Maintenance of fetal membrane integrity by cyclic cellular transitions during gestation and parturition

Fetal membranes line the intra-uterine cavity and perform protective functions during pregnancy. Rupture of membranes before term is deemed ‘catastrophic’ and contributes to infection, preterm birth, and neonatal death. During gestation, membranes repair and remodel through a balanced collagenolytic process of the matrix. Individual sites of membrane remodeling have been identified and termed ‘microfractures.’ However, the roles of membrane cells, amnion epithelial (AEC) and mesenchymal (AMC), and their ability to migrate, insert themselves, and repair these damaged sites (e.g., microfractures) remains unclear. We report that injury to AECs forces proliferation and cellular transitions including epithelial-to-mesenchymal transition (EMT) during migration and the reverse (MET) during wound resealing. Multiple assays established that oxidative stress (OS) at term induces EMT, mediated in part by transforming growth factor beta 1 (TGF-β), TGF-β activated kinase binding protein (TAB1), and p38 mitogen-activated protein kinase (p38 MAPK) signaling in human and mice membranes. This process is balanced during gestation by progesterone (P4) which transitions ‘reservoir’ stromal AMCs into epithelial cells (MET) through its progesterone membrane receptor (PGRMC2) and c-Myc. We speculate, during pregnancy, fetal membrane cells alternatively undergo cyclic transitions (EMT-MET) to maintain membrane homeostasis. Overwhelming OS at term inhibits MET and promotes an overall mesenchymal phenotype by inducing a terminal state of EMT, senescence, and inflammation which contributes to labor initiation. An amnion membrane-organ-on-chip model corroborated these findings. Understanding cellular transitions and signaling mediators at term can help us derive novel therapeutic targets for preterm birth.

Name thesis:degree_name

Cell Biology (Doctoral)

Level thesis:degree_level

Doctoral

Grantor

The University of Texas Medical Branch at Galveston

Author dc:creator

• Richardson, Lauren S

• Fetal membranes, cellular transitions

Handle dc:identifier.uri

https://hdl.handle.net/2152.3/11730

OAI identifier oai:identifier

oai:utmb-ir.tdl.org:2152.3/11730