Epithelial to mesenchymal transition (EMT) of feto-maternal reproductive tissues generates inflammation: a detrimental factor for preterm birth

Abstract

Human pregnancy is a delicate and complex process where multiorgan interactions between two independent systems, the mother, and her fetus, maintain pregnancy. Intercellular interactions that can define homeostasis at the various cellular level between the two systems allow uninterrupted fetal growth and development until delivery. Interactions are needed for tissue remodeling during pregnancy at both fetal and maternal tissue layers. One of the mechanisms that help tissue remodeling is via cellular transitions where epithelial cells undergo a cyclic transition from epithelial to mesenchymal (EMT) and back from mesenchymal to epithelial (MET). Two major pregnancy-associated tissue systems that use EMT, and MET are the fetal membrane (amniochorion) amnion epithelial layer and cervical epithelial cells and will be reviewed here. EMT is often associated with localized inflammation, and it is a well-balanced process to facilitate tissue remodeling. Cyclic transition processes are important because a terminal state or the static state of EMT can cause accumulation of proinflammatory mesenchymal cells in the matrix regions of these tissues and increase localized inflammation that can cause tissue damage. Interactions that determine homeostasis are often controlled by both endocrine and paracrine mediators. Pregnancy maintenance hormone progesterone and its receptors are critical for maintaining the balance between EMT and MET. Increased intrauterine oxidative stress at term can force a static (terminal) EMT and increase inflammation that are physiologic processes that destabilize homeostasis that maintain pregnancy to promote labor and delivery of the fetus. However, conditions that can produce an untimely increase in EMT and inflammation can be pathologic. These tissue damages are often associated with adverse pregnancy complications such as preterm prelabor rupture of the membranes (pPROM) and spontaneous preterm birth (PTB). Therefore, an understanding of the biomolecular processes that maintain cyclic EMT-MET is critical to reducing the risk of pPROM and PTB. Extracellular vesicles (exosomes of 40-160 nm) that can carry various cargo are involved in cellular transitions as paracrine mediators. Exosomes can carry a variety of biomolecules as cargo. Studies specifically using exosomes from cells undergone EMT can carry a pro-inflammatory cargo and in a paracrine fashion can modify the neighboring tissue environment to cause enhancement of uterine inflammation.

The Impact of Periodontal Disease on Preterm Birth and Preeclampsia

“…Plasma levels of TNF-α and PGE2 were found to be elevated in women with periodontitis compared to periodontally healthy women, while pregnant women with periodontitis showed elevated plasma levels of TNF-α, IL-4, and IL-6 [39,67,[69][70][71][72]. Salivary and plasma levels of IL-1β, IL-6, and TNF-α increase with periodontal disease severity [47], and plasma MMP-8 and MMP-9 levels decrease after non-surgical periodontal treatment events, supporting the theory of periodontitis causing increased systemic inflammation.…”

“…Infections and inflammations have been linked in the literature to pregnancy complications such as premature birth and can affect the systemic circulation levels of the aforementioned inflammatory factors. Increased plasma levels of IL-1, IL-6, IL-8, TNF-α, and CRP have been associated with premature or low birthweight births [39,67,[69][70][71][72]. Periodontal patients also exhibit increased pro-inflammatory cytokines and inflammatory mediators.…”

“…These factors, stemming from periodontal tissue inflammation, can diffuse into gingival fluid or enter the circulation [39]. Increased plasma levels of IL-1β, IL-6, TNF-α, CRP, MMP-8, and MMP-9 have been observed in patients with periodontitis [39,67,[69][70][71][72].…”