Extracellular vesicles from maternal uterine cells exposed to risk factors cause fetal inflammatory response

Abstract

Background Fetal cell-derived exosomes (extracellular vesicles, 40–160 nm) are communication channels that can signal parturition by inducing inflammatory changes in maternal decidua and myometrium. Little is known about maternal cell-derived exosomes and their functional roles on the fetal side. This study isolated and characterized exosomes from decidual and myometrial cells grown under normal and inflammatory/oxidative stress conditions and determined their impact on fetal membrane cells. Methods Decidual and myometrial cells were grown under standard culture conditions (control) or exposed for 48 h to cigarette smoke extract or tumor necrosis factor-α, as proxies for oxidative stress and inflammation, respectively. Exosomes were isolated from media (differential ultra-centrifugation followed by size exclusion chromatography), quantified (nano particle tracking analysis), and characterized in terms of their size and morphology (cryo-electron microscopy), markers (dot blot), and cargo contents (proteomics followed by bioinformatics analysis). Maternal exosomes (109/mL) were used to treat amnion epithelial cells and chorion trophoblast cells for 24 h. The exosome uptake by fetal cells (confocal microscopy) and the cytokine response (enzyme-linked immunosorbent assays for IL-6, IL-10, and TNF-α) was determined. Results Exosomes from both decidual and myometrial cells were round and expressed tetraspanins and endosomal sorting complexes required for transport (ESCRT) protein markers. The size and quantity was not different between control and treated cell exosomes. Proteomic analysis identified several common proteins in exosomes, as well as unique proteins based on cell type and treatment. Compared to control exosomes, pro-inflammatory cytokine release was higher in both amnion epithelial cell and chorion trophoblast cell media when the cells had been exposed to exosomes from decidual or myometrial cells treated with either cigarette smoke extract or tumor necrosis factor-α. In chorion trophoblast cells, anti-inflammatory IL-10 was increased by exosomes from both decidual and myometrial cells. Conclusion Various pathophysiological conditions cause maternal exosomes to carry inflammatory mediators that can result in cell type dependent fetal inflammatory response.

Association between Maternal Periodontitis and Development of Systematic Diseases in Offspring

“…Exosomes are released by both maternal and fetal cells, and carry various cargo loads that are reflections of the physiologic and metabolic state of the cells, as well as pathological conditions at the time of their release. Until recently, it was thought that communication between mother and fetus via exosomes took place only through information sent by the fetal cells to the mother’s cells, and thus serum exosomal miRNAs may be used as molecular biomarkers for the prenatal diagnosis of fetal disorders [ 148 ]. However, the latest evidence shows that maternal exposure to various risk factors during pregnancy, specifically those causing oxidative stress and inflammation, can generate exosomes with distinct cargo proteins that can cause a fetal inflammatory response through the delivery of pro-inflammatory mediators [ 149 ].…”

Acute Histological Chorioamnionitis and Birth Weight in Pregnancies With Preterm Prelabor Rupture of Membranes: A Retrospective Cohort Study

“…This hypothesis suggests that placental changes leading to impaired fetal growth are associated with the development of the acute inflammation of the amnion rather than the fetal inflammatory response, as shown in this study. We cannot fully exclude a contribution of fetal membranes on the production of the chemotactic stimuli along with the placenta for the following reasons: i) transporter proteins in the fetal membranes along with nutritional transport system suggests that fetal membranes play an equal role to that of the placenta in drug and nutrients transports (Ganguly et al, 2021;Kammala et al, 2022); ii) endogenous activities in the fetal membranes on cellular level can generate danger signals (Menon and Peltier, 2020;Sheller-Miller and Menon, 2020;Shahin et al, 2021;Shepherd et al, 2021;Tantengco et al, 2021); iii) fetal membranes function can be independent of the placenta and placental involvement (Menon, 2016); iv) fetal growth restriction can increase apoptosis in the chorionic trophoblast cells of fetal membranes and expression of parathyroid-related protein expression in the fetal membranes (Curtis et al, 2000;Murthi et al, 2005); and v) fetal membranes are not the mere extension of the placenta and have their own identity, function and hence, their compromise alone without the placental involvement can be detrimental (Collins et al, 1993;Menon and Moore, 2020). Therefore, functions of fetal membranes might be impaired in pregnancies complicated by the alteration of fetal growth.…”

Fetal inflammatory response at the fetomaternal interface: A requirement for labor at term and preterm*

“…Treatment of these exosomes on fetal cell membranes caused inflammation; however, some of the cells (CTC) also increased IL‐10. These studies are interesting, as maternal inflammation can also be propagated via exosomes, and unlike in the FIR, fetal cells tend to balance the response 151 . Of note, these responses are dependent on the dose of exosomes and their cargo contents.…”

“…[141][142][143][144][145][146][147][148] Similarly, decidual activation is also an inflammatory process where both stromal cells and resident immune cells provide immunohomeostasis that maintains pregnancy. 30,33,149 Decidual activation involves immune cell migration into other fetomaternal uterine tissues, 33,63,81,145,150 whereas the inflammatory process involves endocrine mediators, immune cells, and paracrine factors such as extracellular vesicles 151 and other secreted factors (cytokines, chemokines, and growth factors). Multiple theories exist on the timing of inflammatory signals arriving in maternal uterine tissues and the beginning of parturition; however, the dogma is that maternal activation of the delivery process is a response to various fetomaternal signals.…”