Feto-Maternal Exosome Characterization, Trafficking and Function During Pregnancy and Parturition

Abstract

Endocrine factors and signals of fetal organ maturation are well-reported determinants of the timing of birth and have been studied extensively in both humans and animal models. However, decades of research have not yielded answers to the timing of labor. It is evident that endocrine factors alone are not sufficient to fully address timing or mechanisms of labor, which is reflected in the increasing rates of preterm births and other pregnancy complications in most countries. Differences in the endocrine factors between humans and animals have hampered advances in this field. As an alternative to endocrine factors, the studies presented here report paracrine signals are similar between humans and animal models and are attributed by senescence-associated feto-maternal signaling via exosomes. Oxidative stress in utero, most likely due to increased metabolic activity of the fetus, induces cellular senescence of the fetal membranes. We have reproduced this model in vitro to show human amnion epithelial cells can produce exosomes and when cultured under oxidative stress conditions, exosomes cargo signals of cellular damage and inflammation. Amnion cell-derived exosomes can traffic to the maternal tissues and produce labor-associated changes in maternal cells. Additionally, in murine models of pregnancy, exosomes in maternal plasma increase in number prior to delivery and their cargo also increases in pro-inflammatory mediators as term approaches. Independent of endocrine or systemic inflammation, late gestation exosomes cause preterm labor and labor-associated changes in maternal and fetal tissues. Although a fetal-specific marker in humans allows for the study of fetal exosomes in maternal circulation, to study fetal vs maternal exosome contribution to the initiation of labor in mice, we developed a model which utilizes a dual color fluorescent transgenic Cre reporter mouse. Using this model, we show feto-maternal crosstalk via exosomes occurs during pregnancy and can produce functional changes on both sides of the placenta. Further research into the mechanism of feto-maternal signaling via exosomes at term can contribute to the identification of new biomarkers or interventions to combat preterm labor.