Ovarian Steroids, Mitogen-Activated Protein Kinases, and/or Aspartic Proteinases Cooperate to Control Endometrial Remodeling by Regulating Gene Expression in the Stroma and Glands

Abstract

Explants from nonmenstrual endometria cultured in the absence of ovarian hormones undergo tissue breakdown. Addition of estradiol and progesterone (EP) prevents proteolysis. Explants include stromal and epithelial compartments which play different but complementary roles in endometrial physiology, including tissue remodeling and hormonal response. In order to characterize the cell type-specific contribution to regulation of tissue breakdown, we characterized the transcriptomes of microdissected stromal and glandular areas from endometrial explants cultured with or without EP. The datasets were also compared to other published endometrial transcriptomes. Finally, the contribution of proteolysis, hypoxia, and MAPKs to the regulation of selected genes was further investigated in explant culture. This analysis identified distinct gene expression profiles in stroma and glands, with differential response to EP, but functional clustering underlined convergence in biological processes, further indicating that endometrial remodeling requires cooperation between the two compartments through expression of cell type-specific genes. Only partial overlaps were observed between lists of genes involved in different occurrences of endometrial breakdown, pointing to a limited number of potentially crucial regulators but also to the requirement for additional mechanisms controlling tissue remodeling. We identified a group of genes differentially regulated by EP in stroma and glands among which some were sensitive to MAPKs and/or aspartic proteinases and were not induced by hypoxia. In conclusion, MAPKs and/or aspartic proteinases likely act in concert with EP to locally and specifically control differential expression of genes between degrading and preserved areas of the human endometrium.

Differential Expression of Wnt Signaling Molecules Between Pre- and Postmenopausal Endometrial Epithelial Cells Suggests a Population of Putative Epithelial Stem/Progenitor Cells Reside in the Basalis Layer

“…The low expression level of HSD17␤2 in basalis-like Post-M endometrium reflects the low estrogen hormonal status (2,3). The extracellular matrix/tissue remodeling genes found in the present study agree with others (17,49,50), indicating the active involvement of these molecules in remodeling the endometrium throughout a women's reproductive years (17). The diminished expression of transporter molecules and the secretoglobin family in Post-M compared with Pre-M endometrium (34,46,51) indicates the quiescent state of Post-M endometrial epithelium and confirms the high level of cellular nutrient uptake in cycling functionalis endometrium and their important role in endometrial receptivity.…”

“…These findings suggest that the Wnt signaling pathway is important in endometrial epithelial growth and regression, possibly through down-regulating the proliferative activity of ESP cells postulated to reside in the basalis. In addition, comparison of our data with that of Gaide Chevronnay et al (16,17) demonstrates and confirms that Post-M endometrial epithelium has a similar gene expression profile to the basalis of Pre-M endometrium.…”

“…Differential gene expression of many Wnt family members was identified. Comparative analysis of our endometrial epithelial gene expression profiles with that of endometrial epithelial cells in remodeling endometrium (16,17) also provides new evidence that Post-M endometrial epithelium has a similar gene signature to that of basalis epithelium of menstrual endometrium. Our data suggest that the Wnt signaling pathway may have a role in the function of a population of putative ESP cells possibly located in Post-M and the basalis layer of Pre-M endometrium.…”

“…However, the gene profile of epithelial cells in Post-M and the basalis of Pre-M endometrium has not been previously examined. We therefore compared our gene set with published microarray datasets on endometrial epithelial cells isolated from functionalis vs. basalis using LCM (16,17). From a list of 71 genes identified in the Gaide Chevronnay et al study (16) comparing epithelial cells from functionalis and basalis layer, 21 genes were found in common with Post-M and Pre-M epithelial samples of this study (Supplemental Table 4).…”

“…Differential expression of genes between functionalis and basalis epithelial cells has been identified in menstrual endometrium in a laser capture microdissection (LCM) study (16,17) and between glandular and luminal epithelial compartments in mice (18). Studies using a mouse model have shown that the Wnt signaling pathway is essential for female reproductive tract development (19,20).…”