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.