Dysregulation of plasma membrane transformation in endometrial epithelium: implications for infertility in endometriosis

Background: Endometrial receptivity, a critical prerequisite for successful pregnancy, is impaired in women with endometriosis. Plasma membrane transformation (PMT), a key process involving dynamic remodeling of endometrial epithelial cells, is essential for establishing receptivity during the secretory phase. However, the status of PMT in the eutopic endometrium of women with endometriosis and its potential contribution to infertility are largely unknown. Methods: In this translational study, we investigated the PMT status in endometrial tissues from reproductive-age women with and without endometriosis. We further utilized human endometrial epithelial organoids derived from patient biopsies and a surgically induced mouse model of endometriosis to confirm our findings. PMT markers, including E-cadherin, p-ERM, F-actin, MUC2, and Occludin, and receptivity-associated molecules were analyzed using immunohistochemistry, immunofluorescence, RT-qPCR, Western blotting, and scanning electron microscopy. Results: We found that the dynamic changes in PMT markers observed in normal secretory endometrium, such as E-cadherin downregulation, p-ERM redistribution, and F-actin and MUC2 upregulation, were absent in the eutopic endometrium of women with endometriosis. Organoids derived from endometriosis patients also exhibited significantly reduced expression of receptivity-associated genes, diminished F-actin, persistent apical p-ERM, and aberrant mucin expression. Furthermore, the mouse model of endometriosis showed reduced implantation rates, atrophic pinopodes, and altered PMT markers, accompanied by a loss of induction of LIF and AREG. These findings were consistent across all three models. Conclusions: Our study demonstrates that plasma membrane transformation is aberrantly regulated in the eutopic endometrium of women with endometriosis, leading to impaired epithelial remodeling and compromised receptivity. This disruption represents a novel mechanism of infertility in endometriosis. The findings highlight PMT as a potential therapeutic target for improving endometrial receptivity and offer new insights into the pathological basis of endometriosis-associated infertility.