Procoagulant Extracellular Vesicles Alter Trophoblast Differentiation in Mice by a Thrombo-Inflammatory Mechanism.

Paulina Markmeyer,Anubhuti Gupta,Ruaa Younis,Berend Isermann,Matthias Ruebner,Kunal Kumar Singh,Khurrum Shahzad,Shrey Kohli,Ronald Biemann,Franziska Lochmann,Hanna Huebner

doi:10.3390/ijms22189873

Abstract

Procoagulant extracellular vesicles (EV) and platelet activation have been associated with gestational vascular complications. EV-induced platelet-mediated placental inflammasome activation has been shown to cause preeclampsia-like symptoms in mice. However, the effect of EV-mediated placental thrombo-inflammation on trophoblast differentiation remains unknown. Here, we identify that the EV-induced thrombo-inflammatory pathway modulates trophoblast morphology and differentiation. EVs and platelets reduce syncytiotrophoblast differentiation while increasing giant trophoblast and spongiotrophoblast including the glycogen-rich cells. These effects are platelet-dependent and mediated by the NLRP3 inflammasome. In humans, inflammasome activation was negatively correlated with trophoblast differentiation marker GCM1 and positively correlated with blood pressure. These data identify a crucial role of EV-induced placental thrombo-inflammation on altering trophoblast differentiation and suggest platelet activation or inflammasome activation as a therapeutic target in order to achieve successful placentation.

Highlights

Proper placentation is required for a successful pregnancy outcome
In order to determine the effect of extracellular vesicles (EV)-mediated thrombo-inflammation on placental development, we first studied the gross morphology of the placenta by determining the proportion of spongiotrophoblast (STC) and the labyrinth zone
These results suggest that the effects of EVs on trophoblast differentiation and glycogen-rich cells depend on platelet activation

Summary

Introduction

Proper placentation is required for a successful pregnancy outcome. Vascular complications resulting in placental dysfunction, referred to as gestational vascular diseases (e.g., pre-eclampsia, HELLP), are a leading cause of pregnancy failure and feto-maternal morbidity and mortality. Successful placentation depends on proper trophoblast cell differentiation in humans and mice. Trophoblast cells differentiate into three major layers—the (i) giant trophoblast, the spongiotrophoblast zone (SZ), together comprising the junctional zone (JZ), and the labyrinth zone (LZ) including the syncytiotrophoblast [2,3]. The cells of the ectoplacental cone differentiate into secondary giant trophoblast cells which invade the decidua. This forms the middle layer between the giant trophoblast cells and the labyrinth zone. A key feature of the labyrinth layer of the mouse placenta is the direct contact of mouse trophoblast cells with maternal blood—a characteristic that is present in human placental villi, providing direct access to blood-derived components, such as coagulation regulators, to trophoblast cells

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