Chunjia Wei, Sibing Yi, Yaoqiong Liang, Yue-Qiu Tan, Chaofeng Tu
{"title":"Advances in non-essential testis-enriched genes for human and mouse spermatogenesis.","authors":"Chunjia Wei, Sibing Yi, Yaoqiong Liang, Yue-Qiu Tan, Chaofeng Tu","doi":"10.1093/molehr/gaaf052","DOIUrl":"https://doi.org/10.1093/molehr/gaaf052","url":null,"abstract":"<p><p>Spermatogenesis is a highly complex cellular differentiation process. Recent advances employing knockout or knock-in mouse models have functionally characterized more than 700 genes as essential for male fertility maintenance. Paradoxically, emerging evidence reveals that a substantial proportion of the continuously expanding catalogue of testis-enriched genes exhibits biological dispensability for normal sperm production. To systematically catalogue non-essential testis-enriched genes in murine spermatogenesis, we performed a comprehensive PubMed literature review encompassing studies published up to 1 August 2025. Through stringent inclusion criteria, this analysis consolidates data from 83 publications that identified 261 testis-enriched genes demonstrated to be non-essential for spermatogenesis. We further categorize these genes by their familial relationships and explore potential explanations for the fertile phenotype observed in these knockout models, including genetic redundancy, compensatory mechanisms, differences in knockout strategies, and environmental influences. This review provides a valuable resource to avoid unnecessary expenditures and effort by research teams.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145302062","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":"TGFB1/SMAD3-Driven Macrophage-Myofibroblast Transition Promotes Fibrosis Progression in Endometriosis.","authors":"Yuchan Zhong, Xin Huang, Yujing Li, Ruiying Wang, Xinyu Qiao, Fangyuan Li, Lukanxuan Wu, Chang Liu, Yixian Han, Yunwei Ouyang, Dong Liu, Wei Huang","doi":"10.1093/molehr/gaaf051","DOIUrl":"https://doi.org/10.1093/molehr/gaaf051","url":null,"abstract":"<p><p>Endometriosis is a chronic gynecological disorder characterized by progressive fibrosis, which is closely associated with clinical symptoms such as dysmenorrhea and infertility. While myofibroblast activation is central to fibrogenesis, the cellular origins and regulatory mechanisms remain incompletely understood. This study demonstrates that the macrophage-myofibroblast transition (MMT) is a novel source of myofibroblasts in endometriosis and is regulated by the TGFB1/SMAD3 signaling pathway. Using single-cell RNA sequencing, we identified a distinct subpopulation of CD68+ macrophages co-expressing ACTA2 and extracellular matrix (ECM)-related genes in the human endometrium, which exhibited a myofibroblast-like transcriptional profile and were predominantly located at a fibrotic terminal state along the pseudotime trajectory. Histological and ultrastructural analyses revealed varying degrees of fibrosis and elevated TGFB1 expression in eutopic and ectopic endometrium in endometriosis patients and mouse models. Immunofluorescence confirmed that MMT-positive cells, co-expressing CD68 and α-SMA, were enriched in endometriotic tissues and primarily derived from M2 macrophages. In endometriosis mice, pharmacological inhibition of TGFB1/SMAD3 signaling significantly reduced the number of MMT-positive cells and attenuated collagen deposition, particularly in the eutopic endometrium. Furthermore, reduced ectopic lesion volume and epithelial ultrastructural damage following pathway inhibition suggested impaired ectopic lesion survival. These results demonstrate that the TGFB1/SMAD3 pathway-driven MMT might be a novel contributor to endometrial fibrosis in endometriosis. Targeting the TGFB1/SMAD3 signaling axis may provide a dual antifibrotic and anti-lesion strategy, offering therapeutic potential to intervene in the progression of endometriosis.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145244701","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":"A Review on macrophage biology and its potential role in spontaneous abortion.","authors":"Xiaoxuan Zhao, Xinyi Ding, Qingnan Fan, Xintong Yao, Linxi Jin, Chaochao Sun, Huanxiao Ke, Qujia Yang, Xiaowei Chen, Saiya Ye, Yuepeng Jiang, Hongli Zhao","doi":"10.1093/molehr/gaaf048","DOIUrl":"https://doi.org/10.1093/molehr/gaaf048","url":null,"abstract":"<p><p>Spontaneous abortion (SA) is a challenging and frustrating obstetric complication. Immune dysregulation at the mother-fetal interface has long been recognized as a threat to pregnancy maintenance. Decidual macrophages are key gatekeepers for immune homeostasis at the mother-fetal interface, characterized by their heterogeneity and high plasticity. Abnormalities in their number, function, and phenotype are strongly associated with pregnancy loss. However, the specific regulation mechanisms remain elusive. Here, we outline the origin and identity of the endometrial macrophages and review their diverse changes in phenotypes and functions to pregnancy initiation. More importantly, we highlight the underlying mechanisms mediating aberrant changes in macrophage polarization and functions in the context of SA, involving epigenetic landscape dysregulation, metabolic reprogramming, and aberrant communication between macrophages and other component cells at the maternal-fetal interface. Altogether, these provide a clear framework for understanding the crucial roles and prospective therapeutic targets of macrophages in SA.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145244661","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":"Prophylactic treatment with progesterone decreases murine miscarriage by suppressing the immunostimulatory activity of macrophages.","authors":"Yuki Kaito, Hajime Ino, Yumi Horii, Asako Watanabe, Makoto Nishigaki, Yumene Kubota, Tomoko Ichikawa, Yasuyuki Negishi, Yoshimitsu Kuwabara, Rimpei Morita, Shunji Suzuki","doi":"10.1093/molehr/gaaf050","DOIUrl":"https://doi.org/10.1093/molehr/gaaf050","url":null,"abstract":"<p><p>Miscarriage and preterm birth (PB) remain major challenges in obstetric care and are often associated with excessive inflammation at the feto-maternal interface. Although the role of progesterone (P4) in maintaining pregnancy is well known, its anti-inflammatory effects in immune-mediated pregnancy complications remain poorly understood. In this study, we investigated the impact of prophylactic P4 administration on miscarriage using a mouse model induced by α- galactosylceramide (αGC), a potent activator of invariant natural killer T (iNKT) cells. Prophylactic, but not therapeutic, P4 administration significantly reduced miscarriage rates. Flow cytometry analysis revealed that P4 suppressed the activity of iNKT cells and the production of inflammatory cytokines by these cells in the myometrium. Moreover, P4 reduced the immunostimulatory activity of antigen-presenting cells, particularly macrophages, by downregulating co-stimulatory molecules and interleukin (IL)-12 production. Immunohistochemistry and flow cytometry results demonstrated that the progesterone receptor (PR) was predominantly expressed on myometrial macrophages. Ex vivo experiments further confirmed that P4 directly modulates macrophage function, decreasing IL-12 and increasing IL-10 production. These findings suggest that prophylactic P4 administration mitigates immune activation at the feto-maternal interface by targeting macrophages, thereby suppressing iNKT cell-mediated inflammation and preventing miscarriage. This study highlights the importance of innate immune modulation in reproductive immunology and the potential of P4 as a prophylactic agent for preventing inflammation-associated miscarriage and PB.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145244664","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":"Neutrophils in the female reproductive tract: immune interactions and sperm adaptations.","authors":"Priksha Kuni, Gagan Kajla, Gagandeep Kaur Gahlay","doi":"10.1093/molehr/gaaf045","DOIUrl":"10.1093/molehr/gaaf045","url":null,"abstract":"<p><p>Human fertilization is a coordinated process involving interaction of sperm with the oocyte. As the sperm pass through the female reproductive tract (FRT), they are presented with numerous challenges. These include navigating through highly viscous cervical mucus while evading immune responses to successfully fertilize the oocyte. The female immune system facilitates sperm selection while providing protection against pathogens. Neutrophils, a major component of the innate immune system, use mechanisms such as phagocytosis, neutrophil extracellular trap formation, and trogocytosis to play a crucial role in this process. With the help of sialic acid residues and N glycans present on its glycocalyx as well as certain proteins in the seminal plasma, the sperm modulate the immune responses in the FRT to their advantage. This review examines the various interactions which take place between the sperm and the FRT, the neutrophil-mediated immune reaction occurring in the FRT, as well as the adaptations the sperm employ to overcome the immune challenges. Understanding these mechanisms provides critical insights into fertility and potential therapeutic targets for infertility.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145000931","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":"ACTRT2 deficiency increases spermatogonia vulnerability to ferroptosis.","authors":"Haicheng Chen, Yanqing Li, Daosheng Luo, Yun Xie, Linyan Lv, Jiahui Yao, Menghui Ma, Xiaoyan Liang, Min Zhang, Xiangzhou Sun, Xuenong Zou, Chunhua Deng, Xin Yang, Guihua Liu","doi":"10.1093/molehr/gaaf041","DOIUrl":"https://doi.org/10.1093/molehr/gaaf041","url":null,"abstract":"<p><p>The death of spermatogonia leads to decreased spermatogenesis and male infertility. Indeed, spermatogonia are vulnerable to various external damage factors and would be caused to cell death. However, the mechanism is still unclear. In this study, we found that the actin-related protein T2 (ACTRT2) was specifically expressed in testicular tissue and was associated with spermatogenesis. In vitro, when the cells were treated with busulfan, the proportion of spermatogonial cell line (GC-1) death in the low-ACTRT2 group increased significantly. Reactive oxygen species (ROS) accumulation and typical mitochondrial changes associated with ferroptosis occurred. In vivo, the seminiferous tubules in ACTRT2-/- mice were significantly shrunken. In addition, after being treated with busulfan, spermatogenesis in ACTRT2+/- mice decreased significantly compared to that in wild-type mice. In ACTRT2+/- testes, the expression levels of acyl-CoA synthetase long-chain family member 4 (ACSL4) and Arachidonic acid 15-lipoxygenase-1 (ALOX15) were upregulated, while the expression levels of Solute carrier family 7 member 11 (SLC7A11) and Glutathione peroxidase 4 (GPX4) were downregulated. Finally, we found that the expression of Solute carrier family 11 member 2 (SLC11A2), Iron responsive element binding protein 2 (IREB2), and Transferrin receptor protein 1 (TFRC) increased significantly in the low-ACTRT2 group, which transports iron into the cell to increase the intracellular unstable iron pool. In conclusion, ACTRT2 deficiency leads to intracellular iron overload and damage to mitochondria, ultimately increasing spermatogonia vulnerability to ferroptosis.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144855753","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}
M Louise Hull, Raul Gomez, Warren B Nothnick, Ruth Gruemmer, Katherine A Burns, Mohammed Zahied Johan, Isabella R Land, Stacey A Missmer, Lone Hummelshoj, Erin Greaves, Kaylon L Bruner-Tran
{"title":"WERF Endometriosis Phenome and Biobanking Harmonisation Project for Experimental Models in Endometriosis Research (EPHect-EM-Heterologous): heterologous rodent models.","authors":"M Louise Hull, Raul Gomez, Warren B Nothnick, Ruth Gruemmer, Katherine A Burns, Mohammed Zahied Johan, Isabella R Land, Stacey A Missmer, Lone Hummelshoj, Erin Greaves, Kaylon L Bruner-Tran","doi":"10.1093/molehr/gaaf022","DOIUrl":"10.1093/molehr/gaaf022","url":null,"abstract":"<p><p>Endometriosis, defined as the growth of endometrial-like tissues outside the uterus, is a common disease among women. Numerous in vivo rodent models of endometriosis have been developed to explore multiple aspects of this poorly understood disease. Heterologous models utilize human endometrial tissues engrafted into immunocompromized mice, while homologous models engraft rodent endometrium into immunocompetent mice or rats. Heterologous models of endometriosis more closely replicate the human disease; however, the murine humoral immune response must be suppressed to prevent rejection of the xenograft tissue. Although the innate immune system remains intact, suppression of the humoral response leads to a markedly different local and systemic immune environments compared to humans. Despite this limitation, experiments using heterologous models have contributed significantly to our understanding of endometriosis establishment and progression, the pre-clinical effectiveness of various therapeutic strategies, and genetically modifiable host factors that contribute to disease. Unfortunately, a lack of harmonization of the models used by different laboratories has impeded the reproducibility and comparability of results between groups. Therefore, the World Endometriosis Research Foundation (WERF) formed an international working group of experts in heterologous models of endometriosis to develop guidelines and protocols that could contribute to unifying experimental approaches across laboratories. Nine critical variables were identified: (i) mouse strain; (ii) human tissue type; (iii) hormonal status of the human tissue donor; (iv) human tissue preparation; (v) method and location of tissue placement; (vi) hormonal status of the recipient animal; (vii) whether or not mice were engrafted with human immune cells; (viii) endpoint assessments; and (ix) number and type of replicates. Herein, we outline important considerations for each major variable and make recommendations for unification of approaches. Widespread adoption of harmonized protocols and implementation of standardized documentation and reporting should further improve the reproducibility and translation of experimental findings both within and between laboratories.</p>","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/PMC12237513/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144591743","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}
Melanie Lemaire, Wei Q Deng, Keaton W Smith, Samantha L Wilson
{"title":"Meta-analysis examining fetal sex-specific placental DNA methylation intensities and estimated cell composition post IVF.","authors":"Melanie Lemaire, Wei Q Deng, Keaton W Smith, Samantha L Wilson","doi":"10.1093/molehr/gaaf046","DOIUrl":"10.1093/molehr/gaaf046","url":null,"abstract":"<p><p>Infertility impacts up to 17.5% of reproductive-aged couples worldwide. To aid in conception, many couples turn to ART, such as IVF. IVF can introduce both physical and environmental stressors that may alter DNA methylation regulation, an important and dynamic process during early fetal development. This meta-analysis aims to assess the differences in the placental DNA methylome between spontaneous and IVF pregnancies. Potential datasets were identified by searching the NCBI Gene Expression Omnibus (GEO) using keywords related to IVF in human participant studies published before November 2023. In our combined fetal sex population (N = 575) from three eligible GEO datasets, 127 autosomal cytosine guanine dinucleotides (CpGs) were significant (False Discovery Rate (FDR) <0.05) between IVF (n = 96) and spontaneous (n = 479) placentae, with 47 CpGs considered differentially methylated (FDR < 0.05 and |Δβ| > 0.05). Stratification by fetal sex revealed no significant autosomal CpGs in fetal female placentae (N = 281); however, in the fetal male placentae (N = 294), we identified nine autosomal CpGs that reached statistical significance between IVF (n = 56) and spontaneous (n = 238) placentae, with three CpGs considered differentially methylated. Fetal male placentae had lower proportions of trophoblasts (P < 0.0001) and stromal cells (P = 0.007) and higher proportions of syncytiotrophoblasts (P = 0.0001) compared to fetal female placentae, regardless of conception type. IVF placentae had higher proportions of stromal cells (P = 0.01) and lower proportions of syncytiotrophoblasts (P = 0.01) compared to spontaneous placentae, regardless of sex. Controlling for cell-type proportions in linear models reduced test statistic inflation and identified new significant CpGs that may previously have been masked by cell-type heterogeneity. The results of this meta-analysis are critical to further understand the impact of IVF on tissue epigenetics, which may help with understanding the connections between IVF and negative pregnancy outcomes. Additionally, our study suggests that sex-specific differences in placental DNA methylation and cell composition should be considered as factors for future placental DNA methylation analyses.</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/PMC12462385/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145030249","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":"S14G-Humanin ameliorates ovarian dysfunction in a cyclophosphamide-induced premature ovarian insufficiency mouse model.","authors":"Jin Huang, Dandan Zhang, Liping Zou, Haoyuan Liu, Wei Xia, Changhong Zhu, Meng Rao","doi":"10.1093/molehr/gaaf042","DOIUrl":"10.1093/molehr/gaaf042","url":null,"abstract":"<p><p>Premature ovarian insufficiency (POI) is a major cause of female infertility, for which effective therapies remain limited. S14G-Humanin (HNG), a potent analogue of Humanin, exhibits strong antioxidant and anti-apoptotic properties and has demonstrated cytoprotective effects in various tissues, including the ovary. In this study, a cyclophosphamide (CP)-induced POI mouse model was established to evaluate both the ovarian damage induced by chemotherapy and the protective effects of HNG. HNG administration significantly increased the number of primordial follicles (P = 0.044) and growing follicles (all P > 0.05), as well as corpora lutea (P = 0.09). Moreover, HNG markedly improved oocyte quality (P = 0.009), significantly lowering the proportion of abnormal ovulated oocytes (P = 0.002). Fertility outcomes were also enhanced: CP treatment significantly reduced litter size compared to controls (4.6 ± 1.1 vs 8.0 ± 1.0; P < 0.001), whereas HNG treatment significantly mitigated this reduction (6.2 ± 0.8 vs 4.6 ± 1.1; P = 0.029). Mechanistically, HNG alleviated oxidative stress and apoptosis in ovarian tissues (all P < 0.05), reduced ROS levels (P = 0.034), and restored mitochondrial membrane potential (P = 0.004) in a human granulosa cell line. Furthermore, HNG significantly upregulated PGC-1α expression and enhanced AMPK phosphorylation in both in vivo and in vitro models (both P < 0.05). Collectively, these findings demonstrate that HNG confers significant protection against chemotherapy-induced ovarian damage and highlight its potential as a novel therapeutic agent for chemotherapy-induced ovarian damage.</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":"144855754","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}
Xiaorui Zhang, Jiao Yang, Wenting Yang, Nan Cui, Tingting Duan, Shan Li, Jing Cao, Stephen J Bush, Guoqing Tong
{"title":"Discordant effects of maternal age on the human MII oocyte transcriptome.","authors":"Xiaorui Zhang, Jiao Yang, Wenting Yang, Nan Cui, Tingting Duan, Shan Li, Jing Cao, Stephen J Bush, Guoqing Tong","doi":"10.1093/molehr/gaaf038","DOIUrl":"10.1093/molehr/gaaf038","url":null,"abstract":"<p><p>While advanced maternal age is associated with significant changes in oocyte gene expression, these are not global changes but limited to a fraction of the transcriptome. However, there is little consensus on the specific genes affected, and on the transcriptomic signatures of age-related declines in oocyte quality. To characterize the effects of age on the human MII oocyte transcriptome, here we take a two-part approach. We first generated single-oocyte Smart-seq2 datasets from 10 younger (21-29 years) and 10 older (37-43 years) donors, identifying genes differentially expressed between the two groups, then cross-referenced our results with those of 12 studies (9 human, 3 mouse) performing equivalent analyses using a variety of single-cell transcriptomic or microarray platforms. Technical differences notwithstanding, we found considerable discordance between the datasets, suggesting that age-related signatures of differential gene expression are not easily reproducible. Independent corroboration of age-associated changes in expression was limited to few genes, with the vast majority only supported by one of the 13 datasets, including our own. Nevertheless, we identified 40 genes whose expression significantly altered with age in multiple studies, highlighting common processes underlying ageing, including dysregulated proteostasis. As human Smart-seq2 oocyte libraries are challenging to procure and rare in public archives, we next implemented a meta-analytic method for their re-use, combining our 20 oocytes with 130 pre-existing libraries sourced from 12 different studies and representing a continuous age range of 18-43 years. We identified 25 genes whose expression level significantly correlated with age and corroborated 14 of these genes with RT-PCR, including the proteasomal subunits PSMA1 and PSMA2, both of which were downregulated in older oocytes. Overall, our findings are consistent with both pronounced inter-oocyte heterogeneity in transcription and with oocyte ageing being a multifactorial process to which bona fide transcriptomic changes may only play a restricted role, while proteomic changes play more pronounced roles.</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/PMC12360849/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144743149","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}