Molecular human reproduction最新文献

{"title":"Functional heterogeneity in trophoblast stem cells derived from recurrent pregnancy loss products of conception.","authors":"Qi Fu, Keisuke Kozai, Xingrao Ke, Joseph M Varberg, Sheng Xia, Ashley S Howard, Michael Lydic, Kristin Holoch, Courtney Marsh, Elin Grundberg, Kaela M Varberg","doi":"10.1093/molehr/gaag033","DOIUrl":"10.1093/molehr/gaag033","url":null,"abstract":"<p><p>Recurrent pregnancy loss (RPL), defined as two or more consecutive miscarriages, affects 1-5% of couples attempting to conceive and most frequently occurs between 6 and 8 weeks of gestation, coinciding with critical stages of placental development. Despite this temporal association, placental contributions to RPL pathogenesis remain poorly understood. We hypothesized that trophoblast lineage development, including extravillous trophoblast (EVT) and syncytiotrophoblast (STB) differentiation, are disrupted in RPL. To test this hypothesis, we established and functionally characterized human trophoblast stem (TS) cell lines derived from products of conception (POC) obtained from consenting idiopathic RPL cases. Four TS cell lines were successfully derived from five POC samples, representing both normal and abnormal karyotypes. All established TS cell lines exhibited canonical stem-state trophoblast features, including epithelial morphology, ELF5 promoter hypomethylation, expression of trophoblast-specific microRNAs, and trophoblast marker expression. Despite this preserved identity, TS cell lines displayed marked heterogeneity in proliferation and differentiation capacity. TS cells derived from POC with abnormal karyotypes exhibited prolonged doubling times and impaired differentiation, while those from normal karyotypes more closely resembled cytotrophoblast-derived control TS cells. Although all TS cells formed morphologically comparable STB spheroids, functional deficits in human chorionic gonadotropin β secretion were observed in a cell-line-specific manner. EVT differentiation capacity varied substantially across POC-derived TS cell lines. Transcriptomic analyses revealed karyotype-associated transcriptional heterogeneity, including enrichment of senescence- and cell cycle-associated pathways across subsets of POC-derived TS cell lines. Together, these findings demonstrate that patient-specific TS cell lines retain trophoblast identity yet exhibit meaningful functional heterogeneity that becomes evident upon differentiation, underscoring the importance of functional validation in newly established in vitro placental cell lines. Overall, POC-derived TS cells are a powerful platform for investigating molecular mechanisms underlying RPL.</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/PMC13293087/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148055311","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":"Circulating transfer RNA-derived fragment abundance after experimental endometriosis induction in baboons.","authors":"Hanna Surmann, Ramanaiah Mamillapalli, Niraj Joshi, Gregory Burns, Asgerally T Fazleabas, Hugh S Taylor","doi":"10.1093/molehr/gaag032","DOIUrl":"10.1093/molehr/gaag032","url":null,"abstract":"<p><p>Endometriosis is a chronic systemic disease affecting ∼10-15% of women of reproductive age, often resulting in chronic pelvic pain and infertility. Despite its high prevalence, diagnosis is frequently delayed. tRNA-derived fragments (tRFs) are an emerging class of small non-coding RNAs that have been implicated in gene regulation and various pathological processes but remain understudied in endometriosis. This study aimed to characterize temporal changes in circulating tRF abundance after experimentally induced endometriosis in a baboon model. Endometriosis was induced in eight female baboons, and peripheral blood samples were collected at five time points post-inoculation. RNA was extracted from serum samples and sequenced to profile tRF abundance. Differential expression analysis was performed. Significant changes in tRFs were observed as early as 3 months after induction. A ranking based on log fold change and adjusted P-values revealed the 10 most significantly altered tRFs. These tRFs demonstrated consistent differential abundance throughout all time points. This is the first study to investigate circulating tRFs in endometriosis. Our longitudinal findings suggest that tRFs may serve as promising candidate biomarkers for endometriosis.</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":"148016415","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":"How decidualization dysregulation reshapes the nanomechanics of endometrial stromal cells.","authors":"Ana Laura Schafir, Alejandra Marilina Fernandez, Laura Del Carmen Fernández, Lourdes Materazzi, Lara Castagnola, Vanesa Hauk, Marcela Irigoyen, Antonio Cattaneo, Diego Gnocchi, Lautaro Tessari, Lorena Sigaut, Elizabeth Soczewski, Silvina Ponce Dawson, Esteban Grasso, Soledad Gori, Lía Isabel Pietrasanta, Rosanna Ramhorst","doi":"10.1093/molehr/gaag037","DOIUrl":"10.1093/molehr/gaag037","url":null,"abstract":"<p><p>Decidualization of endometrial stromal cells is a critical process for establishing uterine receptivity and successful embryo implantation, involving coordinated biochemical, cellular, and biomechanical remodeling. Emerging evidence indicates that this process is associated with activation of endoplasmic reticulum stress (ERS) and the development of distinct stromal subpopulations, including mature and senescent decidual cells. However, how these pathways integrate to regulate the mechanical properties of the endometrium remains unclear. Here, we investigated the impact of decidualization dysregulation on stromal cell nanomechanics and its contribution to implantation failure. Our first approach used an in vitro decidualization model of human endometrial stromal cells (cell line), in which an excessive ERS was induced by thapsigargine. Then, decidualization, senescence and unfolded protein response were evaluated by molecular analyses, cellular nanomechanical properties by atomic force microscopy, and decidual functionality with a blastocyst-like spheroid implantation assay (using Swan71 cells). Decidualization induced a significant decrease in cellular stiffness (Young's modulus), consistent with a more permissive phenotype for embryo implantation. In contrast, exacerbated ERS-induced prior to decidualization-disrupted the balance between mature and senescent decidual cells and prevented this biomechanical softening, restoring stiffness to levels comparable to those on nondecidualized cells. Functionally, these alterations impaired trophoblast adhesion and expansion in vitro. Finally, to provide a physiologically relevant view of how decidualization operates in vivo, we studied endometrial samples from fertile women (N = 13) and from women with recurrent implantation failure (N = 11). These patients exhibited reduced expression of key decidualization and senescence markers evaluated by qPCR, similar to our results with exacerbated ERS, supporting the clinical relevance of our findings. Together, our results demonstrate that successful decidualization requires tight coordination between ERS, cellular senescence, and biomechanical remodeling. Disruption of this integrated program leads to a mechanically nonpermissive endometrium, providing a novel mechanistic framework for implantation failure.</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":"148239589","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":"Endometriomas are heterogeneous for functional FSH receptor expression and steroidogenic function.","authors":"Can Benlioglu, Yashar Esmaeilian, Sevgi Yusufoglu, Hesam Ghafouri Kalajahi, Batuhan Altay, Seda Ates, Serdar Aydin, Uzeyir Kalkan, Pinar Bulutay, Ceyda Acilan, Kayhan Yakın, Volkan Adsay, Sule Yildiz, Bulent Urman, Ozgur Oktem","doi":"10.1093/molehr/gaag014","DOIUrl":"10.1093/molehr/gaag014","url":null,"abstract":"<p><p>We investigated whether ovarian endometriomas uniformly express functional FSH receptors (FSHR) and respond to FSH by activating transcriptional programs that drive aromatase and steroid hormone production. Endometrioma cyst capsules were obtained from 18 patients undergoing surgery between January 2020 and December 2024. FSHR and steroidogenic pathway components were evaluated using qRT-PCR, quantitative immunoblotting, and immunohistochemistry. To assess FSH responsiveness, explant cultures were exposed to FSH, and the expression of five FSH-responsive CYP19A1 (aromatase) transcript variants (alternative exons I.1, I.2; I.3; I.4, and promoter II) was quantified; estradiol (E2) and progesterone (P4) were measured in spent culture media. Human granulosa cells served as positive controls for steroidogenesis/FSHR, and the eutopic endometrium served as the estrogen receptor profiling control. FSHR transcripts were detected in all endometriomas and were several-fold higher than in granulosa-cell controls; however, FSHR protein abundance was lower and highly variable, and transcript-protein levels were discordant, indicating marked mRNA-protein uncoupling. FSH did not elicit a uniform aromatase response: only selected transcript variants were upregulated in a lesion-dependent manner, and induction of one or more CYP19A1 variants did not consistently translate into increased E2 output. Moreover, E2 production did not correlate with aromatase protein abundance. Protein expression of StAR and downstream steroidogenic enzymes (CYP11A1/SCC, 3β-HSD, and 17β-HSD) also showed substantial inter-patient heterogeneity. Collectively, ovarian endometriomas exhibit pronounced heterogeneity in functional FSHR expression, steroidogenic enzyme profiles, FSH-driven aromatase transcript programs, and hormone output, which may contribute to variable lesion behavior during ovarian stimulation; findings were derived from unilateral endometriomas and may not generalize to multifocal disease or other lesion types.</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":"147317730","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":"Cell-penetrating alpha-synuclein accelerates the late stages of the acrosome reaction in human sperm.","authors":"Micaela Vanina Buzzatto, Jorge Ernesto Ibáñez, Claudia Nora Tomes","doi":"10.1093/molehr/gaag024","DOIUrl":"10.1093/molehr/gaag024","url":null,"abstract":"<p><p>Secretory vesicles discharge their contents into the extracellular space through fusion pores; the behaviour of these structures regulates release kinetics. In sperm, acrosomal contents are released after the expansion of multiple pores formed when the plasma and acrosomal membranes fuse. Alpha-synuclein is required after pore opening during the human sperm acrosome reaction (AR). Here, we investigated its role in AR kinetics, specifically in pore expansion. We introduced cell-penetrating His6-TAT-alpha-synuclein into human sperm and monitored progesterone-induced AR by time-lapse fluorescence microscopy using an anti-CD46 antibody. Fluorescence traces from individual cells revealed that the AR follows a sigmoidal profile with a steeper slope in cells exposed to His6-TAT-alpha-synuclein plus progesterone than in progesterone-only controls. This acceleration was most pronounced in the later phase of the curves, which suggests that alpha-synuclein enhances pore dilation. It is generally assumed that pore expansion proceeds immediately after opening without modulation; our results challenge this view. Thus, the contribution of this study to the sperm biology field is that pore dilation is regulated. Its contribution to the cell biology field is to provide new insight into the physiological role of alpha-synuclein beyond the nervous system and to raise the possibility of its conserved function across different cell types.</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":"147776542","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":"Call for papers-shaping reproduction in 3D: organoids, assembloids, and emerging models.","authors":"Diana Monsivais, Francesca E Duncan, Michele Boiani","doi":"10.1093/molehr/gaag012","DOIUrl":"https://doi.org/10.1093/molehr/gaag012","url":null,"abstract":"","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":"32 1","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147355873","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":"The impact of obesity on placental vascular development and function.","authors":"Isha Ramanlal, Joanna L James, Anna L Boss","doi":"10.1093/molehr/gaag002","DOIUrl":"10.1093/molehr/gaag002","url":null,"abstract":"<p><p>Maternal obesity is complicating an increasing number of pregnancies globally and is associated with a heightened risk of adverse obstetric and fetal outcomes. The placenta, which mediates maternal-fetal exchange, is postulated to be a key mediator of these outcomes. The development of the extensively branched placental vascular network, driven by spatial and temporal regulation of angiogenic cues, is critical to ensure efficient exchange capacity. In maternal obesity, the placenta exhibits lipotoxicity, inflammation, and a range of cellular stresses, which may impair angiogenic signalling and endothelial metabolism, thereby disrupting vascular development. Understanding the timing and nature of obesity-induced disruptions to placental vascular development is important to improve clinical monitoring, inform the development of targeted interventions to improve fetal outcomes, and reduce obesity-associated pregnancy complications. This review synthesizes the current literature on the impact of maternal obesity on the placental vasculature, considering how changes in vascular architecture, angiogenic factors, and endothelial cell metabolism intersect to lead to dysfunction. Furthermore, we propose a conceptual framework to explain how distinct combinations of placental alterations may underlie the heightened risk of divergent fetal growth outcomes (both pathologically large and small babies) commonly observed in obese pregnancies.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145966608","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":"Embryo secretome regulation of the endometrial epithelial transcriptome: development of a model to test for embryo viability.","authors":"Zhixing Jin, Yifan Wang, Abigail Freeman Blatchford, Helena Rodriguez-Caro, Luyao Wang, Christian M Becker, Pedro Melo, Tim Child, Rebecca Dragovic, Ingrid Granne, Jennifer H Southcombe","doi":"10.1093/molehr/gaaf062","DOIUrl":"10.1093/molehr/gaaf062","url":null,"abstract":"<p><p>The aim of this study was to develop an advanced in vitro model of human endometrium using single-cell-derived endometrial epithelial organoids, enabling the study of embryo secretome-endometrial crosstalk at the maternal-fetal interface. Single-cell-derived organoids generated from endometrial tissue of a parous 39-year-old woman recapitulated hormone-responsive decidualization, as demonstrated by expression of SPP1 and acetyl-α-tubulin. When cultured in embryo culture media, organoid viability was maintained with no cytotoxicity, but proliferation was suppressed, likely due to the lower concentrations of the required factors in organoid growth media. Organoids were stimulated with culture supernatants from morphologically good-quality embryos with known pregnancy outcomes (live birth (n = 4) vs no pregnancy (n = 4)). Transcriptomic profiling (RNA-sequencing) revealed that 32 genes were differentially expressed (DEGs) in organoids exposed to the culture supernatants from live-birth embryos versus non-pregnant outcomes: 24 upregulated and 8 downregulated. These DEGs were enriched for biological processes related to cell motility and cytoskeletal dynamics. In conclusion, soluble factors secreted by human blastocysts achieving live birth selectively modulate the endometrial epithelial transcriptome, enhancing pathways involved in cytoskeletal remodeling and immune modulation. This embryo-directed remodeling likely facilitates endometrial receptivity for successful implantation to occur. Our organoid model provides a robust platform for further investigating implantation failure.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12957937/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145911744","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":"The Legacy Series: shining light on our origins to inform the future of reproductive science and medicine.","authors":"Francesca E Duncan","doi":"10.1093/molehr/gaag011","DOIUrl":"https://doi.org/10.1093/molehr/gaag011","url":null,"abstract":"","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":"32 1","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147458710","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":"Aberrant progesterone receptor (PGR) expression is associated with estrogen receptor 1 (ESR1) expression in the endometrium from infertile women with endometriosis.","authors":"Sohyeon Yun, Soo Lim Kim, Eunhee M Jeong, Da-Hye Kang, Keun Cheon Kim, Tae Hoon Kim, Steve L Young, Bruce A Lessey, Jung-Yoon Yoo, Jae-Wook Jeong","doi":"10.1093/molehr/gaag006","DOIUrl":"10.1093/molehr/gaag006","url":null,"abstract":"<p><p>Estrogen receptor 1 (ESR1) and progesterone receptor (PGR) are essential regulators for endometrial receptivity and embryo implantation. Their expression is dysregulated in women with endometriosis-associated infertility. However, the relationship between ESR1 and PGR within the same endometrial cellular compartments has not been clearly defined. In this study, we examined ESR1 and PGR expression and their correlation in mid-secretory phase eutopic endometrium from fertile women without endometriosis (n = 9) and infertile women with endometriosis (n = 11) using immunohistochemistry and multiplex immunofluorescence. ESR1 levels were significantly reduced in endometrial stromal cells from infertile women with endometriosis compared to controls, and this attenuation of ESR1 was tightly associated with reduced PGR expression. In contrast, although epithelial PGR is normally downregulated in receptive mid-secretory phase endometrium, aberrant epithelial PGR overexpression was strongly correlated with epithelial ESR1 levels in infertile women with endometriosis. Multiplex immunofluorescence and AI-assisted single-cell quantitative analysis further confirmed a significant positive correlation between ESR1 and PGR in both stromal and epithelial compartments in the endometriosis group. These findings reveal compartment-specific dysregulation of ESR1 and PGR expression and identify aberrant ESR1-PGR co-expression as a potential molecular feature of a non-receptive eutopic endometrium in endometriosis-associated infertility, underscoring the importance of disrupted steroid hormone signaling in impaired implantation.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13233088/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146125737","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}