gestation and identify differences in cargo. Establishing the association between pEV cargo and the placental transcriptome/proteome and determining whether pEV cargo is altered in FGR could provide insights into the mechanisms of disease, lead to new diagnostic tests and potentially identify therapeutic targets.

Lay abstract: In one out of every 13 pregnancies, a problem with how the placenta grows and works mean the baby doesn’t grow properly inside the womb. This is called fetal growth restriction (FGR); it can be difficult to detect and is currently untreatable. When it occurs in the middle stages of pregnancy there is a high risk of stillbirth or of the baby needing very early delivery. I want to understand why this happens, how we can identify it and how we may be able to treat it. Extracellular vesicles (EVs) are small packages of protein and RNA (instructions for proteins and genes) produced by most cells. EVs from placental cells (pEVs) can be found in the blood of pregnant women. They have a placental protein on the outside which can be used to bind them and separate them from EVs produced by the mother’s cells. I believe that studying the proteins and RNA inside pEVs will give us a way to tell what is happening in the placenta during the pregnancy. This could help identify pregnancies with FGR, tell us more about why it happens and identify possible treatments. In this project I will: (1) find the best way of separating pEVs from the mother’s blood (2) compare the amounts of protein and RNA in the placenta to the amounts in pEVs from blood samples taken close to delivery (3) look for proteins and RNAs that have different levels in pEVs from FGR pregnancies than pregnancies with normally grown babies.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH