Polycomb subunit BMI1 determines uterine progesterone responsiveness essential for normal embryo implantation.
Xin Qiliang,Kong Shuangbo,Yan Junhao,Qiu Jingtao,He Bo,Zhou Chan,Ni Zhangli,Bao Haili,Huang Lin,Lu Jinhua,Xia Guoliang,Liu Xicheng,Chen Zi-Jiang,Wang Chao,Wang Haibin
The Journal of clinical investigation
Natural and synthetic progestogens have been commonly used to prevent recurrent pregnancy loss in women with inadequate progesterone secretion or reduced progesterone sensitivity. However, the clinical efficacy of progesterone and its analogs for maintaining pregnancy is variable. Additionally, the underlying cause of impaired endometrial progesterone responsiveness during early pregnancy remains unknown. Here, we demonstrated that uterine-selective depletion of BMI1, a key component of the polycomb repressive complex-1 (PRC1), hampers uterine progesterone responsiveness and derails normal uterine receptivity, resulting in implantation failure in mice. We further uncovered genetic and biochemical evidence that BMI1 interacts with the progesterone receptor (PR) and the E3 ligase E6AP in a polycomb complex-independent manner and regulates the PR ubiquitination that is essential for normal progesterone responsiveness. A close association of aberrantly low endometrial BMI1 expression with restrained PR responsiveness in women who had previously had a miscarriage indicated that the role of BMI1 in endometrial PR function is conserved in mice and in humans. In addition to uncovering a potential regulatory mechanism of BMI1 that ensures normal endometrial progesterone responsiveness during early pregnancy, our findings have the potential to help clarify the underlying causes of spontaneous pregnancy loss in women.
Alterations in Epithelial Cell Polarity During Endometrial Receptivity: A Systematic Review.
Whitby Sarah,Zhou Wei,Dimitriadis Evdokia
Frontiers in endocrinology
Background:Abnormal endometrial receptivity is one of the major causes of embryo implantation failure and infertility. The plasma membrane transformation (PMT) describes the collective morphological and molecular alterations occurring to the endometrial luminal epithelium across the mid-secretory phase of the menstrual cycle to facilitate implantation. Dysregulation of this process directly affects endometrial receptivity and implantation. Multiple parallels between these alterations to confer endometrial receptivity in women have been drawn to those seen during the epithelial-mesenchymal transition (EMT) in tumorigenesis. Understanding these similarities and differences will improve our knowledge of implantation biology, and may provide novel therapeutic targets to manage implantation failure. Methods:A systematic review was performed using the Medline (Ovid), Embase, and Web of Science databases without additional limits. The search terms used were "(plasma membrane* or cell membrane*) and transformation*" and "endometrium or endometrial." Research studies on the PMT or its regulation in women, discussing either the endometrial epithelium, decidualized stroma, or both, were eligible for inclusion. Results:A total of 198 articles were identified. Data were extracted from 15 studies that matched the inclusion criteria. Collectively, these included studies confirmed the alterations occurring to the endometrial luminal epithelium during the PMT are similar to those seen during the EMT. Such similarities included alterations to the actin cytoskeleton remodeling of adherens junctions, integrin expression and epithelial-stromal communication. These were also some differences between these processes, such as the regulation of tight junctions and mucins, which need to be further researched. Conclusions:This review raised the prospect of shared and distinct mechanisms existing in PMT and EMT. Further investigation into similarities between the PMT in the endometrium and the EMT in tumorigenesis may provide new mechanistic insights into PMT and new targets for the management of implantation failure and infertility.
Hashimoto's thyroiditis impairs embryo implantation by compromising endometrial morphology and receptivity markers in euthyroid mice.
Wu Zhangbi,Cai Yaojun,Xia Qin,Liu Tiantian,Yang Hao,Wang Fen,Wang Nan,Yu Zhen,Yin Chunying,Wang Qunan,Zhu Defa
Reproductive biology and endocrinology : RB&E
BACKGROUND:Although thyroid dysfunction caused by Hashimoto's thyroiditis (HT) is believed to be related to implantation failure due to the underdevelopment of the receptive uterus, it is unknown whether HT itself, even in the euthyroid state, impairs embryo implantation associated with endometrial receptivity defects. To address whether HT itself can affect endometrial receptivity accompanied by implantation alterations, a euthyroid HT model was established in mice. METHODS:Female NOD mice were immunized twice with thyroglobulin and adjuvant to induce the experimental HT model. Four weeks after the second treatment, the mice were normally mated, and pregnant ones were sacrificed in implantation window for thyroid-related parameter and steroid hormones measurements by electrochemiluminescence immunoassay and enzyme-linked immunosorbent assay and implantation site number calculation by uptake of Chicago Blue dye. In addition, certain morphological features of endometrial receptivity were observed by hematoxylin-eosin staining and scanning electron microscopy, and the expression of other receptivity markers were analyzed by immunohistochemistry, RT-qPCR or Western Blot. RESULTS:HT mice displayed intrathyroidal monocyte infiltration and elevated serum thyroid autoantibody levels without thyroid dysfunction, defined as euthyroid HT in humans. Euthyroid HT resulted in implantation failure, fewer pinopodes, retarded pinopode maturation, and inhibited expression of receptivity markers: estrogen receptor α (ERα), integrin β3, leukemia inhibitory factor (LIF), and cell adhesion molecule-1 (ICAM-1). Interestingly, despite this compromised endometrial receptivity response, no statistical differences in serum estradiol or progesterone level between groups were found. CONCLUSIONS:These findings are the first to indicate that HT induces a nonreceptive endometrial milieu in the euthyroid state, which may underlie the detrimental effects of HT itself on embryo implantation.