Placental Exosomes During Gestation: Liquid Biopsies Carrying Signals for the Regulation of Human Parturition
Authors: Salomon Carlos , Nuzhat Zarin , Dixon Christopher L. , Menon Ramkumar 
Published: January 2018

Parturition is defined as the action or process of giving birth to offspring. Normal term human parturition
ensues following the maturation of fetal organ systems typically between 37 and 40 weeks of gestation. Our
conventional understanding of how parturition initiation is signaled revolves around feto-maternal immune and
endocrine changes occurring in the intrauterine cavity. These changes in turn correlate with the sequence of fetal
growth and development. These important physiological changes also result in homeostatic imbalances which
result in heightened inflammatory signaling. This disrupts the maintenance of pregnancy, thus leading to laborrelated
changes. However, the precise mechanisms of the signaling cascades that lead to the initiation of parturition
remain unclear, although exosomes may be a mediator of this process. Exosomes are a subtype of extracellular
vesicles characterised by their endocytic origin. This involves the trafficking of intraluminal vesicles into
multivesicular bodies (MVB) and then exocytosis via the plasmatic membranes. Exosomes are highly stable
nanovesicles that are released by a wide range of cells and organs including the human placenta and fetal membranes.
Interestingly, exosomes from placental origin have been uncovered in maternal circulation across gestation.
In addition, their concentration is higher in pregnancies with complications such as gestational diabetes and
preeclampsia. In normal gestation, the concentration of placental exosomes in maternal circulation correlates with
placental weight at third trimester. The role of placental exosomes across gestation has not been fully elucidated,
although recent studies suggest that placental exosomes are involved in maternal-fetal inmmuno-tolerance, maternal
systemic inflammation and nutrient transport. The content of exosomes is of particular importance, encompassing
a large range of molecules such as mRNA, miRNAs, DNA, lipids, cell-surface receptors, and protein
mediators. These can in turn interact with either adjacent or distal cells to reprogram their phenotype and regulate
their function. Many of the pro-parturition proinflammatory mediators reach maternal compartments from the
fetal side via circulation, but major impediments remain, such as degradation at various levels and limited halflife
in circulation. Recent findings suggest that a more effective mode of communication and signal transport is
through exosomes, where signals are protected and will not succumb to degradation. Thus, understanding how
exosomes regulate key events throughout pregnancy and parturition will provide an opportunity to understand the
mechanisms involved in the maternal and fetal metabolic adaptations during normal and pathological pregnancies.
Subsequently, this will assist in identifying those pregnancies at risk of developing complications. This may
also allow more appropriate modifications of their clinical management. This review will hence examine the
current body of data to summarise our understanding of how signaling pathways lead to the beginning of parturition.
In addition, we propose that extracellular vesicles, namely exosomes, may be an integral component of these
signaling events by transporting specific signals to prepare the maternal physiology to initiate parturition. Understanding
these signals and their mechanisms in normal term pregnancies can provide insight into pathological
activation of these signals, which can cause spontaneous preterm parturition. Hence, this review expands on our
knowledge of exosomes as professional carriers of fetal signals to instigate human parturition.