Cofilin Localization in the Epithelium of Human Endometrium Changes During the Menstrual Cycle and in Endometriosis.

The human uterine epithelium displays a distinct polarized organization within apical, lateral, and basal plasma membrane domains. Regulation of the actin cytoskeleton plays a role in establishment of epithelial cell polarity and protein trafficking. Actin dynamics, referring to the dynamics between actin polymerization and depolymerization, are regulated by actin-binding proteins such as cofilin. Cofilin binds to both monomeric (G) and filamentous (F) actin; its major known function is depolymerization of F-actin. This allows branching of actin filaments and cytoskeleton reorganization. In its inactive form, cofilin binds to monomeric G-actin. We have previously shown that cofilin participates in actin dynamics regulation during decidualization of human stromal fibroblasts. To investigate cofilin in human endometrium during the menstrual cycle, we localized cofilin in paraffin embedded fixed sections through immunohistochemical staining. During the proliferative phase of the menstrual cycle, cofilin is localized both in the apical and basolateral sides of luminal epithelial cells. Dual staining of cofilin and monomeric G-actin (represented by staining for DNAse I) indicated cofilin-G-actin colocalization in both locations. Interestingly, during the secretory phase of the menstrual cycle this colocalization was only present on the basolateral side of luminal epithelium cells; cofilin was not detected on the apical part. This suggests that inactive G-actin-bound cofilin translocates from the apical to the basolateral side of luminal epithelium. These findings imply that the different signals coming to the endometrium during preparation for blastocyst implantation in the secretory phase of the menstrual cycle have an effect on cofilin location thus regulating its participation in actin/cytoskeleton rearrangement in epithelial cells. Endometriosis is a chronic disease causing pain and infertility in more than 10% of reproductive age women. To investigate whether there is a different pattern of actin remodeling in endometriosis, we investigated cofilin localization in a baboon (Papio anubis) endometriosis model. The staining pattern of cofilin in baboon uterine endometrium of healthy animals confirmed our previous observations in human epithelial tissue. Proteins involved in regulation of cofilin activity (LIM kinase, slingshot, and binding protein 14-3-3) are localized along with cofilin. A very different staining pattern was detected in baboons with severe spontaneous endometriosis. In the secretory phase of the menstrual cycle, this tissue had a very similar pattern to the proliferative phase in a normal animal; distinct cofilin staining was observed in the apical parts of the luminal and glandular epithelium. This indicates that this severe dyssynchrony in menstrual cycle phases in an animal with endometriosis is connected with improper cytoskeleton rearrangements. This suggests that luminal epithelial cells of the endometrium are not properly prepared for blastocyst arrival, since these cells allow attachment of trophoblast cells to their apical pole during embryo implantation. In summary, we suggest that cofilin-mediated actin reorganization of uterine epithelial cells during the secretory phase might be important in preparation for implantation; dysregulation of this reorganization may lead to decreased fertility in women suffering from endometriosis (ARRA NIH HD044713 grant to ZS). (platform)