Review: Fetal-maternal communication via extracellular vesicles – Implications for complications of pregnancies

doi:10.1016/j.placenta.2016.12.001

Placenta

Volume 54, June 2017, Pages 83-88

https://doi.org/10.1016/j.placenta.2016.12.001 Get rights and content

Abstract

The maternal physiology experiences numerous changes during pregnancy which are essential in controlling and maintaining maternal metabolic adaptations and fetal development. The human placenta is an organ that serves as the primary interface between the maternal and fetal circulation, thereby supplying the fetus with nutrients, blood and oxygen through the umbilical cord. During gestation, the placenta continuously releases several molecules into maternal circulation, including hormones, proteins, RNA and DNA. Interestingly, the presence of extracellular vesicles (EVs) of placental origin has been identified in maternal circulation across gestation. EVs can be categorised according to their size and/or origin into microvesicles (∼150–1000 nm) and exosomes (∼40–120 nm). Microvesicles are released by budding from the plasmatic membrane, whereas exosome release is by fusion of multivesicular bodies with the plasmatic membrane. Exosomes released from placental cells have been found to be regulated by oxygen tension and glucose concentration. Furthermore, maternal exosomes have the ability to stimulate cytokine release from endothelial cells. In this review, we will discuss the role of EVs during fetal-maternal communication during gestation with a special emphasis on exosomes.

Introduction

The human placenta is a unique, transient organ that ensues its development with the implantation of the blastocyst in the uterine wall [1]. Throughout pregnancy, it provides nutrition, gas exchange, waste removal, a source of haematopoietic stem cells and endocrine and immune support for the developing fetus, as well as the point of molecular exchange between the maternal and fetal systems [2].

Functionally, the human placenta is a villous tree covered with an abundance of trophoblast cells that can be classified as cytotrophoblast (CT), extravillous trophoblasts (EVTs) and syncytiotrophoblasts. These cells have specific functions during gestation [3], where syncytiotrophoblasts are in direct contact with the maternal circulation for nutrients [4]. The human placenta can release a wide range of molecules which enable the maternal physiology to accommodate fetal requirements during gestation. Interestingly, it has been described that the placenta can also communicate with the maternal physiology via extracellular vesicles (EVs) [5], [6], [7].

An increase in the release of EVs into maternal circulation as the pregnancy progresses has been noted in both healthy and pathological pregnancies, GDM, and PE [6], [7], [8], [9]. Interestingly, the presence of exosomes has been identified in maternal plasma as early as 6 weeks of gestational age [9]. These vesicles encapsulate a diverse cargo of proteins, lipids and nucleic acids that are constitutively released into the maternal circulation. They are subsequently taken up by cells of the maternal immune and vascular systems, hence modulating the overall maternal physiological system to adapt to pregnancy-induced changes [6]. Nevertheless, in complicated pregnancies, this mode of cell signalling plays a role in the manifestation of physical symptoms of disease states. This is particularly because the release of the EVs is dependent upon the microenvironment that they are exposed to [10].

This review will discuss the current body of knowledge on EVs during gestation with emphasis on the trafficking of placental vesicles into maternal circulation to regulate immune and metabolic adaptations to pregnancy. However, there is a gap in the literature pertaining to the standardisation of isolation methods to enrich specific populations of EVs, such as exosomes.

Section snippets

General characteristics of extracellular vesicles

A growing amount of evidence has emerged identifying EVs as a form of intercellular communication [11]. EVs (50 nm-2 um) are lipid-bilayer structures released from cells into the extracellular environment. They contain an array of proteins, lipids, RNAs and DNA. They are released from several cell types, such as trophoblasts [12], erythrocytes [13] and endothelial cells [14]. Initially thought to be cellular ‘debris’, EVs were later observed to interact with and modulate the bioactivity of

Placental vesicles in maternal circulation

Exosomes and microvesicles are released under normal and pathological conditions, with more potent effects on the physiology of target cells than single-molecule mediators such as lipids, hormones or cytokines. Placental vesicles have been identified in maternal circulation across gestation [7]. Notably, the secretion of vesicles was found to be increased during pregnancies complicated by gestational diabetes [7] and preeclampsia [18]. Moreover, EV release during pregnancy is modulated by

Potential roles of EVs during gestation

Placental EVs have been shown to constitute immunosuppressive factors released by the placenta to prevent fetal rejection. They also protect the semi-allogenic fetus through the suppression of various modulatory signals in the maternal immune system and inhibiting T-lymphocyte activation and natural killer cells that are detrimental to pregnancy [31]. As the fetus is antigenically distinct from the mother, it is necessary to deploy a tolerant immune response preventing the rejection of the

EVs in fetal circulation

Maternal-fetal trafficking is the bidirectional passage of maternal cells to fetal circulation and fetal cells to maternal circulation. It is responsible for the migration of different cytokines and other factors to fetal circulation during pregnancy. This phenomenon suggests that pathophysiological changes occuring due to complicated pregnancies may be reflected in the fetal circulation. As discussed previously [48], [49], the presence of maternal microchimerism in fetal circulation play roles

Conclusions and perspectives

EVs represent a mechanism of maternal-fetal interaction during gestation (Fig. 1). As EVs have several origins and mechanisms of secretion within the microenviroment, we suggest that exosomes and their content might be a better representation of the function and metabolic state of the cell of origin. Several studies have clearly established the presence of EVs released from the placenta into maternal circulation. Further, it has been illustrated that these EVs have a wide range of functions

Conflict of interest statement

The authors declare that they have no conflict of interests.

Acknowledgements

This review was generated as part of the Queensland Perinatal Consortium Inaugural Conference held on July 15th 2016 in Brisbane, Queensland Australia. The conference was supported by an Intra-Faculty Collaborative Workshop grant from the Faculty of Medicine, The University of Queensland. CS hold a Lions Medical Research Foundation Fellowship.

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Citation Excerpt :
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Review: Fetal-maternal communication via extracellular vesicles – Implications for complications of pregnancies

Abstract

Introduction

Section snippets

General characteristics of extracellular vesicles

Placental vesicles in maternal circulation

Potential roles of EVs during gestation

EVs in fetal circulation

Conclusions and perspectives

Conflict of interest statement

Acknowledgements

Placenta

Am. J. obstetrics Gynecol.

Placenta

Placenta

Curr. Biol.

Placenta

Placenta

Placenta

Exp. Cell Res.

Placenta

Clin. Chim. Acta

Immunol. Today

Placenta

Placenta

Placenta

Mol. Cell.Endocrinol.

J. Reproductive Immunol.

EBioMedicine

Placenta

Regen. Med. Blood

Int. J. Gynaecol. obstetrics official organ Int. Fed. Gynaecol. Obstetrics

The placenta: a multifaceted, transient organ, Philosophical transactions of the Royal Society of London

Biol. Sci.

What is the placenta?

Am. J. obstetrics Gynecol.

Vascular Biology of the Placenta

Update of syncytiotrophoblast derived extracellular vesicles in normal pregnancy and preeclampsia

J. reprod. Immunol.

A gestational profile of placental exosomes in maternal plasma and their effects on endothelial cell migration

PloS One

Gestational diabetes mellitus is associated with changes in the concentration and bioactivity of placenta-derived exosomes in maternal circulation across gestation

Diabetes

Placenta-derived exosomes continuously increase in maternal circulation over the first trimester of pregnancy

J. Transl. Med.

Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles

Annu. Rev. Cell Dev. Biol.

Extravillous trophoblast cells-derived exosomes promote vascular smooth muscle cell migration

Front. Pharmacol.

Multicolor flow cytometry and nanoparticle tracking analysis of extracellular vesicles in the plasma of normal pregnant and pre-eclamptic women

Biol. Reprod.