Extracellular vesicles as critical mediators of maternal-fetal communication during pregnancy and their potential role in maternal metabolism
Introduction
Maternal metabolism is programmed to provide adequate nutrients and metabolites to support the proper growth and development of the fetus. The early stages of pregnancy are generally anabolic, characterized by an increase in the storage of fats, triglycerides, and glycogen in the mother's body, whereas the later stages of pregnancy are catabolic, where glucose and fatty acids are mobilized from the maternal system and transferred to the fetus [1] In co-ordination with these metabolic changes, maternal insulin sensitivity decreases across gestation, and declines to nearly 56% at 34–36 weeks of pregnancy. Accordingly, this decrease in insulin sensitivity is compensated for by a nearly 3-fold increase in pancreatic insulin secretion [2]. These changes in insulin sensitivity and insulin secretion in the maternal system are synchronized with the demands of the growing fetus, and results in the transfer of adequate glucose and other fuels across the placenta. At cellular level, this decrease in insulin sensitivity is attributed to defects in the post-insulin receptor signalling, such as decreased expression, and tyrosine phosphorylation of the insulin receptor and Insulin Receptor Substrate-1 (IRS-1) molecule in skeletal muscle tissues [3]. Interestingly, a rapid reversal in insulin resistance soon after delivery (on removal of the placenta) has been reported [4], which implies that the hormones and factors derived from the placenta have intriguing roles in modulating the changes in insulin sensitivity during pregnancy. Studies have deciphered the role of placental hormones, particularly placental growth hormone and cytokines, in the development of insulin resistance during pregnancy [5,6]. However, a study by Kirwan et al., 2002, analysed the longitudinal changes in the placental hormones and cytokines with the changes in the insulin sensitivity across gestation and identified that only TNF-α was a strong predictor of changes in insulin sensitivity, whereas placental hormones and cortisol did not correlate with changes of insulin sensitivity in late gestation [6]. Hence, in addition to reproductive hormones and inflammatory mediators, several other factors might be involved in the regulation of maternal metabolism during pregnancy. Interestingly, growing evidence shows that the concentration and bioactivity of placenta derived-EVs changes across normal gestation and in pregnancy-associated disorders [[7], [8], [9], [10]]. However, our understanding of metabolic regulation during pregnancy is incomplete, and studies to elucidate the role of EVs, particularly placenta-derived EVs in maternal metabolism might address this gap. Recent studies emphasise the role of a wide range of EVs (highlighting their diversity) in cell-to-cell communication and intercellular signalling, including their utility in the diagnosis of disease onset and treatment monitoring.
Section snippets
EVs heterogeneity
EVs are membrane-enclosed vesicles secreted from a wide range of cells, including cells within the human placenta. They are secreted into the extracellular space and contain specific cargo such as proteins, nucleic acids and lipids [11]. The cargo carried by the EVs can be transferred to recipient cells in a neighbouring or distant location, and are capable of eliciting biological responses in their target cells [12]. Thus, EVs are an interesting mode of intercellular communication and cell
EVs during pregnancy
Pregnancy is a period of various physiological adaptations that are essential for the proper growth and development of the fetus. Although studies have identified placental hormones and inflammatory mediators such as cytokines and TNFα as important regulators of maternal physiology, several of the cellular mechanisms associated with this phenomenon need to be elucidated [23]. Interestingly, pregnancy is characterized by higher concentrations of circulating EVs, including sEVs and m/lEVs
EVs in metabolism
Metabolic homeostasis is maintained by complex interactions between different tissues and cell-to-cell communication is an important aspect of this phenomenon. Notably, EV biogenesis mechanisms can interact with the changes in the extracellular milieu, leading to alterations in the release of EVs, their content, as well as their effect on target cells [[40], [41], [42]] For example, metabolic stress such as hypoxia or oxidative stress triggers an increased release of sEVs from trophoblast cells
EVs in maternal metabolism in GDM
GDM is glucose intolerance that is first diagnosed during pregnancy [73]. GDM is characterized by insulin resistance in skeletal muscle tissues and inadequate insulin secretion to overcome the insulin resistance observed in these patients [74]. The expression of insulin signalling molecules such as insulin receptor, IRS-1 and p85α subunit of PI3K are decreased, with reduction in tyrosine phosphorylation in GDM [3]. GDM is characterized by adverse pregnancy outcomes and an increased future risk
Conclusions and future directions
The ability of EVs to carry biologically active molecules that change with the extracellular microenvironment, and their ability to induce biological responses in recipient cells is an exciting area of research and is receiving great interest in the research community. Studies involving cell-to-cell communication via EVs is an emerging field and much of the recent research has focussed on EVs in metabolic disorders such as obesity and type 2 diabetes. Metabolic adaptation is key to the
Acknowledgements
Presented at the PAA Placental Satellite Symposium 2018, which was supported by NIH Conference Grant HD084096. CS is supported by Lions Medical Research Foundation, Diabetes Australia, and Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT 1170809). SN has a Scholarship from the University of Queensland, funded by the Commonwealth Government of Australia.
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