Abstract
BackgroundIn women dynamic changes in uterine tissue architecture occur during each menstrual cycle. Menses, characterised by the shedding of the upper functional layer of the endometrium, is the culmination of a cascade of irreversible changes in tissue function including stromal decidualisation, inflammation and production of degradative enzymes. The molecular mechanisms that contribute to the rapid restoration of tissue homeostasis at time of menses are poorly understood.MethodologyA modified mouse model of menses was developed to focus on the events occurring within the uterine lining during endometrial shedding/repair. Decidualisation, vaginal bleeding, tissue architecture and cell proliferation were evaluated at 4, 8, 12, and 24 hours after progesterone (P4) withdrawal; mice received a single injection of bromodeoxyuridine (BrdU) 90 mins before culling. Expression of genes implicated in the regulation of mesenchymal to epithelial transition (MET) was determined using a RT2 PCR profiler array, qRTPCR and bioinformatic analysis.Principal FindingsMice exhibited vaginal bleeding between 4 and 12 hours after P4 withdrawal, concomitant with detachment of the decidualised cell mass from the basal portion of the endometrial lining. Immunostaining for BrdU and pan cytokeratin revealed evidence of epithelial cell proliferation and migration. Cells that appeared to be in transition from a mesenchymal to an epithelial cell identity were identified within the stromal compartment. Analysis of mRNAs encoding genes expressed exclusively in the epithelial or stromal compartments, or implicated in MET, revealed dynamic changes in expression, consistent with a role for reprogramming of mesenchymal cells so that they could contribute to re-epithelialisation.Conclusions/SignificanceThese studies have provided novel insights into the cellular processes that contribute to re-epithelialisation post-menses implicating both epithelial cell migration and mesenchymal cell differentiation in restoration of an intact epithelial cell layer. These insights may inform development of new therapies to induce rapid healing in the endometrium and other tissues and offer hope to women who suffer from heavy menstrual bleeding.
Highlights
The human endometrium displays a remarkable ability to undergo cyclical episodes of proliferation, angiogenesis, differentiation, inflammation and tissue breakdown occurring up to 400 times during a women’s reproductive life
Recent microscopy studies have revealed that shedding of the endometrium is a locally occurring, progressive process, with areas of partially shed, as well as shed and regenerating endometrium observed in close proximity within the tissue [3,4]
Analysis of genes identified as up-stream regulators of Cdh1 and Cdh2, both of which changed in a dynamic way in our uterine tissue, highlighted both an association with MMPs as well as with Smad2 which we have previously identified as involved in TGFß signaling in human endometrial stromal cells [27]
Summary
The human endometrium displays a remarkable ability to undergo cyclical episodes of proliferation, angiogenesis, differentiation (decidualisation), inflammation and tissue breakdown (menses) occurring up to 400 times during a women’s reproductive life. Menstruation, the shedding of the upper functional layer of the endometrium, represents the culmination of a molecular cascade initiated by withdrawal of progesterone following the regression of the corpus luteum [1,2]. Rapid restoration of tissue integrity at the time of menses is essential to avoid excess blood loss and to ensure the endometrium can regenerate in response to the sex steroid hormones oestrogen and progesterone in preparation for a potential pregnancy. Menses, characterised by the shedding of the upper functional layer of the endometrium, is the culmination of a cascade of irreversible changes in tissue function including stromal decidualisation, inflammation and production of degradative enzymes. The molecular mechanisms that contribute to the rapid restoration of tissue homeostasis at time of menses are poorly understood
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