Human fetal membranes at term: Dead tissue or signalers of parturition?

Abstract

Various endocrine, immune, and mechanical factors produced by feto-maternal compartments at term increase intrauterine inflammatory loads to induce labor. The role of fetal (placental) membranes (amniochorion) as providers of parturition signals has not been well investigated. Fetal membranes line the intrauterine cavity and grow with and protect the fetus. Fetal membranes exist as an entity between the mother and fetus and perform unique functions during pregnancy. Membranes undergo a telomere-dependent p38 MAPK-induced senescence and demonstrate a decline in functional and mechanical abilities at term, showing signs of aging. Fetal membrane senescence is also allied with completion of fetal maturation at term as the fetus readies for delivery, which may also indicate the end of independent life and longevity of fetal membranes as their functional role concludes. Fetal membrane senescence is accelerated at term because of oxidative stress and increased stretching. Senescent fetal membranes cells produce senescence-associated secretory phenotype (SASP-inflammation) and also release proinflammatory damage-associated molecular patterns (DAMPs), namely HMGB1 and cell-free fetal telomere fragments. In a feedback loop, SASP and DAMPs increase senescence and enhance the inflammatory load to promote labor. Membranes increase the inflammatory load to disrupt homeostatic balance to transition quiescent uterine tissues toward a labor phenotype. Therefore, along with other well-described labor-promoting signals, senescent fetal membranes may also contribute to human term parturition.

Keywords: Amniochorion; Cell free fetal DNA; DAMPs; Pregnancy; Preterm birth; SASP; Senescence; Sterile inflammation.

Figure 1. A model depicting different stages of transformation of fetal amnion membranes from normal to senescent phenotype in response to reactive oxygen species (ROS) at term generating signals that can initiate labor-associated changes

1. ROS is increased in the amniotic fluid at term, and these molecules can accelerate a telomere-dependent senescence process that is functional in fetal amniotic membranes.

2. ROS induces p38 MAPK-mediated senescence of amnion cells.

3. Senescent cells are inflammatory and produce SASP that consists of cytokines, chemokines, growth factors, matrix degrading enzymes, and other biochemicals.

4. SASP further accelerates progression of senescence in amnion cells

5. Tissue injury due to senescence also produces DAMP marker release. DAMPs include HMGB-1, HSP-70, H-3, IL-33, cell-free fetal telomere fragments, and degraded DNA.

6. SASP and DAMPs can further increase inflammatory load by chemotaxis and activation of leukocytes in the membranes and in other feto-maternal uterine compartments.

7. The overall increase of inflammation due to SASP, DAMPs, and immune cell activation contributes to sterile inflammation.

8. The sterile inflammatory markers can be propagated to other feto-maternal tissues (chorion, decidua, myometrium, and cervix), causing labor-associated changes and primarily increasing the inflammatory load to imbalance the quiescence status to transform into an active form. These changes could include 1) decidual immune activation, chemotaxis, and leukocyte and NK cell activations; 2) myometrial functional progesterone withdrawal (and inflammation; and 3) cervical ripening by inflammatory activation. Increasing inflammation in each compartment causes labor-associated changes.