Exosomes Cause Preterm Birth in Mice: Evidence for Paracrine Signaling in Pregnancy

Abstract

Endocrine factors and signals of fetal organ maturation are reported determinants of birth timing. To test the hypothesis that paracrine signaling by exosomes are key regulators of parturition, maternal plasma exosomes from CD-1 mice were isolated and characterized throughout gestation and the biological pathways associated with differentially-expressed cargo proteins were determined. Results indicate that the shape and size of exosomes remained constant throughout gestation; however, a progressive increase in the quantity of exosomes carrying inflammatory mediators was observed from gestation day (E)5 to E19. In addition, the effects of late-gestation (E18) plasma exosomes derived from feto-maternal uterine tissues on parturition was determined. Intraperitoneal injection of E18 exosomes into E15 mice localized in maternal reproductive tract tissues and in intrauterine fetal compartments. Compared to controls that delivered at term, preterm birth occurred in exosome-treated mice on E18 and was preceded by increased inflammatory mediators on E17 in the cervix, uterus, and fetal membranes but not in the placenta. This effect was not observed in mice injected with early-gestation (E9) exosomes. This study provides evidence that exosomes function as paracrine mediators of labor and delivery.

Changes in mediators of pro‐cell growth, senescence, and inflammation during murine gestation

“…Fetal membranes were collected from CD‐1 mice on E13, E15, E17, E18 (day prior to labor), and E19 (day of labor) as previously described . Mice were sacrificed by CO 2 asphyxiation, and fetal membranes were collected to perform immunohistochemistry, Western blotting, and Luminex assays.…”

“…To localize proteins of interest in fetal membrane tissues, IHC was performed as previously described . Briefly, fetal membranes collected from CD‐1 mice were fixed in 4% paraformaldehyde at 4°C overnight.…”

Extracellular vesicles in normal pregnancy and pregnancy‐related diseases

“…A recent study in mouse model also suggests that non‐specific inflammation builds up gradually across late gestation and reaches the peak at the day before the expected delivery. Exosomes from uterine tissues at late gestation contain pro‐inflammatory cargos and could affect birth timing by promoting local inflammatory responses in foetal membranes …”

“…The levels of pro‐inflammatory cytokines are positively associated with maternal BMI . Moreover, the inflammatory cargos in exosomes are involved in preterm labour (PTB) by inducing a localized inflammatory response in mice . By using sequential windowed acquisition of all theoretical mass spectra (SWATH‐MS) to screen differentially expressed proteins in circulating maternal exosomes, Menon et al show that inflammation‐associated molecules are enriched in PTB exosomes, suggesting that inflammation likely affects labour process through exosomes.…”

Exosomes as a Source of Cancer Biomarkers: Advances in Electrochemical Biosensing of Exosomes

“…Exosomes secreted by stem cells act as inhibitors of tumour angiogenesis and modulators of a tumour secretome and growth . Circulating myocardial microRNAs carried by exosomes are responsible for the cross‐talk between ischemic heart and bone marrow and thereby make possible the systemic response to cardiac injury required for cardiac repair and circulating microRNAs were involved in signalling causing pre‐term birth in mice . Since exosomes can carry cargo across the blood‐brain barrier and they lack an immune response, they play an important role in the development and progression of neurodegenerative and mental diseases, as well as in neurophysiological processes .…”