Berta Cava-Cami, Antonio Galvao, Heidi Van Ranst, William A Stocker, Craig A Harrison, Johan Smitz, Michel De Vos, Gavin Kelsey, Ellen Anckaert
{"title":"Pro-cumulin addition in a biphasic in vitro oocyte maturation system modulates human oocyte and cumulus cell transcriptomes.","authors":"Berta Cava-Cami, Antonio Galvao, Heidi Van Ranst, William A Stocker, Craig A Harrison, Johan Smitz, Michel De Vos, Gavin Kelsey, Ellen Anckaert","doi":"10.1093/molehr/gaaf001","DOIUrl":"10.1093/molehr/gaaf001","url":null,"abstract":"<p><p>Biphasic IVM can be offered as a patient-friendly alternative to conventional ovarian stimulation in IVF patients predicted to be hyper-responsive to ovarian stimulation. However, cumulative live birth rates after IVM per cycle are lower than after conventional ovarian stimulation for IVF. In different animal species, supplementation of IVM media with oocyte-secreted factors (OSFs) improves oocyte developmental competence through the expression of pro-ovulatory genes in cumulus cells. Whether the addition of OSFs in human biphasic IVM culture impacts the transcriptome of oocytes and cumulus cells retrieved from small antral follicles in minimally stimulated non-hCG-triggered IVM cycles remains to be elucidated. To answer this, human cumulus-oocyte complexes (COCs) that were fully surrounded by cumulus cells or partially denuded at the time of retrieval were cultured in a biphasic IVM system either without or with the addition of pro-cumulin, a GDF9:BMP15 heterodimer. Oocytes and their accompanying cumulus cells were collected separately, and single-cell RNA-seq libraries were generated. The transcriptomic profile of cumulus cells revealed that pro-cumulin upregulated the expression of genes involved in cumulus cell expansion and proliferation while downregulating steroidogenesis, luteinization, and apoptosis pathways. Moreover, pro-cumulin modulated the immature oocyte transcriptome during the pre-maturation step, including regulating translation, apoptosis, and mitochondria remodeling pathways in the growing germinal vesicle oocytes. The addition of pro-cumulin also restored the transcriptomic profile of matured metaphase II oocytes that were partially denuded at collection. These results suggest that cumulus cell and oocyte transcriptome regulation by pro-cumulin may increase the number of developmentally competent oocytes after biphasic IVM treatment. Future studies should assess the effects of pro-cumulin addition in human biphasic IVM at the proteomic level and the embryological outcomes, particularly its potential to enhance outcomes of oocytes that are partially denuded at COC collection.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11842067/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143040250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ron Peek, Sanne van der Coelen, Marie-Madeleine Dolmans
{"title":"Gene expression analysis of ovarian follicles and stromal cells in girls with Turner syndrome.","authors":"Ron Peek, Sanne van der Coelen, Marie-Madeleine Dolmans","doi":"10.1093/molehr/gaae043","DOIUrl":"10.1093/molehr/gaae043","url":null,"abstract":"<p><p>In patients with mosaic Turner syndrome, the ovarian somatic cells (granulosa and stromal cells) display a high level of aneuploidy with a 45,X karyotype, which may affect gene expression in the ovary and contribute to their reduced fertility. The aim of the current research is to study the effect of aneuploidy of somatic ovarian cells on gene expression in ovarian cortex stromal cells and small ovarian follicles from mosaic (45,X/46,XX) Turner syndrome patients. To this end, ovarian cortical tissue was obtained by laparoscopic surgery from eight mosaic Turner syndrome patients (aged 5-19 years) and eight controls (aged 6-18 years). The tissue was fractionated to obtain purified follicles and stromal cells. Part of the purified fractions was used to determine the X chromosomal content of ovarian cells of Turner syndrome patients by interphase FISH, while the remaining part was used to compare the gene expression profile of these cells to controls. The results demonstrated that high level 45,X haploidy in cortical stromal cells of Turner syndrome patients had no effect on gene expression, gross morphology of the ovary, or histological appearance of the cortex compared to controls. Gene expression analysis of purified small follicles of Turner syndrome patients with mainly 45,X granulosa cells revealed aberrant expression of 11 genes. Of these, six were upregulated (CD24, TLR1, EPHA2, PLXND1, ST6GALNAC5, and NOX4) while five genes (CRYAB, DLX1, PCYT2, TNFRSF8, and CA12) were downregulated compared to follicles of controls. Interestingly, the overexpressed genes in these small follicles were all associated with more advanced stages of follicular development. The consequences of this abnormal gene expression in follicles for Turner syndrome patients remain to be investigated, but they are likely to affect fertility.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11655625/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824374","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"mTOR inhibitors as potential therapeutics for endometriosis: a narrative review.","authors":"Akiko Nakamura, Yuji Tanaka, Tsukuru Amano, Akie Takebayashi, Akimasa Takahashi, Tetsuro Hanada, Shunichiro Tsuji, Takashi Murakami","doi":"10.1093/molehr/gaae041","DOIUrl":"10.1093/molehr/gaae041","url":null,"abstract":"<p><p>Mammalian target of rapamycin (mTOR) inhibitors have been used clinically as anticancer and immunosuppressive agents for over 20 years, demonstrating their safety after long-term administration. These inhibitors exhibit various effects, including inhibition of cell proliferation, interaction with the oestrogen and progesterone pathways, immunosuppression, regulation of angiogenesis, and control of autophagy. We evaluated the potential of mTOR inhibitors as therapeutic agents for endometriosis, examined the secondary benefits related to reproductive function, and assessed how their side effects can be managed. We conducted a thorough review of publications on the role of the mTOR pathway and the effectiveness of mTOR inhibitors in endometriosis patients. These results indicate that the mTOR pathway is activated in endometriosis. Additionally, mTOR inhibitors have shown efficacy as monotherapies for endometriosis. They may alleviate resistance to hormonal therapy in endometriosis, suggesting a potential synergistic effect when used in combination with hormonal therapy. The potential reproductive benefits of mTOR inhibitors include decreased miscarriage rates, improved implantation, and prevention of age-related follicular loss and ovarian hyperstimulation syndrome. Activation of the mTOR pathway has also been implicated in the malignant transformation of endometriosis. Preclinical studies suggest that the dosage of mTOR inhibitors needed for treating endometriosis may be lower than that required for anticancer or immunosuppressive therapy, potentially reducing dosage-dependent side effects. In conclusion, while mTOR inhibitors, which allow for pregnancy during oral administration, show potential for clinical use in all stages of endometriosis, current evidence is limited to preclinical studies, and further research is needed to confirm clinical effectiveness.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11634386/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695640","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yuan Zhu, Bo Zheng, Yuting Zhang, Mengyun Li, Yuan Jiang, Jidong Zhou, Yang Zhang, Nannan Kang, Min Wu, Yuan Yan, Jun Xing, Jianjun Zhou
{"title":"Ectopic endometrial stromal cell-derived extracellular vesicles encapsulating microRNA-25-3p induce endometrial collagen I deposition impairing decidualization in endometriosis.","authors":"Yuan Zhu, Bo Zheng, Yuting Zhang, Mengyun Li, Yuan Jiang, Jidong Zhou, Yang Zhang, Nannan Kang, Min Wu, Yuan Yan, Jun Xing, Jianjun Zhou","doi":"10.1093/molehr/gaae042","DOIUrl":"https://doi.org/10.1093/molehr/gaae042","url":null,"abstract":"<p><p>Endometrial collagen I undergoes dynamic degradation and remodelling in response to endometrial stromal cell (ESC) decidualization and embryo implantation. However, excessive collagen I deposition in the endometrium during the implantation window may impair decidualization, causing embryo implantation failure in patients with endometriosis (EMS). We found that endometrial collagen I expression during the mid-secretory phase was increased in the EMS group of patients. Collagen I stimulation resulted in decreased expression of the decidualization markers prolactin and insulin-like growth factor binding protein-1 in ESCs, impeding ESC transformation to a decidual morphology and decreasing the blastocyst-like spheroid expansion area in vitro. Treatment with extracellular vesicles (EVs) derived from the ectopic ESCs of EMS patients (EMS-EVs) increased collagen I expression in vivo and in vitro and decreased the blastocyst-like spheroid expansion area. Furthermore, EV microRNA (miRNA) sequencing revealed that there were 40 upregulated and 77 downregulated miRNAs in EMS-EVs when compared to the EVs derived from ESCs in the endometrium of control patients (CTL-EVs), including increased expression of miR-25-3p that targets phosphatase and tensin homolog (PTEN). We also found that PTEN expression was decreased and p-Akt expression was increased in the endometrium of EMS patients and EMS-EV-treated ESCs. miR-25-3p transfected ESCs exhibited increased collagen I, decreased PTEN, and increased p-Akt. Additionally, an EV uptake study further showed that EMS-EVs were preferentially taken up by ESCs rather than by endometrial epithelial cells. These results suggest that EMS-EVs encapsulating miR-25-3p might be preferentially taken up by eutopic ESCs where they may induce endometrial collagen I deposition to impair ESC decidualization in EMS.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":"30 12","pages":""},"PeriodicalIF":3.6,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142886104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rebecca L Wilson, Jenna Kropp Schmidt, Baylea N Davenport, Emily Ren, Logan T Keding, Sarah A Shaw, Michele L Schotzko, Kathleen M Antony, Heather A Simmons, Thaddeus G Golos, Helen N Jones
{"title":"Placental gene therapy in nonhuman primates: a pilot study of maternal, placental, and fetal response to non-viral, polymeric nanoparticle delivery of IGF1.","authors":"Rebecca L Wilson, Jenna Kropp Schmidt, Baylea N Davenport, Emily Ren, Logan T Keding, Sarah A Shaw, Michele L Schotzko, Kathleen M Antony, Heather A Simmons, Thaddeus G Golos, Helen N Jones","doi":"10.1093/molehr/gaae038","DOIUrl":"10.1093/molehr/gaae038","url":null,"abstract":"<p><p>Currently, there are no placenta-targeted treatments to alter the in utero environment for administration to pregnant women who receive a diagnosis of fetal growth restriction (FGR). Water-soluble polymers have a distinguished record of clinical relevance outside of pregnancy. We have demonstrated the effective delivery of polymer-based nanoparticles containing a non-viral human insulin-like growth factor 1 (IGF1) transgene to correct placental insufficiency in small animal models of FGR. Our goals were to extend these studies to a proof-of-concept study in the pregnant macaque, establish feasibility of nanoparticle-mediated gene therapy delivery to trophoblasts, and investigate the acute maternal, placental, and fetal responses to treatment. Pregnant macaques underwent ultrasound-guided intraplacental injections of nanoparticles (GFP- or IGF1-expressing plasmid under the control of the trophoblast-specific PLAC1 promoter complexed with a HPMA-DMEAMA co-polymer) at approximately gestational day 100 (term = 165 days). Fetectomy was performed 24 h (GFP; n = 1), 48 h (IGF1; n = 3) or 10 days (IGF1; n = 3) after nanoparticle delivery. Routine pathological assessment was performed on biopsied maternal tissues and placental and fetal tissues. Maternal blood was analyzed for complete blood count (CBC), immunomodulatory proteins and growth factors, progesterone (P4), and estradiol (E2). Placental ERK/AKT/mTOR signaling was assessed using Western blot and qPCR. Fluorescent microscopy and in situ hybridization confirmed placental uptake and transient transgene expression in villous syncytiotrophoblast. No off-target expression was observed in either maternal or fetal tissues. Histopathological assessment of the placenta recorded observations not necessarily related to the IGF1 nanoparticle treatment. In maternal blood, CBCs, P4, and E2 remained within the normal range for pregnant macaques across the treatment period. Changes to placental ERK and AKT signaling at 48 h and 10 days after IGF1 nanoparticle treatment indicated an upregulation in placental homeostatic mechanisms to prevent overactivity in the normal pregnancy environment. The lack of adverse maternal reaction to nanoparticle-mediated IGF1 treatment, combined with changes in placental signaling to maintain homeostasis, indicates no deleterious impact of treatment during the acute phase of study.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11562130/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142583312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Poppy Downing, Madeleine Howe, Michaela Sacco, Leilani L Santos, Ellen Menkhorst, Wan Tinn Teh, Tarana Lucky, Wei Zhou, Evdokia Dimitriadis
{"title":"WD-repeat containing protein-61 regulates endometrial epithelial cell adhesion indicating an important role in receptivity.","authors":"Poppy Downing, Madeleine Howe, Michaela Sacco, Leilani L Santos, Ellen Menkhorst, Wan Tinn Teh, Tarana Lucky, Wei Zhou, Evdokia Dimitriadis","doi":"10.1093/molehr/gaae039","DOIUrl":"10.1093/molehr/gaae039","url":null,"abstract":"<p><p>Endometrial receptivity is crucial for successful embryo implantation during early pregnancy. The human endometrium undergoes remodeling within each menstrual cycle to prepare or become receptive to an implanting blastocyst in the mid-secretory phase. However, the mechanisms behind these changes are not fully understood. Recently, using hormone-treated endometrial organoids to model receptivity, we identified that the transcriptional regulator WD-repeat-containing protein-61 (WDR61) was reduced in organoids derived from infertile women. In this study, we aimed to determine the role of WDR61 in endometrial receptivity. Here, we demonstrated that WDR61 immunolocalizes in the nuclei and cytosol of endometrial glandular epithelium, luminal epithelium, and stroma. The staining intensity of WDR61 was significantly higher during the receptive mid-secretory phase compared to the non-receptive proliferative phase in fertile women. In a functional experiment to model blastocyst adhesion to the endometrial epithelium, we found that adhesion of cytotrophoblast progenitor spheroids was blocked when siRNA was used to knockdown WDR61 in primary endometrial epithelial cells. Similarly, in Ishikawa cells (a receptive human endometrial epithelial cell line), siRNA knockdown of WDR61 significantly reduced the cell adhesive and proliferative capacities. qPCR revealed that WDR61 knockdown reduced expression of key genes involved in receptivity including HOXD10, MMP2, and CD44. Chromatin immunoprecipitation sequencing demonstrated that WDR61 directly targeted 2022 genes in Ishikawa cells, with functions including focal adhesion, intracellular signaling and epithelial-mesenchymal transition. Overall, these findings suggest that WDR61 promotes endometrial receptivity by modulating epithelial cell focal adhesions, proliferation, and epithelial-mesenchymal transition.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11630898/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142624166","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Understanding the heterogeneity of natural killer cells at the maternal-fetal interface: implications for pregnancy health and disease.","authors":"Yuying Zhang, Liangtao Yang, Dongyong Yang, Songchen Cai, Yanjun Wang, Linlin Wang, Yuye Li, Longfei Li, Tailang Yin, Lianghui Diao","doi":"10.1093/molehr/gaae040","DOIUrl":"10.1093/molehr/gaae040","url":null,"abstract":"<p><p>Natural killer (NK) cells are the most abundant leukocytes located at the maternal-fetal interface; they respond to pregnancy-related hormones and play a pivotal role in maintaining the homeostatic micro-environment during pregnancy. However, due to the high heterogeneity of NK cell subsets, their categorization has been controversial. Here, we review previous studies on uterine NK cell subsets, including the classic categorization based on surface markers, functional molecules, and developmental stages, as well as single-cell RNA sequencing-based clustering approaches. In addition, we summarize the potential pathways by which endometrial NK cells differentiate into decidual NK (dNK) cells, as well as the differentiation pathways of various dNK subsets. Finally, we compared the alterations in the NK cell subsets in various pregnancy-associated diseases, emphasizing the possible contribution of specific subsets to the development of the disease.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142682247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Baoying Liao, Weixuan Chen, Xinyu Qi, Chuyu Yun, Yanli Pang
{"title":"Interleukin-22 improves ovulation in polycystic ovary syndrome via STAT3 signaling.","authors":"Baoying Liao, Weixuan Chen, Xinyu Qi, Chuyu Yun, Yanli Pang","doi":"10.1093/molehr/gaae037","DOIUrl":"10.1093/molehr/gaae037","url":null,"abstract":"<p><p>Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disease, which leads to serious impairment of reproductive health in women of child-bearing age. Anovulation or oligo-ovulation is a common clinical manifestation of PCOS patients. A disturbance of the ovarian immune microenvironment contributes to the disorders of follicle development and ovulation; however, the underlying mechanism remains unclear. Here we demonstrated the protective effect of immune factor interleukin-22 (IL-22) on PCOS follicle development and ovulation. Follicular IL-22 levels were significantly lower in PCOS patients than in the control group and were positively correlated with oocyte fertilization rate and high-quality embryo rate. Additionally, IL-22 evidently improved follicle development in vitro and promoted ovulation-related gene expression, which was disrupted by the depletion of interleukin-22 receptor 1 (IL-22R1) or inhibition of STAT3 in granulosa cells. This indicates that IL-22 acts through IL-22R1 and the STAT3 signaling pathway to promote follicle development and ovulation in PCOS. In summary, this study has elucidated the vital role of the ovarian immune microenvironment in follicle development and ovulation. Application of IL-22 may provide new insights into the treatment of PCOS patients.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Correction to: Sphingosine-1-phosphate restores endothelial barrier integrity in ovarian hyperstimulation syndrome.","authors":"","doi":"10.1093/molehr/gaae035","DOIUrl":"10.1093/molehr/gaae035","url":null,"abstract":"","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":"30 10","pages":""},"PeriodicalIF":3.6,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Min Yong, Honggui Zhou, Yuhua Zeng, Yuqin Yao, Hongtao Zhu, Jianguo Hu
{"title":"Reduced expression of SMAD7 and consequent reduction of autophagy promotes endometrial stromal-myofibroblast transition and fibrosis.","authors":"Min Yong, Honggui Zhou, Yuhua Zeng, Yuqin Yao, Hongtao Zhu, Jianguo Hu","doi":"10.1093/molehr/gaae036","DOIUrl":"10.1093/molehr/gaae036","url":null,"abstract":"<p><p>Abnormal autophagy and the transforming growth factor-β (TGFβ)-SMAD3/7 signaling pathway play an important role in the development of intrauterine adhesions (IUAs); however, the exact underlying mechanisms remain unclear. In this study, we used IUA patient tissue and SMAD7 conditional knockout mice to detect whether SMAD7 effected IUA via regulation of autophagy and the TGFβ-SMAD3 signaling pathway. We applied a combination of techniques for the detection of p-SMAD3, SMAD7, autophagy and fibrosis-related proteins, autophagic flux, and analysis of the SMAD3 binding site. Endometrial tissue of patients with IUA exhibited lower expression levels of SMAD7. In endometrial stromal cells, silencing of SMAD7 inhibited autophagic flux, whereas overexpressed SMAD7 promoted autophagic flux. This SMAD7-mediated autophagic flux regulates the stromal-myofibroblast transition, and these phenotypes were regulated by the TGFβ-SMAD3 signaling pathway. SMAD3 directly binds to the 3'-untranslated region of transcription factor EB (TFEB) and inhibits its transcription. SMAD7 promoted autophagic flux by inhibiting SMAD3, thereby promoting the expression of TFEB. In SMAD7 conditional knockout mice, the endometria showed a fibrotic phenotype. Simultaneously, autophagic flux was inhibited. On administering the autophagy activator rapamycin, this endometrial fibrosis phenotype was partially reversed. The loss of SMAD7 promotes endometrial fibrosis by inhibiting autophagic flux via the TGFβ-SMAD3 pathway. Therefore, this study reveals a potential therapeutic target for IUA.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470213","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}