Molecular human reproduction最新文献

{"title":"Integrated lipidomics and transcriptomics reveal the key role of ceramides in the development of endometriosis.","authors":"Shanshan Mei, Nan Ding, Mengyi Cheng, Chen Zhang, Jinli Miao, Mengli Liu, Xiaojun Shi, Xinyan Wang","doi":"10.1093/molehr/gaag047","DOIUrl":"10.1093/molehr/gaag047","url":null,"abstract":"<p><p>Endometriosis (EMs) is a chronic gynecological disease with poorly understood pathogenesis. This study integrated lipidomics and transcriptomics to systematically investigate aberrant sphingolipid metabolism in EMs, aiming to identify pathogenic mechanisms and therapeutic targets. Differential metabolites and genes in EMs lesions were identified through multi-omics profiling, followed by gene-metabolite network construction via MetaboAnalyst. EMs mouse models were established by intraperitoneal endometrial transplantation. Mice received ceramide (Cer) or EMs therapeutics for 2 weeks. Lesion size, cytokines, Cer levels, apoptosis, SMPD3 expression, and CD206+ macrophage infiltration were assessed using ELISA, TUNEL, western blot, RT‑qPCR, flow cytometry, and dual immunofluorescence. Integrated analysis revealed substantial metabolic and transcriptional alterations in EMs lesions. Sphingomyelin (SM) emerged as a central network hub, while Cer, generated via SMPD3-mediated SM hydrolysis, was markedly accumulated in lesions. In vivo, exogenous Cer(d18:1/20:0) supplementation exacerbated Cer accumulation, enhanced anti-apoptotic capacity, intensified inflammatory responses, and promoted CD206+ macrophage infiltration. Conversely, effective EMs therapeutics suppressed Cer accumulation, downregulated macrophage SMPD3 expression, and reduced CD206+ macrophage infiltration. Collectively, we identify the SM-SMPD3-Cer axis as a novel metabolic driver of EMs progression. Pathological Cer accumulation facilitates lesion development by promoting inflammation, enhancing CD206+ macrophage polarization, and suppressing apoptosis. These findings provide new metabolic insights and a theoretical foundation for Cer-targeted therapeutic strategies in endometriosis.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148712414","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":"Placental plasminogen activator inhibitor 1 is induced by platelet-derived TGF-β independently of TGF-β receptor 3 and is upregulated in preeclampsia.","authors":"Désirée Forstner, Azra Kulovic-Sissawo, Freya Lyssy, Jacqueline Guettler, Djenana Vejzovic, Beate Rinner, Daniel Kummer, Nadja Kupper, Christina Stern, Michael Gruber, Lena Neuper, Christine Daxboeck, Anubhuti Gupta, Shrey Kohli, Berend Isermann, Martin Gauster","doi":"10.1093/molehr/gaag040","DOIUrl":"10.1093/molehr/gaag040","url":null,"abstract":"<p><p>Preeclampsia is a pregnancy complication associated with de novo gestational hypertension, proteinuria, and dysregulations in the coagulation and fibrinolytic systems. Platelet-derived factors include various growth and differentiation factors, such as transforming growth factor (TGF)-β. The TGF-β type III receptor (TGFBR3), also known as betaglycan, is a co-receptor for the TGF-β superfamily and an important regulator of reproduction and fetal development. Here, we test the hypothesis whether or not TGFBR3 is involved in platelet-mediated upregulation of placental plasminogen activator inhibitor-1 (PAI-1). Perivillous fibrin deposits and PAI-1 levels were analyzed via immunohistochemistry, gene expression as well as protein expression in healthy and preeclamptic placental tissue. Placental villi and trophoblast cell line BeWo were incubated in presence or absence of washed platelets from pregnant women, platelet-derived soluble factors, or platelet-derived extracellular vesicles. Additionally, BeWo cells were treated with TGF-β-receptor inhibitors and silenced for TGFBR3 expression. PAI-1 and its encoding gene SERPINE1, as well as perivillous fibrin deposits, were significantly increased towards term of gestation and showed a significant upregulation in placental villi from preeclamptic pregnancies. Furthermore, SERPINE1 and PAI-1 were substantially upregulated in response to washed platelets and platelet-derived factors, but not to platelet-derived extracellular vesicles. The upregulation of SERPINE1 was blocked to control levels with the TGF-β inhibitor P144, whereas silencing of TGFBR3 had no effect. Our results suggest that platelet-derived factors induce placental PAI-1 expression independently of TGF-β receptor 3. Increased maternal platelet activation may contribute to significantly upregulated placental PAI-1 and perivillous fibrin deposits in preeclampsia.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13387163/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148352531","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":"Maternal DNA repair safeguards genome stability during the oocyte-to-embryo transition.","authors":"Mateus P Grejo, J Djaci Augusto Neto, Angélica C Dos Santos, Lindomar O Alves, Carolina H Macabelli, Sérgio A G Pereira-Júnior, Tainã F Cardoso, Anand K Pandey, Suellen G B Clemente, Deborah N Yokomizo, Marcelo M Seneda, Ricardo P Nociti, Flávio V Meirelles, Patrick F Chinnery, Rodrigo A P Martins, Pierre-Olivier Frappart, Marcos R Chiaratti","doi":"10.1093/molehr/gaag050","DOIUrl":"10.1093/molehr/gaag050","url":null,"abstract":"<p><p>De novo mutations are a major source of genetic variation and disease risk, yet the developmental timing and mechanisms underlying their origin require further investigation. While germ cells have traditionally been considered the primary source of these mutations, increasing evidence suggests that a substantial fraction arise after fertilization. Here, we investigated the role of maternal DNA repair in shaping mutagenesis during this critical window by using a mouse model with oocyte-specific disruption of the homologous recombination factor RAD51 and a combination of cellular and molecular analyses. Loss of maternal RAD51 led to the accumulation of DNA double-strand breaks in oocytes without impairing their growth, meiotic maturation, or fertilization competence. In contrast, embryos derived from RAD51-deficient oocytes exhibited increased DNA damage and developmental delay during early cleavage stages. Whole-genome sequencing revealed a significant increase in de novo variants in offspring, the majority displaying intermediate allele frequencies consistent with post-zygotic mosaic mutations. These findings confirm that maternal DNA repair safeguards genome stability across the oocyte-to-embryo transition and identify early embryogenesis as a major source of de novo mutations, with implications for reproductive biology and the origins of genetic diseases.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148887837","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":"Stem cell-based embryo models as a tool for reproductive biology.","authors":"Alfonso Martinez Arias, Andre Dias, Maneesha Inamdar","doi":"10.1093/molehr/gaag030","DOIUrl":"10.1093/molehr/gaag030","url":null,"abstract":"<p><p>ART has transformed clinical practice but still faces modest success rates, poorly defined implantation conditions, and persistent gaps in understanding early human development. At the same time, research in human reproductive biology remains strikingly underfunded relative to its medical and social impact. Over the last decade, advances in human pluripotent stem cell (PSC) biology have generated a suite of technologies that can recapitulate early stages of human development from blastocyst formation to early gastrulation in vitro. Here, we review how such models can be harnessed to interrogate lineage specification, embryo-endometrium crosstalk, the origins of aneuploidy and implantation failure, and the developmental basis of placental and yolk sac disorders, with a focus on primates. We argue that integrating stem cell-derived embryo models into reproductive research agendas offers a tractable experimental framework to improve ART outcomes and address major unmet needs in human reproductive health.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13244796/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147874885","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":"Investigating the role of a testis-expressed gene Tex2 in spermatogenesis in mice.","authors":"Guicheng Zhao, Suyan Wang, Gan Shen, Liangchai Zhuo, Tiechao Ruan, Xiang Wang, Chuan Jiang, Yao Liu, Xiaohui Jiang, Dingming Li, Ying Shen","doi":"10.1093/molehr/gaag031","DOIUrl":"10.1093/molehr/gaag031","url":null,"abstract":"<p><p>The testis-expressed (TEX/Tex) genes are highly expressed in the testes of various species. Several members of the TEX catalog have been suggested to play a role in spermatogenesis, but the functions of most members remain unknown. Here, we initially confirmed that TEX2 is significantly upregulated in spermatids and further successfully generated a Tex2 knockout (KO) mouse model using CRISPR/Cas9 technology. However, we found that the Tex2 KO male mice were fertile. Interestingly, Papanicolaou staining and scanning electron microscopy showed slight abnormalities in sperm morphology and reduced sperm motility as assessed by computer-assisted sperm analysis in Tex2 KO mice. Collectively, despite Tex2 having enriched expression in mouse testis, our genetic KO studies revealed that Tex2 is not essential for spermatogenesis or fertility in male mice, although its absence in sperm causes subtle abnormalities in morphology and motility.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148016386","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":"Assessing efficacy of ADCY10 inhibitors in cervical mucus.","authors":"Justine Fischoeder, Jai G Marathe, Deborah J Anderson, Lonny R Levin, Jochen Buck, Carla Ritagliati","doi":"10.1093/molehr/gaag035","DOIUrl":"10.1093/molehr/gaag035","url":null,"abstract":"<p><p>Male fertility depends on sperm motility, which enables sperm to traverse the female reproductive tract to the site of fertilization. Soluble adenylyl cyclase (sAC) is a key regulator of sperm motility, defining it as a promising non-hormonal contraceptive target for women and men. To evaluate the efficacy of sAC inhibitors under conditions mimicking the female reproductive tract, we employed a capillary assay using cervical mucus isolated from humans or cows as well as methylcellulose, a viscoelastic liquid that simulates cervical mucus. Addition of a sAC inhibitor, either directly to semen, modeling an on-demand male contraceptive, or to the cervical mucus, approximating a female contraceptive, effectively blocked sperm migration. These studies provide proof-of-concept for the efficacy of sAC inhibitors under physiologically relevant conditions.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13275317/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148163033","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":"Developing anti-Müllerian hormone as an ovarian reserve biomarker.","authors":"Bart C J M Fauser","doi":"10.1093/molehr/gaag021","DOIUrl":"10.1093/molehr/gaag021","url":null,"abstract":"<p><p>The first anti-Müllerian hormone (AMH) radioimmunoassay became available for clinical use in the early 2000s. This MHR Legacy Series review discusses key contributions from our own group towards establishing AMH as a robust ovarian reserve biomarker. Initial studies in female volunteers demonstrated decreasing serum AMH concentrations with increasing female age, along with a direct correlation between AMH levels and the number of antral follicles. The most relevant clinical conditions where measurements of serum AMH appear to be of great value include the diagnosis of various forms of ovarian dysfunction, especially polycystic ovary syndrome and premature ovarian insufficiency. In addition, a close correlation between initial serum AMH levels and ovarian response to standard stimulation for IVF has been firmly established, resulting in the development of a safe and effective AMH-based algorithm for individualized ovarian stimulation. Another area, beyond our own research, where AMH serum measurements have proven to be of great clinical significance is oncofertility. The capacity of AMH levels to predict fecundity-either spontaneous or following infertility treatment-or forecast age of menopause later in life remains uncertain and needs more well-designed, prospective, follow-up studies.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":"32 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13132654/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147817699","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":"Cyclic stretch activates endometrial stromal cells to enhance migration and invasion via mechanosensitive p38 MAPK and F-actin in vitro.","authors":"Yu-Yin Liu, Yu-Hang Zhang, Chu-Jun Jiang, Xue-Wei Wu, Shu-Lin Zhong, Shu-Yi Wu, Ming-Xiu Wu, Xiao-Jun Yang","doi":"10.1093/molehr/gaag019","DOIUrl":"10.1093/molehr/gaag019","url":null,"abstract":"<p><p>Adenomyosis (AM) is traditionally explained by biochemical dysregulation at the endometrial-myometrial interface, leading to passive displacement of endometrial stromal cells (ESCs). However, the uterus is a highly mechanosensitive organ. Aberrant myometrial hypercontractility in AM may expose ESCs to chronic mechanical stimulation. Whether such mechanical cues can modulate ESCs' behavior under in vitro conditions remains incompletely understood. This study hypothesizes that cyclic mechanical strain-independent of biochemical cues-can induce a pro-migratory and pro-invasive ESC phenotype in vitro. Immortalized human ESCs (hESCs) were subjected to cyclic uniaxial stretching (12% strain, 0.2 Hz, 48 h) to model sustained mechanical loading. We evaluated cellular morphology, migration and invasion (wound healing and Transwell assays), cytoskeletal remodeling (F-actin), extracellular matrix (ECM) related proteins, transcriptomic changes (RNA-sequencing), and MAPK pathway activation. The functional involvement of p38 MAPK was tested using the selective inhibitor Adezmapimod. The results indicated that cyclic stretch induced marked cellular elongation without increasing apoptosis. RNA-sequencing revealed 580 differentially expressed genes enriched in migration and ECM remodeling. Functionally, stretched hESCs exhibited enhanced migration and invasion capacity in vitro, accompanied by elevated F-actin, fibronectin, and CTGF. Mechanistically, mechanical strain triggered selective activation of the p38 MAPK pathway, without affecting ERK or JNK. Pharmacological inhibition of p38 attenuated stretch-associated cytoskeletal remodeling, ECM-related protein expression, and cell motility. Together, these findings demonstrate that cyclic mechanical stretch, as an underexplored non-biochemical factor, can promote a motile and invasive stromal cell phenotype in vitro via a p38 MAPK/F-actin-associated mechanism. While these results do not establish causality for AM development in vivo, they suggest a potential mechanotransduction pathway through which abnormal uterine mechanics may influence stromal cell behavior. Targeting mechanotransduction-such as p38 inhibition-may represent novel mechano-therapeutics for AM. This warrants further investigation using more complex and physiologically relevant models.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147513474","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":"Assessment and supplementation of antioxidant amines in male infertility-are we approaching clinical implementation?","authors":"Coraline Lugart, Nikaïa Smith, Ingrid Plotton, Célia Ravel, Charles R Lefèvre","doi":"10.1093/molehr/gaag025","DOIUrl":"10.1093/molehr/gaag025","url":null,"abstract":"<p><p>Male infertility remains unexplained in a substantial proportion of cases, despite extensive clinical and biological investigations. Oxidative stress has emerged as a central pathophysiological mechanism underlying impaired sperm function, yet current diagnostic and therapeutic strategies inadequately capture the complexity of redox regulation within the male reproductive tract. In this narrative review, we revisit both the historical foundations and recent advances supporting a pivotal role for a specific class of metabolites: polyamines (spermine, spermidine, and putrescine) and carnitine, which we propose to collectively term antioxidant amines. These compounds are present at exceptionally high concentrations in seminal plasma, tightly regulated by androgen-dependent and metabolic pathways, and critically involved in redox homeostasis, mitochondrial function, chromatin stabilization, and sperm maturation. We synthesize evidence from classical biochemical studies, contemporary metabolomics, and translational research linking antioxidant amine imbalance to altered semen parameters and male subfertility. Importantly, we highlight recent analytical advances that now make the targeted quantification of these metabolites technically feasible in clinical laboratories using routinely available liquid chromatography-mass spectrometry (LC-MS) platforms. Beyond their diagnostic potential, we critically discuss experimental and clinical data on antioxidant amine supplementation, emphasizing both their therapeutic potential and the need for balanced dosing strategies to avoid deleterious effects associated with excess exposure. Altogether, this review positions antioxidant amines at the crossroads of pathophysiology, laboratory medicine, and clinical intervention in male infertility. By integrating historical insights with modern analytical and translational perspectives, we argue that antioxidant amines are finally ready to move from overlooked metabolites to actionable biomarkers and therapeutic targets in reproductive medicine.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147776550","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":"Beyond neurobiology: cellular prion protein (PRNP) as an emerging regulator of decidual and utero-placental vascular function.","authors":"Rumela Bose Banerjee, Rupasri Ain","doi":"10.1093/molehr/gaag026","DOIUrl":"10.1093/molehr/gaag026","url":null,"abstract":"<p><p>The establishment of a functional utero-placental interface depends on the precise temporal and spatial coordination of blastocyst attachment, decidual transformation, trophoblast invasion, and uterine spiral artery remodeling (SAR). Disruption of these tightly regulated processes underlies major placental pathologies, including preeclampsia, fetal growth restriction, and stillbirth. Although significant advances have been made in defining the molecular networks governing placental development, the contribution of cellular prion protein (PRNP) remains poorly characterized, warranting a focused review. Classically studied in the context of neurobiology and prion-associated neurodegenerative diseases, PRNP is now emerging as an important regulator of reproductive and vascular physiology. This review provides an overview of current evidence supporting non-neuronal roles of PRNP during early pregnancy, with particular emphasis on decidualization and utero-placental vascular adaptation. PRNP displays dynamic expression in the uterine glands, decidua, and vascular smooth muscle cells (VSMCs), where it contributes to tight-junction integrity, decidual cell survival, and autophagic homeostasis. Within the vascular compartment, PRNP regulates trophoblast-directed VSMC phenotypic switching by limiting proliferation, promoting platelet-derived growth factor-β-focal adhesion kinase-dependent migration, and protecting VSMCs from TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, processes essential for effective SAR. Notably, PRNP expression is transcriptionally regulated by odd-skipped related transcription factor 1 (OSR1), which is itself negatively modulated by trophoblast cells. Collectively, these findings position PRNP beyond its traditional neurobiological role as a sensitive molecular indicator of decidual competence and vascular remodeling status, highlighting its potential as a biomarker and therapeutic target in placental disorders.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147931463","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}