Elsevier

Placenta

Volume 98, 1 September 2020, Pages 60-68
Placenta

Extracellular vesicles as critical mediators of maternal-fetal communication during pregnancy and their potential role in maternal metabolism

https://doi.org/10.1016/j.placenta.2020.06.011Get rights and content

Highlights

  • Extracellular vesicles (EVs) are mediators of cell to cell communication.

  • EVs concentration and bioactivity is altered in pregnancy and pregnancy-related disorders.

  • Placenta responds to changes in the extracellular environment by altering the secretion and bioactivity of EVs.

  • Circulating EVs in GDM pregnancies carry signals that can induce changes in maternal systemic glucose homeostasis.

Abstract

Extracellular vesicles (EVs) have been implicated in the pathophysiology of metabolic disorders by transferring biologically active molecules such as miRNAs and proteins to recipient cells, and influencing their metabolic pathways. Pregnancy is one of the greatest metabolic challenges faced by both the mother and the growing fetus, and this is fine-tuned by several factors, including hormones, soluble molecules, and molecules encapsulated in EVs released from the placenta. A wide range of EVs originating from the placenta are present in maternal circulation, and changes in their circulating levels and bioactivity (i.e., capacity to induce changes in the target cells) have been associated with several complications of pregnancies, including gestational diabetes mellitus (GDM), preeclampsia, preterm birth, and fetal growth restriction. Complications of pregnancies are associated with maternal metabolic dysfunction with short- and long-term consequences for both mother and child. However, the potential roles of circulating EVs originating from the placenta and other tissues (e.g. adipose tissue), on changes in maternal metabolism during normal and pregnancy complications have not been fully described. The aim of this brief review, thus, is to discuss the diversity of EVs, and their potential roles in the metabolic alterations during pregnancy, with a special focus on GDM.

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.

References (94)

  • S. Katzenell et al.

    Characterization of negatively charged phospholipids and cell origin of microparticles in women with gestational vascular complications

    Thromb. Res.

    (2012)
  • R.A. Dragovic et al.

    Isolation of syncytiotrophoblast microvesicles and exosomes and their characterisation by multicolour flow cytometry and fluorescence Nanoparticle Tracking Analysis

    Methods

    (2015)
  • O. Elfeky et al.

    Influence of maternal BMI on the exosomal profile during gestation and their role on maternal systemic inflammation

    Placenta

    (2017)
  • C. Rask-Madsen et al.

    Vascular complications of diabetes: mechanisms of injury and protective factors

    Cell Metabol.

    (2013)
  • E. Kakazu et al.

    Hepatocytes release ceramide-enriched pro-inflammatory extracellular vesicles in an IRE1α-dependent manner

    J. Lipid Res.

    (2016)
  • P. Hirsova et al.

    Lipid-induced signaling causes release of inflammatory extracellular vesicles from hepatocytes

    Gastroenterology

    (2016)
  • Y. Chen et al.

    Syncytiotrophoblast-derived microparticle shedding in early-onset and late-onset severe pre-eclampsia

    Int. J. Gynaecol. Obstet.

    (2012)
  • M. Hod et al.

    The International Federation of Gynecology and Obstetrics (FIGO) Initiative on gestational diabetes mellitus: a pragmatic guide for diagnosis, management, and care

    Int. J. Gynaecol. Obstet.: the official organ of the International Federation of Gynaecology and Obstetrics

    (2015)
  • P.M. Catalano et al.

    Longitudinal changes in glucose metabolism during pregnancy in obese women with normal glucose tolerance and gestational diabetes mellitus

    Am. J. Obstet. Gynecol.

    (1999)
  • M. Hod et al.

    Evidence in support of the international association of diabetes in pregnancy study groups’ criteria for diagnosing gestational diabetes worldwide in 2019

    Am. J. Obstet. Gynecol.

    (2019)
  • D.J. Drucker et al.

    The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes

    Lancet

    (2006)
  • T. Sáez et al.

    Fetoplacental endothelial exosomes modulate high d-glucose-induced endothelial dysfunction

    Placenta

    (2018)
  • T. Sáez et al.

    Human umbilical vein endothelium-derived exosomes play a role in foetoplacental endothelial dysfunction in gestational diabetes mellitus

    Biochim. Biophys. Acta (BBA) - Mol. Basis Dis.

    (2018)
  • R.M. Johnstone et al.

    Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes)

    J. Biol. Chem.

    (1987)
  • K.Y. Lain et al.

    Metabolic changes in pregnancy

    Clin. Obstet. Gynecol.

    (2007)
  • J.E. Friedman et al.

    Impaired glucose transport and insulin receptor tyrosine phosphorylation in skeletal muscle from obese women with gestational diabetes

    Diabetes

    (1999)
  • J.P. Kirwan et al.

    Reversal of insulin resistance postpartum is linked to enhanced skeletal muscle insulin signaling

    J. Clin. Endocrinol. Metab.

    (2004)
  • L.A. Barbour et al.

    Human placental growth hormone increases expression of the P85 regulatory unit of phosphatidylinositol 3-kinase and triggers severe insulin resistance in skeletal muscle

    Endocrinology

    (2004)
  • J.P. Kirwan et al.

    TNF-α is a predictor of insulin resistance in human pregnancy

    Diabetes

    (2002)
  • C. Salomon et al.

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

    Diabetes

    (2016)
  • S. Sarker et al.

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

    J. Transl. Med.

    (2014)
  • M. Colombo et al.

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

    Annu. Rev. Cell Dev. Biol.

    (2014)
  • M. Tkach et al.

    Why the need and how to approach the functional diversity of extracellular vesicles

    Philos. Trans. R. Soc. Lond. B Biol. Sci.

    (2018)
  • J. Lötvall et al.

    Minimal experimental requirements for definition of extracellular vesicles and their functions: a position statement from the International Society for Extracellular Vesicles

    J. Extracell. Vesicles

    (2014)
  • C. Théry et al.

    Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines

    J. Extracell. Vesicles

    (2018)
  • J.M. Stein et al.

    Ectocytosis caused by sublytic autologous complement attack on human neutrophils. The sorting of endogenous plasma-membrane proteins and lipids into shed vesicles

    Biochem. J.

    (1991)
  • S. Caruso et al.

    Apoptotic cell-derived extracellular vesicles: more than just debris

    Front. Immunol.

    (2018)
  • B. Meehan et al.

    Oncosomes - large and small: what are they, where they came from?

    J. Extracell. Vesicles

    (2016)
  • M. Aalberts et al.

    Prostasomes: extracellular vesicles from the prostate

    Reproduction

    (2014)
  • L.A. Barbour et al.

    Cellular mechanisms for insulin resistance in normal pregnancy and gestational diabetes

    Diabetes Care

    (2007)
  • C. Salomon et al.

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

    Front. Pharmacol.

    (2014)
  • R. Menon et al.

    Circulating exosomal miRNA profile during term and preterm birth pregnancies: a longitudinal study

    Endocrinology

    (2019)
  • M. Knight et al.

    Shedding of syncytiotrophoblast microvilli into the maternal circulation in pre‐eclamptic pregnancies

    BJOG An Int. J. Obstet. Gynaecol.

    (1998)
  • S.J. Germain et al.

    Systemic inflammatory priming in normal pregnancy and preeclampsia: the role of circulating syncytiotrophoblast microparticles

    J. Immunol.

    (2007)
  • S.S. Luo et al.

    Human villous trophoblasts express and secrete placenta-specific microRNAs into maternal circulation via exosomes

    Biol. Reprod.

    (2009)
  • C.A. Lok et al.

    Circulating platelet-derived and placenta-derived microparticles expose Flt-1 in preeclampsia

    Reprod. Sci.

    (2008)
  • L. Fishman et al.

    Developmental phase-specific alkaline phosphatase isoenzymes of human placenta and their occurrence in human cancer

    Canc. Res.

    (1976)
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