Placental small extracellular vesicles: Current questions and investigative opportunities

Sadovsky, Yoel; Ouyang, Yi‐Bing; Powell, Juliana S.; Li, Hui; Mouillet, Jean-François; Morelli, Adrián E.; Sorkin, Alexander; Margolis, Leonid

doi:10.1016/j.placenta.2020.03.002

Cited by 32 publications

(33 citation statements)

References 96 publications

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“…The syncytiotrophoblast (SYN), formed by fusion of underlying mononuclear trophoblasts, is a syncytium that covers the~12 m 2 surface of chorionic villi and is bathed in maternal blood to allow all nutritional and waste exchanges between mother and fetus (3,(13)(14)(15)(16). The SYN also secretes pregnancy hormones and releases extracellular vesicles in maternal blood (17,18). A second category of trophoblasts, the extravillous trophoblasts, are located at the tip of placental villi, forming columns of mononuclear cells that anchor villi into the maternal endometrium (12).…”

Section: Introductionmentioning

confidence: 99%

Human Placental Trophoblasts Infected by Listeria monocytogenes Undergo a Pro-Inflammatory Switch Associated With Poor Pregnancy Outcomes

et al. 2021

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The placenta controls the growth of the fetus and ensures its immune protection. Key to these functions, the syncytiotrophoblast (SYN) is a syncytium formed by fusion of underlying mononuclear trophoblasts. The SYN covers the placental surface and is bathed in maternal blood to mediate nutritional and waste exchanges between the mother and fetus. The bacterial pathogen Listeria monocytogenes breaches the trophoblast barrier and infects the placental/fetal unit resulting in poor pregnancy outcomes. In this work, we analyzed the L. monocytogenes intracellular lifecycle in primary human trophoblasts. In accordance with previous studies, we found that the SYN is 20-fold more resistant to infection compared to mononuclear trophoblasts, forming a protective barrier to infection at the maternal interface. We show for the first time that this is due to a significant reduction in L. monocytogenes uptake by the SYN rather than inhibition of the bacterial intracellular division or motility. We here report the first transcriptomic analysis of L. monocytogenes-infected trophoblasts (RNA sequencing). Pathway analysis showed that infection upregulated TLR2, NOD-like, and cytosolic DNA sensing pathways, as well as downstream pro-inflammatory circuitry (NF-κB, AP-1, IRF4, IRF7) leading to the production of mediators known to elicit the recruitment and activation of maternal leukocytes (IL8, IL6, TNFα, MIP-1). Signature genes associated with poor pregnancy outcomes were also upregulated upon infection. Measuring the release of 54 inflammatory mediators confirmed the transcriptomic data and revealed sustained production of tolerogenic factors (IL-27, IL-10, IL-1RA, TSLP) despite infection. Both the SYN and mononuclear trophoblasts produced cytokines, but surprisingly, some cytokines were predominantly produced by the SYN (IL-8, IL-6) or by non-fused trophoblasts (TNFα). Collectively, our data support that trophoblasts act as placental gatekeepers that limit and detect L. monocytogenes infection resulting in a pro-inflammatory response, which may contribute to the poor pregnancy outcomes if the pathogen persists.

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Section: Introductionmentioning

confidence: 99%

Human Placental Trophoblasts Infected by Listeria monocytogenes Undergo a Pro-Inflammatory Switch Associated With Poor Pregnancy Outcomes

et al. 2021

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“…The copyright holder for this preprint this version posted November 19, 2021. ; https://doi.org/10.1101/2021.11.18.468660 doi: bioRxiv preprint considering the amount of data already available concerning their composition and function [26,29,32]. By using the gold-standard method based on differential ultracentrifugation followed by density gradient ultracentrifugation, we were able to isolated sEVs devoid of viral particles in a rigorous manner.…”

Section: Discussionmentioning

confidence: 99%

“…For example, there can be uptaken by Natural Killer cells [21,22] or by primary placental fibroblasts [23]. Although the understanding of the biological relevance of placental EVs in vivo remains limited, recent findings highlight their roles in cell-cell communication underlying the feto-placenta-maternal dialogue during pregnancy [24][25][26].…”

Section: Introductionmentioning

confidence: 99%

Human Cytomegalovirus modifies placental small extracellular vesicle secretion and composition towards a proviral phenotype to enhance infection of fetal recipient cells

Bergamelli¹,

Martin²,

Aubert³

et al. 2021

Preprint

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Although placental small extracellular vesicles (sEVs) are extensively studied in the context of pregnancy, little is known about their role during human cytomegalovirus (hCMV) congenital infection, especially at the beginning of pregnancy. In this study, we examined the consequences of hCMV infection on sEVs production and composition using an immortalized human cytotrophoblast cell line derived from first trimester placenta. By combining complementary approaches of biochemistry, imaging techniques and quantitative proteomic analysis, we showed that hCMV infection increased the yield of sEVs produced by cytotrophoblasts and modified their protein composition towards a proviral phenotype. We further demonstrated that sEVs secreted by hCMV-infected cytotrophoblasts potentiated infection in naive recipient cells of fetal origin, including neural stem cells. Importantly, the enhancement of hCMV infection was also observed with sEVs prepared from either an ex vivo model of infected histocultures from early placenta or from the amniotic fluid of patients naturally infected by hCMV at the beginning of pregnancy. Based on these findings, we propose that placental sEVs could be key actors favoring viral dissemination to the fetal brain during hCMV congenital infection.

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“…Indeed, the literature devoted to placental EVs can sometimes lead to confusion as to the nature of the EVs examined. Some studies have rigorously examined the different categories of EVs, and have underlined the importance of small EVs (sEVs, i.e., exosomes) in several pathologies of pregnancy (Adam et al, 2017;Salomon and Rice, 2017;Sadovsky et al, 2020), even if large EVs (also called microvesicles) also play an undeniable role during pregnancy. Notably, an antiviral role has been specifically attributed to sEVs derived from isolated cytotrophoblasts of term placenta (Delorme-Axford et al, 2013;Ouyang et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

“…Thus, sEVs may represent valuable non-invasive biomarkers reflecting the status of the placenta and of the pregnancy (Mitchell et al, 2015;Jin and Menon, 2018). Moreover, as sEVs can be internalized by recipient cells and exert biological function, any alteration of their cargo may modify their normal activity (Kalluri and LeBleu, 2020;Sadovsky et al, 2020). In this context, it is important to develop relevant models which allow preparation of placental sEVs in a robust and reproducible manner, in order to guarantee their use for downstream analysis.…”

Section: Introductionmentioning

confidence: 99%

Human Cytomegalovirus Infection Changes the Pattern of Surface Markers of Small Extracellular Vesicles Isolated From First Trimester Placental Long-Term Histocultures

Bergamelli

Martin

Bénard

et al. 2021

Front. Cell Dev. Biol.

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Extracellular vesicles (EVs) have increasingly been recognized as key players in a wide variety of physiological and pathological contexts, including during pregnancy. Notably, EVs appear both as possible biomarkers and as mediators involved in the communication of the placenta with the maternal and fetal sides. A better understanding of the physiological and pathological roles of EVs strongly depends on the development of adequate and reliable study models, specifically at the beginning of pregnancy where many adverse pregnancy outcomes have their origin. In this study, we describe the isolation of small EVs from a histoculture model of first trimester placental explants in normal conditions as well as upon infection by human cytomegalovirus. Using bead-based multiplex cytometry and electron microscopy combined with biochemical approaches, we characterized these small EVs and defined their associated markers and ultrastructure. We observed that infection led to changes in the expression level of several surface markers, without affecting the secretion and integrity of small EVs. Our findings lay the foundation for studying the functional role of EVs during early pregnancy, along with the identification of new predictive biomarkers for the severity and outcome of this congenital infection, which are still sorely lacking.

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Placental small extracellular vesicles: Current questions and investigative opportunities

Cited by 32 publications

References 96 publications

Human Placental Trophoblasts Infected by Listeria monocytogenes Undergo a Pro-Inflammatory Switch Associated With Poor Pregnancy Outcomes

Human Placental Trophoblasts Infected by Listeria monocytogenes Undergo a Pro-Inflammatory Switch Associated With Poor Pregnancy Outcomes

Human Cytomegalovirus modifies placental small extracellular vesicle secretion and composition towards a proviral phenotype to enhance infection of fetal recipient cells

Human Cytomegalovirus Infection Changes the Pattern of Surface Markers of Small Extracellular Vesicles Isolated From First Trimester Placental Long-Term Histocultures

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