Fetal membranes (amniochorion) protect the fetus during pregnancy. At term, senescence (aging) and inflammation cause functional and mechanical instability to membrane cells, contributing to parturition. Premature senescence and membrane dysfunctions are associated with preterm birth (PTB) and preterm premature rupture of the membranes (pPROM). However, cellular-level changes contributing to membrane stability during gestation and its dysfunction leading to labor and delivery are still unclear. Recent studies of senescent term and preterm membranes revealed ?microfractures? (MFs), sites of cellular remodeling. MFs are resealed during gestation to maintain membrane integrity. Higher numbers of MFs and their increased morphometry (depth and width) in term labor, pPROM, and PTB membranes compared to respective controls suggest MFs' resealing is compromised. Amnion epithelial cells in MFs have been observed undergoing epithelial mesenchymal transition (EMT). Further, these cells showed proliferative and resealing properties of deepithelialized (nude/cell free) areas to stabilize membranes. At the healing edge of MFs, amnion mesenchymal cells exhibited a reverse phenomenon, mesenchymal-epithelial transition (MET). From these findings, we postulate that cellular transitions are essential for maintaining fetal membrane integrity. We hypothesize that MFs are areas of membrane remodeling and their increased number and morphometry are associated with failure to remodel and dysfunctional membranes. Understanding intercellular and cell-matrix interactions causing MFs' development and their resealing will help us to determine how oxidative stress (OS) and inflammation can contribute to the persistence of MFs and dysfunctional membrane status in PTB and pPROM.
Two specific aims to be tested are Specific Aim 1: To investigate the dynamic remodeling of the fetal membrane epithelium in an in vitro model of cell-free (nude) membranes during OS and infection / inflammation compared to normal conditions;
Specific Aim 2 : To determine cell migration, matrix degradation, and cellular transition associated with MFs' formation using a fetal membrane organ-on-a-chip approach. This multidisciplinary proposal combines cell and molecular biological and bioengineering approaches designed to overcome the limitations of classic 2D cell cultures by developing a fetal membrane-on-a-chip using organ-on-chip technologies. This model system will maintain multiple cell types in close proximity with constant dynamic interactions, similar to the conditions in utero. We will elucidate causative molecular mechanisms of (normal and abnormal) biologic MFs' formation and how they contribute to PTB and pPROM. Understanding cellular-level mechanisms will allow us to design strategies to minimize MFs' development to strengthen intrauterine cavities and reduce the risk of PTB and pPROM.

Public Health Relevance

Fetal membranes of the uterine cavity form microfractures (fissures that allow cells and amniotic fluid to leak through) that can disrupt pregnancy in response to infection or other unexpected conditions and lead to preterm birth. In normal pregnancies, these fractures are healed or sealed by cellular mechanisms called transitions, which are not easy to study using traditional cell culture methods because they do not facilitate observation of cell-cell interactions, as in an in utero environment. To study fetal membrane functions, we will recreate the entire cell and extracellular matrix components of the membrane on a chip (organ-on-chip) and study how infection and oxidative stress (factors associated with preterm birth) can disrupt and destabilize membranes, which will improve our knowledge of fetal membrane function as well as generate a methodology that is adaptable to various research fields.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Pregnancy and Neonatology Study Section (PN)
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Ilekis, John V
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University of Texas Med Br Galveston
Obstetrics & Gynecology
Schools of Medicine
United States
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