Research ArticleReproductive Biology

Reversible EMT and MET mediate amnion remodeling during pregnancy and labor

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Science Signaling  11 Feb 2020:
Vol. 13, Issue 618, eaay1486
DOI: 10.1126/scisignal.aay1486

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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 normally weakens just before parturition; aberrant weakening can lead to premature rupture. Richardson et al. found that amnions from mice and human term births exhibited increased EMT compared to amnions before the onset of labor and that oxidative stress stimulated EMT in preterm amnions. Oxidative stress and transforming growth factor–β (TGF-β), which are increased at the end of pregnancy, promoted EMT, whereas the pregnancy maintenance hormone P4 promoted MET. The authors propose that balanced EMT and MET maintain amnion homeostasis until the accumulation of oxidative stress and inflammatory factors trigger irreversible EMT, amnion weakening, and membrane rupture at parturition.

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 cultures established from amnion membranes from nonlaboring, 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 progesterone receptor membrane component 2 (PGRMC2) and c-MYC. Our results indicate that amnion membrane cells dynamically transition between epithelial and mesenchymal states to maintain amnion integrity and repair membrane damage, as well as in response to inflammation and mechanical damage to protect the fetus until parturition. An irreversible EMT and the accumulation of AMCs characterize the amnion membranes at parturition.

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