Molecular human reproduction最新文献

{"title":"Down-regulation of IGFBP2 mediates endometrial epithelial cells senescence in thin endometrium.","authors":"Zihan Zhou, Zhenhua Zhou, Chunying Ye, Nana Li, Yaru Zhu, Panmei Ma, Jing Wu, Yali Hu, Haixiang Sun, Guangfeng Zhao","doi":"10.1093/molehr/gaaf032","DOIUrl":"10.1093/molehr/gaaf032","url":null,"abstract":"<p><p>Thin endometrium (TE) is generally recognized as a contributing factor to reduced pregnancy rates and adverse perinatal outcomes, yet the pathogenesis of the disease remains elusive. We conducted an analysis and validation of single-cell RNA sequencing data pertaining to TE and demonstrated that insulin-like growth factor binding protein 2 (IGFBP2) expression is down-regulated, resulting in the senescence of endometrial epithelial cells. In both human primary endometrial epithelial cells and the Ishikawa cell (IKC) line (a well-established endometrial-derived epithelial cell), the introduction of recombinant human IGFBP2 protein effectively alleviates hydrogen peroxide (H2O2)-induced cellular senescence. Notably, it demonstrates superior performance compared to the well-known anti-aging agent Dasatinib in specific aspects. Specifically, transfecting IGFBP2 protein siRNAs promotes cyclin-dependent kinase inhibitor 1A (P21) accumulation through the phosphatidylinositol 3-kinase (PI3K)/AKT serine/threonine kinase (AKT) signaling pathway by regulating phosphatase and tensin homolog deleted on chromosome 10 (PTEN) activity. Furthermore, administering IGFBP2 protein or Dasatinib to TE mouse models, which was established by endometrial curettage combined with H2O2 instillation, restored endometrial thickness by inhibiting senescence. Our findings demonstrate that down-regulation of IGFBP2 protein plays a pivotal role in mediating the senescence of endometrial epithelial cells in TE. This offers novel insights into elucidating the pathogenesis of TE and identifying potential new therapeutic targets.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144699025","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":"Identification of transcription factors that regulate placental sFLT1 expression.","authors":"Qing Yong, Carin van der Keur, Jacqueline D H Anholts, Hanneke Kapsenberg, Hailiang Mei, Jan A Bruijn, Michael Eikmans, Hans J Baelde","doi":"10.1093/molehr/gaaf031","DOIUrl":"10.1093/molehr/gaaf031","url":null,"abstract":"<p><p>Increased soluble FMS-like tyrosine kinase 1 (sFLT1) levels have been associated with preeclampsia, chronic kidney diseases, and kidney transplant rejection. However, lower levels of sFLT1 exhibit beneficial properties in various processes, such as the organization of the actin cytoskeleton in podocytes and immune regulation in healthy pregnancy. Therefore, understanding the transcriptional regulation of sFLT-1 and preserving appropriate expression levels are critical for effective treatment of preeclampsia and other diseases. Cytotrophoblasts (CTBs) were isolated from three first-trimester placentas and differentiated into extravillous trophoblasts (EVTs) for 6 days. RNA was extracted at different time points and used for RNA sequencing. Differentially expressed genes (DEGs) and transcription factors (DETFs) were analyzed. Transcription factor (TF) enrichment analysis and pathway analysis were performed on DEGs screened from EVTs and CTBs. TF inhibitors were added to primary CTBs directly or during CTB to EVT differentiation to confirm the regulatory effect of TFs on sFLT1 expression. In total, 197 TFs were differentially expressed between CTBs and EVTs, among which 15 DETFs (EPAS1, ETS1, TBX3, CEBPB, FLI1, TEAD4, GATA4, TBX2, LMX1B, ARNT, FOXM1, ERF, PRDM1, TFAP2A, and NR2F2) that potentially regulate sFLT1 expression were predicted by ChEA3 and KnockTF software. The mRNA levels of 15 DETFs were validated upon CTBs differentiation into both EVTs and syncytiotrophoblasts. The regulatory effects of FOXM1 and CEBPB were confirmed in vitro experiments, and their expression patterns were validated during CTBs differentiation into EVTs and in first-trimester placentas. Pathway analysis showed that FLT1 was involved in P13K-Akt, Rap1, MAPK, Ras, and HIF-1 signaling pathways, focal adhesion, and cytokine-cytokine receptor interaction. Protein-protein interaction analysis showed that FLT4, PDGFB, TGFB1, IL6R, TNFRSF1B, CSF1R, and TGFB2 interact with FLT1. The identified TFs can serve as therapeutic targets in preeclampsia to keep the sFLT1 levels within appropriate limits.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12286775/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144601003","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":"Permutation tests to assess sex differences in omics data.","authors":"Julian K Christians","doi":"10.1093/molehr/gaaf047","DOIUrl":"10.1093/molehr/gaaf047","url":null,"abstract":"<p><p>It is common to sex-stratify analyses of omics data and to report effects as 'sex-specific' when they are significant in only one sex. However, when analysing hundreds or thousands of molecules, this approach will yield many spurious 'sex-specific' effects if not supported by significant interactions. I illustrate this problem using an RNA sequencing dataset showing almost no significant sex by treatment interactions, but where sex-stratified analyses yield hundreds of 'sex-specific' effects of treatment. These 'sex-specific' effects could be spurious or could be real but not show interactions due to low statistical power. To distinguish these possibilities, I describe permutation tests, which provide an intuitive way to determine if a pattern of observations differs from what would be expected due to chance. For this dataset, assigning sex at random often generates more 'sex-specific' effects than the real data, demonstrating that there is little evidence of sex differences. Next, I simulate an RNA sequencing dataset that includes genes modelled to have sex-specific effects of a condition. As expected, analysis of this simulated dataset yields both significant interactions and sex-specific effects in sex-stratified analyses. While stratified analyses detect a higher number of sex-specific effects than the analysis of interactions, they erroneously identify genes not modelled to show sex-specific effects more often than interactions. A permutation test confirms that the number of sex-specific effects observed in the simulated dataset is greater than expected due to chance. Permutation tests can be applied to omics studies of sex differences, simultaneously providing (i) a clear and simple demonstration of the problems of sex-stratified analyses, and (ii) additional evidence of sex-specific effects where these are present. R code is provided for permutations, simulations, and plots to visualize potential sex-specific effects, which can be adapted to other types of data.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145092156","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":"Bitter taste signaling pathway is required for spermatogenesis and maintenance of male fertility in mice.","authors":"Feng Li, Ling-Ling Liu, Bo-Wen Niu, Meng-Min Zhu, Qian Gao, Yu Huang, Lixiang Chen, Boying Qin, Xiaohui Zhou","doi":"10.1093/molehr/gaaf040","DOIUrl":"10.1093/molehr/gaaf040","url":null,"abstract":"<p><p>Recently, the expression of bitter taste receptors and their downstream taste signaling cascade has been widely found outside the gustatory system, indicating important physiological functions of bitter taste receptors in various extraoral organs, including testis, but little is known about their functions in spermatogenesis. Here, we describe the localization and expression pattern of taste signaling transduction molecules in the testis. Genetic mutation of bitter signaling transduction molecules decreased the litter size, the IVF rate, and the diameter of seminiferous tubules and even resulted in empty seminiferous tubules. Transmission electron microscopy observations further revealed that overdeveloped acrosomes adhered to atrophic round spermatids in double-mutant mice. Mutant mice lacking bitter taste receptor signaling exhibited a dysfunction of adenosine 5'-monophosphate-activated protein kinase and inducible nitric oxide synthase signaling pathways, and a decreased expression of zonula occludens-1 and β-catenin in testis, indicating a disruption for the structure and functions of the blood-testis barrier. Transcriptome analysis further showed that bitter taste signaling deficiency can alter the expression profile of transcripts related to signal pathways, hormone synthesis, cell adhesion molecules, the chemokine signaling pathway, and cell metabolism in the testis, which finally contribute to impaired male fertility. In short, our work provides previously unidentified in vivo evidence that bitter taste signaling plays a critical role in the maintenance of normal spermatogenesis. These data further support the concept that bitter taste receptors exert functions outside the gustatory system and may have implications for the diagnosis and management of human male infertility.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144874177","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":"Fertility is compromised after oocyte-specific deletion of microtubule severing protein Katanin A1.","authors":"Wai Shan Yuen, Qing-Hua Zhang, Monique Dunstan, Deepak Adhikari, Anne E O'Connor, Jessica E M Dunleavy, Moira K O'Bryan, John Carroll","doi":"10.1093/molehr/gaaf034","DOIUrl":"10.1093/molehr/gaaf034","url":null,"abstract":"<p><p>Katanins are microtubule severing enzymes that play roles in diverse cell functions including meiotic and mitotic spindle formation. To address the role of Katanin p60 isozymes in mammalian oocytes, we have used the ZP3-CreLox approach to specifically delete Katanin A1 (KATNA1) and Katanin A-like 1 (KATNAL1) from the start of oocyte growth. Here, we show that KATNAL1 is not required for normal fertility, but deletion of KATNA1 causes a 50% decrease in fertility. Further investigation in Katna1-/- oocytes revealed no effect on MI spindle morphology but a modest effect on the morphology of MII spindles. This was accompanied by a decreased rate of fertilization, but Katna1-/+ heterozygous embryos that reached the 2-cell stage developed at normal rates to the blastocyst stage. Parthenogenetic activation of Katna1-/- oocytes to generate diploid homozygous embryos revealed a reduced rate of blastocyst formation. Further, the Katna1-/- parthenogenetic blastocysts had a reduced diameter, decreased cell number, and increased nuclear size. Taken together, our data indicate KATNA1, but not KATNAL1, plays a role in MII spindle function and mitotic cell divisions of the preimplantation embryo. The ability of the paternal allele to rescue preimplantation development suggests the origin of the decrease in the fertility of conditional Katna1-/- mice lies in abnormalities arising in the egg to embryo transition prior to embryonic genome activation.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12343050/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642878","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":"Correction to: WERF Endometriosis Phenome and Biobanking Harmonisation Project for Experimental Models in Endometriosis Research (EPHect-EM-Heterologous): heterologous rodent models.","authors":"","doi":"10.1093/molehr/gaaf033","DOIUrl":"10.1093/molehr/gaaf033","url":null,"abstract":"","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":"31 3","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12304412/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144732278","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":"HOXC4 promotes proliferation of endometriotic stromal cells via the SLIT2-ROBO1 axis.","authors":"Yuqi Yang, Bo Yin, Cenyu Li, Xinjue Dong, Menghui Wang, Junhui Su, Xinyi Tang, Ruijie Chen, Qingquan Li, Ding Ding","doi":"10.1093/molehr/gaaf037","DOIUrl":"10.1093/molehr/gaaf037","url":null,"abstract":"<p><p>Current interventions for endometriosis mainly involve hormone therapies but have limited efficacy and unacceptable side effects due to the lack of selectivity to distinguish between endometriosis and endometrial tissues. Elucidating the molecular mechanism underlying the rapid growth of endometrial-like stromal cells, one of the main components of endometriotic lesions, will pave a path for more effective treatment of endometriosis. In the current study, we utilized transcriptome sequencing to compare the transcriptional profiles of endometrial-like stromal cells from endometriosis and endometrial tissues and demonstrated that Homeobox C4 (HOXC4) is preferentially expressed in endometriotic lesions. HOXC4 is indispensable for the proliferation of stromal cells from endometriosis, but not those from endometrial tissues. Mechanistically, HOXC4 acts as a transcription factor to promote the expression of Slit Guidance Ligand 2 (SLIT2) and thereby increases the p38 MAPK activity via the SLIT2 receptor roundabout guidance receptor 1 (ROBO1). Considering the essential role of the p38 MAPK activity in facilitating the development of ectopic endometrium, our findings strongly support the idea of HOXC4, as well as the SLIT2-ROBO1 axis, being potential therapeutic targets for endometriosis.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718193","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":"Overexpression of high affinity Type I adenosine receptors promotes the growth of uterine leiomyomas.","authors":"Rodrigo Rosado, Xiaofang Guo, Jake Rymer, Burak Un, Begum Aydogan Mathyk, Jun Cai, Brittney Short, Umit Kayisli, Thomas J Rutherford, Matthew L Anderson","doi":"10.1093/molehr/gaaf025","DOIUrl":"10.1093/molehr/gaaf025","url":null,"abstract":"<p><p>Leiomyomas are benign proliferations of uterine smooth muscle found in 60% of women. A spatial redistribution of ecto-5'-nucleotidase (CD73, NT5E) that results in reduced extracellular concentrations of adenosine has recently been described in leiomyomas. However, the mechanisms by which altered extracellular adenosine levels contribute to leiomyoma growth remain poorly understood. To address this deficiency, a series of tissue specimens and primary cultures generated from matched specimens of myometrium and leiomyoma were used. Overexpression of Type 1 adenosine receptors (ADORA1) was observed when matched specimens and primary cultures were interrogated by RT-qPCR and western blot. By immunohistochemistry, ADORA1 expression was diffusely observed in myocytes in the leiomyoma complex, with only limited expression in vascular and other structures. Overexpression of ADORA1 was also observed in fibroblasts and multiple smooth muscle subtypes in the leiomyoma complex when single-cell transcriptomics data were interrogated. Incubation with N6-cyclopentyladenosine (CPA), a selective ADORA1 agonist, resulted in decreased proliferation of primary leiomyoma cultures, accompanied by decreased intracellular cAMP and enhanced cyclin D1 and phospho-AKT1 expression. To confirm the specificity of this observation, ADORA1 expression was directly targeted by siRNA, resulting in decreased proliferation, increased intracellular cAMP, and lower levels of cyclin D1 and phospho-AKT1. Collectively, these data indicate that overexpression of the ADORA1 receptor is a robust feature of uterine leiomyomas, where its activation by residual levels of extracellular adenosine potentially contributes to tumor growth by regulating AKT1-mediated signaling.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144258573","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":"Wnt9b enables androgen action to maintain Wolffian ducts in mice.","authors":"McKenna J Crossen, Shuai Jia, Joan S Jorgensen, Andrew M Kelleher, Rulang Jiang, Fei Zhao","doi":"10.1093/molehr/gaaf035","DOIUrl":"10.1093/molehr/gaaf035","url":null,"abstract":"<p><p>The Wolffian duct (WD) is the embryonic primordium that gives rise to the epididymis, vas deferens, and seminal vesicle. The androgen action in the mesenchyme is the predominant driver for fetal WD maintenance, which is essential for male fertility. However, the androgen's capability of promoting WD maintenance was completely lost in the absence of Wnt9b in mice. In this study, we followed up with this interesting phenomenon and revealed cellular and molecular mechanisms whereby Wnt9b facilitates WD maintenance in male embryos. Wnt9b belongs to the WNT family of secreted proteins and is expressed in the WD epithelium. We found that WD degeneration in Wnt9b-/- male embryos was accompanied by decreased cell proliferation in the epithelium but not in the mesenchyme during sexual differentiation. Wnt9b deletion did not impair testicular androgen synthesis but altered androgen receptor (AR) expression pattern. The percentage of AR-positive cells in the mesenchyme was significantly reduced, which can be the cause of decreased epithelial proliferation. Wnt9b actions can be transduced by both β-catenin-dependent and β-catenin-independent pathways in the context of target cells. Transcriptomic analysis of embryonic day (E) 12.5 Wnt9b+/+ and Wnt9b-/- mesonephroi revealed that expression of multiple WNT/β-catenin-target genes was reduced in the absence of Wnt9b. Deletion of mesenchymal β-catenin led to caudal WD degeneration and cystic formation in the cranial region. Taken together, our study uncovers the important WNT9B-AR signaling axis that mediates the epithelial-mesenchymal interaction in WD development.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642879","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: WERF Endometriosis Phenome and Biobanking Harmonisation Project for Experimental Models in Endometriosis Research (EPHect-EM-Homologous): homologous rodent models.","authors":"","doi":"10.1093/molehr/gaaf036","DOIUrl":"10.1093/molehr/gaaf036","url":null,"abstract":"","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":"31 3","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12304422/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144732279","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}