Reversible EMT and MET mediate amnion remodeling during pregnancy and labor

Abstract

The amnion is remodeled during pregnancy to protect the growing fetus it contains, and it is particularly dynamic just before and during labor. By combining ultrastructural, immunohistochemical, and Western blotting analyses, we found that human and mouse amnion membranes during labor were subject to epithelial to mesenchymal transition (EMT), mediated in part by the p38 mitogen-activated protein kinase (MAPK) pathway responding to oxidative stress. Primary human amnion epithelial cell (AEC) cultures established from amnion membranes from non-laboring, cesarean section deliveries exhibited EMT after exposure to oxidative stress, and the pregnancy maintenance hormone progesterone (P4) reversed this process. Oxidative stress or transforming growth factor β (TGF-β) stimulated EMT in a manner that depended on TGF-β–activated kinase 1 binding protein 1 (TAB1) and p38 MAPK. P4 stimulated the reverse transition, MET, in primary human amnion mesenchymal cells (AMCs) through the progesterone receptor membrane component 2 (PGRMC2) and c-MYC. Our results indicated that amnion membrane cells dynamically transition between epithelial and mesenchymal states to maintain amnion integrity, repair membrane damage, and in response to inflammation and mechanical damage and protect the fetus until parturition. An irreversible EMT and accumulation of AMCs characterize the amnion membranes at parturition.

One Sentence Summary

Balanced EMT and MET maintain amnion integrity during pregnancy, and increased EMT is associated with labor.

Remodeling the amnion

During pregnancy, the amniotic membrane undergoes growth, repair, and remodeling processes that depend on epithelial-to-mesenchymal transition (EMT) and the reverse, MET. The membrane weakens near the end of pregnancy in preparation for parturition, and aberrant weakening can lead to premature rupture. Richardson et al. found that amnions from mice and human term births exhibited increased epithelial-to-mesenchymal transition (EMT) and that oxidative stress stimulated EMT in preterm amnions. Experiments using primary human amnion epithelial and mesenchymal cells indicated that oxidative stress and transforming growth factor β (TGF-β), both of which increase at the end of pregnancy, promoted EMT, whereas the pregnancy maintenance hormone progesterone promoted MET. The authors propose that balanced EMT and MET maintain amnion homeostasis until the accumulation of oxidative stress and inflammatory factors trigger an irreversible EMT that leads to amnion weakening and membrane rupture at parturition.