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- Author: Jie Jin x
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Department of Obstetrics and Gynecology, Guangzhou Women and Children’s Medical Center, Guangzhou, China
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In brief
Failure to induce mesenchymal–epithelial transition (MET) during stromal cell decidualization can lead to consequences such as impaired fertility in patients with endometriosis. METTL3-mediated m6A modification plays an important role in attenuating MET and defective decidualization of endometrial stromal cells and contributes to the development of reduced endometrial receptivity in endometriosis.
Abstract
Mesenchymal–epithelial transition (MET)-mediated endometrial decidualization is pivotal for achieving endometrial receptivity and successful pregnancy. We observed blockade of MET in the eutopic secretory endometrium of patients with endometriosis, but the underlying mechanism is unknown. In this study, real-time PCR was used to detect PRL and IGFBP1 expression, whereas western blotting was used to detect the expression of MET markers and METTL3. Phalloidin staining was used to identify changes in cell morphology. M6A levels were quantified using a colorimetric method and m6A dot blots, and functional analysis was performed using spheroid adhesion assays. We first found that increased E-cadherin expression was accompanied by decreased vimentin and Slug expression in the eutopic secretory endometrium of individuals with endometriosis. We also detected a significant increase in both the m6A level and the expression of the related methyltransferase METTL3. Finally, METTL3 expression was negatively correlated with PRL, IGFBP1, and MET markers expression. Collectively, our findings suggest that METTL3 mediates m6A modification, thereby inhibiting MET formation within the eutopic secretory endometrium of patients with endometriosis. Increased METTL3-mediated m6A modification plays a crucial role in attenuating MET formation and decidualization impairment in endometrial stromal cells, ultimately contributing to compromised endometrial receptivity in individuals with endometriosis. These insights could lead to the identification of potential therapeutic targets for improving both endometrial receptivity and pregnancy rate among individuals affected by endometriosis.
Key Laboratory of Reproduction Regulation of NPFPC, SIPPR, IRD, Fudan University, Shanghai, People’s Republic of China
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Key Laboratory of Reproduction Regulation of NPFPC, SIPPR, IRD, Fudan University, Shanghai, People’s Republic of China
Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, People’s Republic of China
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Key Laboratory of Reproduction Regulation of NPFPC, SIPPR, IRD, Fudan University, Shanghai, People’s Republic of China
Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, People’s Republic of China
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Key Laboratory of Reproduction Regulation of NPFPC, SIPPR, IRD, Fudan University, Shanghai, People’s Republic of China
Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, People’s Republic of China
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The dysfunction of NK cells in women with endometriosis (EMS) contributes to the immune escape of menstrual endometrial fragments refluxed into the peritoneal cavity. The reciprocal communications between endometrial stromal cells (ESCs) and lymphocytes facilitate the development of EMS. However, the mechanism of these communications on cytotoxicity of natural killer (NK) cells in endometriotic milieus is still largely unknown. To imitate the local immune microenvironment, the co-culture systems of ESCs from patients with EMS and monocyte-derived macrophages or of ESCs, macrophages and NK cells were constructed. The cytokine levels in the co-culture unit were evaluated by ELISA. The expression of functional molecules in NK cells was detected by flow cytometry (FCM). The NK cell behaviors in vitro were analyzed by cell counting kit-8 and cytotoxic activation assays. After incubation with ESCs and macrophages, the expression of CD16, NKG2D, perforin and IFN-γ, viability and cytotoxicity of NK cells were significantly downregulated. The secretion of interleukin (IL)-1β, IL-10 and transforming growth factor (TGF)-β in the co-culture system of ESCs and macrophages was increased. Exposure with anti-IL-10 receptor β neutralizing antibody (αhIL-10Rβ) or αTGF-β could partly reverse these effects of ESCs and macrophages on NK cells in vitro. These results suggest that the interaction between macrophages and ESCs downregulates cytotoxicity of NK cells possibly by stimulating the secretion of IL-10 and TGF-β, and may further trigger the immune escape of ectopic fragments and promote the occurrence and the development of EMS.
Department of Obstetrics and Gynaecology, Key Laboratory of Assisted Reproduction, Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Neuroscience Research Institute, Center for Reproductive Medicine, Peking University Third Hospital, No. 49, North Huayuan Road, Haidian District, Beijing 100191, China
Department of Obstetrics and Gynaecology, Key Laboratory of Assisted Reproduction, Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Neuroscience Research Institute, Center for Reproductive Medicine, Peking University Third Hospital, No. 49, North Huayuan Road, Haidian District, Beijing 100191, China
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Department of Obstetrics and Gynaecology, Key Laboratory of Assisted Reproduction, Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Neuroscience Research Institute, Center for Reproductive Medicine, Peking University Third Hospital, No. 49, North Huayuan Road, Haidian District, Beijing 100191, China
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Department of Obstetrics and Gynaecology, Key Laboratory of Assisted Reproduction, Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Neuroscience Research Institute, Center for Reproductive Medicine, Peking University Third Hospital, No. 49, North Huayuan Road, Haidian District, Beijing 100191, China
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Department of Obstetrics and Gynaecology, Key Laboratory of Assisted Reproduction, Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Neuroscience Research Institute, Center for Reproductive Medicine, Peking University Third Hospital, No. 49, North Huayuan Road, Haidian District, Beijing 100191, China
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Department of Obstetrics and Gynaecology, Key Laboratory of Assisted Reproduction, Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Neuroscience Research Institute, Center for Reproductive Medicine, Peking University Third Hospital, No. 49, North Huayuan Road, Haidian District, Beijing 100191, China
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Department of Obstetrics and Gynaecology, Key Laboratory of Assisted Reproduction, Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Neuroscience Research Institute, Center for Reproductive Medicine, Peking University Third Hospital, No. 49, North Huayuan Road, Haidian District, Beijing 100191, China
Search for other papers by Liying Yan in
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Department of Obstetrics and Gynaecology, Key Laboratory of Assisted Reproduction, Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Neuroscience Research Institute, Center for Reproductive Medicine, Peking University Third Hospital, No. 49, North Huayuan Road, Haidian District, Beijing 100191, China
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Department of Obstetrics and Gynaecology, Key Laboratory of Assisted Reproduction, Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Neuroscience Research Institute, Center for Reproductive Medicine, Peking University Third Hospital, No. 49, North Huayuan Road, Haidian District, Beijing 100191, China
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Department of Obstetrics and Gynaecology, Key Laboratory of Assisted Reproduction, Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Neuroscience Research Institute, Center for Reproductive Medicine, Peking University Third Hospital, No. 49, North Huayuan Road, Haidian District, Beijing 100191, China
Department of Obstetrics and Gynaecology, Key Laboratory of Assisted Reproduction, Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Neuroscience Research Institute, Center for Reproductive Medicine, Peking University Third Hospital, No. 49, North Huayuan Road, Haidian District, Beijing 100191, China
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Polycystic ovary syndrome (PCOS) is a complex endocrine and metabolic disorder with unclear etiology and unsatisfactory management. Effects of diets on the phenotype of PCOS were not fully understood. In the present study, we applied 45 and 60% high-fat diets (HFDs) on a rat model of PCOS induced by postnatal DHEA injection. We found that both DHEA and DHEA+HFDs rats exhibited reproductive abnormalities, including hyperandrogenism, irregular cycles and polycystic ovaries. The addition of HFDs, especially 60% HFDs, exaggerated morphological changes of ovaries and a number of metabolic changes, including increased body weight and body fat content, impaired glucose tolerance and increased serum insulin levels. Results from qPCR showed that DHEA-induced increased expression of hypothalamic androgen receptor and LH receptor were reversed by the addition of 60% HFDs. In contrast, the ovarian expression of LH receptor and insulin receptor mRNA was upregulated only with the addition of 60% HFDs. These findings indicated that DHEA and DHEA+HFDs might influence PCOS phenotypes through distinct mechanisms: DHEA affects the normal function of hypothalamus–pituitary–ovarian axis through LH, whereas the addition of HFDs exaggerated endocrine and metabolic dysfunction through ovarian responses to insulin-related mechanisms. We concluded that the addition of HFDs yielded distinct phenotypes of DHEA-induced PCOS and could be used for studies on both reproductive and metabolic features of the syndrome.
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Key Laboratory of Reproduction Regulation of NPFPC, SIPPR, IRD, Fudan University, Shanghai, People’s Republic of China
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Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, People’s Republic of China
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Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, People’s Republic of China
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Key Laboratory of Reproduction Regulation of NPFPC, SIPPR, IRD, Fudan University, Shanghai, People’s Republic of China
Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, People’s Republic of China
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Macrophages play an important role in the origin and development of endometriosis. Estrogen promoted the growth of decidual stromal cells (DSCs) by downregulating the level of interleukin (IL)-24. The aim of this study was to clarify the role and mechanism of IL-24 and its receptors in the regulation of biological functions of endometrial stromal cells (ESCs) during endometriosis. The level of IL-24 and its receptors in endometrium was measured by immunohistochemistry. In vitro analysis was used to measure the level of IL-24 and receptors and the biological behaviors of ESCs. Here, we found that the expression of IL-24 and its receptors (IL-20R1 and IL-20R2) in control endometrium was significantly higher than that in eutopic and ectopic endometrium of women with endometriosis. Recombinant human IL-24 (rhIL-24) significantly inhibited the viability of ESCs in a dosage-dependent manner. Conversely, blocking IL-24 with anti-IL-24 neutralizing antibody promoted ESCs viability. In addition, rhIL-24 could downregulate the invasiveness of ESCs in vitro. After co-culture, macrophages markedly reduced the expression of IL-24 and IL-20R1 in ESCs, but not IL-22R1. Moreover, macrophages significantly restricted the inhibitory effect of IL-24 on the viability, invasion, the proliferation relative gene Ki-67, proliferating cell nuclear antigen (PCNA) and cyclooxygenase2 (COX-2), and the stimulatory effect on the tumor metastasis suppressor gene CD82 in ESCs. These results indicate that the abnormally low level of IL-24 in ESCs possibly induced by macrophages may lead to the enhancement of ESCs’ proliferation and invasiveness and contribute to the development of endometriosis.
