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

Endometrial receptivity, a critical prerequisite for successful pregnancy, has been reported to be impaired in women with endometriosis; however, the underlying mechanisms remain unclear. 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. We examined PMT-associated markers in eutopic endometrial tissues from reproductive-age women with and without endometriosis, patient-derived endometrial epithelial organoids, and an endometriosis mouse model. E-cadherin, phosphorylated ezrin/radixin/moesin (p-ERM), filamentous actin (F-actin), mucin 2 (MUC2), occludin, and receptivity-associated molecules were assessed using immunohistochemistry, immunofluorescence, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and scanning electron microscopy. Secretory-phase changes in E-cadherin, p-ERM, F-actin, and MUC2 observed in eutopic endometrium from women without endometriosis were attenuated or absent in women with endometriosis. Following hormone-induced secretory differentiation, organoids derived from women with endometriosis showed reduced F-actin staining, persistent apical p-ERM localization, and altered MUC2 and mucin 4 (MUC4) staining compared with control organoids. The endometriosis mouse model showed significantly fewer implantation sites than controls ( P < 0.05), altered pinopode morphology, abnormal PMT-associated marker profiles, and attenuated induction of receptivity-associated genes. Endometriosis was associated with altered PMT-related epithelial remodeling in human eutopic endometrial tissues, patient-derived organoids, and an endometriosis mouse model. These observations suggest a possible link between abnormal epithelial remodeling and impaired receptivity, but do not establish that PMT abnormalities cause infertility. Functional studies are needed to determine their contribution to embryo attachment and their potential relevance to treatment. Visual summary of the study workflow. This study utilized eutopic endometrial tissues from women without endometriosis (fertilecontrols: proliferative phase NP, n = 15; secretory phase NS, n = 13) and women with endometriosis-associated infertility (proliferative phase EP, n = 15; secretory phase ES, n = 14), alongside patient-derived endometrial epithelial organoids (controls, n = 5; endometriosis, n = 5), and a murine endometriosis model ( n = 5 per group) to investigate epithelial remodeling during implantation (GD3) and implantation outcomes (GD8)