Molecular human reproduction最新文献

Adenomyosis-the ectopic presence of endometrial glands and stroma within the myometrium-affects reproductive-age women and is associated with pain, bleeding, and subfertility, yet the immune events that precede pregnancy remain poorly defined. To address this, we investigated how the uterine immune microenvironment evolves before conception in a tamoxifen-induced murine model of adenomyosis. At one and three months post-induction, we analyzed uterine tissue by immunofluorescence, flow cytometry, and quantitative polymerase chain reaction. We found that adenomyotic uteri exhibited a sustained elevation of interleukin-6 messenger RNA, a transient interleukin-10 rise at one month, and stable cyclooxygenase-2 levels. Interleukin-6 receptor messenger RNA and signal transducer and activator of transcription 3 messenger RNA were both transiently downregulated at one month and returned to control levels by three months. Early in disease development, total macrophage numbers declined and displayed an alternative (M2) activation phenotype, followed by a selective loss of classically activated (M1) macrophages at later stages. B lymphocytes were consistently enriched, indicating enhanced humoral activity. Although overall T-cell counts remained stable, the CD3+ compartment underwent a marked shift from double-negative T lymphocytes toward T helper and cytotoxic subsets, coinciding with the transient signaling changes. Limitations of our study include reliance on a single animal model, analysis at only two timepoints, and lack of functional assessment of regulatory T cells. Future work should incorporate finer temporal profiling, single-cell transcriptomics, and validation in human tissues. These findings highlight dynamic innate-adaptive crosstalk as an early driver of adenomyosis pathology and suggest that targeting interleukin-6-mediated pathways may inform biomarker development and novel immunomodulatory interventions.

Ovarian fibrosis is increasingly recognized as a pivotal factor contributing to ovarian aging, dysfunction and female infertility. It results from chronic or repetitive ovarian injury, such as that caused by repeated ovulation, which induces inflammation and excessive extracellular matrix (ECM) deposition, predominantly by activated fibroblasts and myofibroblasts. The key molecular pathways driving ovarian fibrosis include transforming growth factor-beta (TGF-β) /Smad signaling, Wnt/β-catenin and PI3K/Akt pathways, which orchestrate fibroblast activation, ECM remodeling and tissue stiffening. Elevated collagen types I and III, fibronectin and hyaluronan characterize the fibrotic ovarian stroma, disrupting normal folliculogenesis and steroidogenesis. Ovarian fibrosis is also implicated in reproductive pathologies such as polycystic ovary syndrome (PCOS), premature ovarian insufficiency (POI) and endometriosis, and may contribute to an increased risk of ovarian cancer, although definitive causal links require further elucidation. Current therapeutic strategies remain largely experimental, focusing on antifibrotic agents such as pirfenidone, TGF-β inhibitors and modulation of oxidative stress, alongside emerging interventions such as stem cell therapies, which are offer potential avenues for intervention in the ovary. This review synthesizes current insights into the cellular and molecular mechanisms driving ovarian fibrosis, its association with reproductive disorders, and emerging therapeutic strategies. It underscores key knowledge gaps and emphasizes the need for future research focused on fibroblast activation, inflammatory signaling and immune-ECM interactions to facilitate the development of targeted, long-term interventions aimed at preventing or reversing ovarian fibrosis and preserving female fertility.

Nlrp5 encodes a core component of the subcortical maternal complex (SCMC) a cytoplasmic protein structure unique to the mammalian oocyte and cleavage-stage embryo. NLRP5 mutations have been identified in patients presenting with early embryo arrest, recurrent molar pregnancies and imprinting disorders. Correct patterning of DNA methylation over imprinted domains during oogenesis is necessary for faithful imprinting of genes. It was previously shown that oocytes with mutation in the human SCMC gene KHDC3L had globally impaired methylation, indicating that integrity of the SCMC is essential for correct establishment of DNA methylation at imprinted regions. Here, we present a multi-omic analysis of an Nlrp5-null mouse model, which in germinal vesicle (GV) stage oocytes displays a misregulation of a broad range of maternal proteins, including proteins involved in several key developmental processes. This misregulation likely underlies impaired oocyte developmental competence. Amongst impacted proteins are several epigenetic modifiers, including a substantial reduction in DNMT3L; we show that de novo DNA methylation is attenuated in Nlrp5-null oocytes, including at some imprinting control regions. This provides evidence for a mechanism of epigenetic impairment in oocytes which could contribute to downstream misregulation of imprinted genes.

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 mouse models of endometriosis, 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.

The death of spermatogonia leads to decreased spermatogenesis and male infertility. Spermatogonia are vulnerable to various external damaging factors, which can cause cell death. However, the mechanism is still unclear. In this study, we found that the actin-related protein T2 (ACTRT2) is specifically expressed in testicular tissue and is associated with spermatogenesis. In vitro, when GC-1 cells (spermatogonial cell line) were treated with busulfan, the proportion of cell death in the low-ACTRT2 group increased significantly. Reactive oxygen species 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 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.

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.

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 catalog of testis-enriched genes exhibits biological dispensability for normal sperm production. To systematically catalog 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.

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.

Mammalian oocyte maturation is a tightly regulated process essential for successful fertilization and embryonic development. Meiotic resumption in mammalian oocytes is controlled by various regulatory factors, including the tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein (YWHA/14-3-3). However, the specific functions of individual YWHA isoforms in oocyte meiosis remain poorly understood. In this study, we revealed that knockdown of Ywhaz, one of the isoforms of YWHA, using short interfering RNA (siRNA) or morpholino oligomers (MOs), accelerates meiotic resumption in mouse oocytes. To elucidate the mechanism underlying YWHAZ-mediated meiotic resumption, we thus explored its interactions with potential target proteins. Co-immunoprecipitation and immunofluorescence analyses demonstrated a physical interaction between YWHAZ and phosphorylated CDC25B. Additionally, we identified the protein kinases responsible for YWHAZ phosphorylation at distinct residues. Specifically, JNK1, CSNK1A1/CKIα, and protein kinase B (PKB/Akt) were found to phosphorylate YWHAZ at Serine 184/186, Threonine 232, and Serine 58, respectively. Notably, phosphorylation of YWHAZ at serine 58 by PKB/Akt promoted meiotic resumption in mouse oocytes. Furthermore, we found the formation of a heterodimer between YWHAZ and YWHAQ. Our results provide insights into the PKB/Akt-YWHAZ-CDC25B signalling pathway and illuminate the functional influence of YWHAZ phosphorylation in meiotic regulation.