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Human Myometrial Cell Fate under Chronic Oxidative Stress for Leiomyomagenesis

ABSTRACT: Uterine Leiomyoma are the most common benign tumors in women of reproductive age. Studies show that both leiomyoma and surrounding myometrium exist in a state of high oxidative stress, characterized by reactive oxygen species (ROS) production and impaired antioxidant defenses including defects of manganese superoxide dismutase (MnSOD). Oxidative stress has been proposed as a driver of leiomyoma initiation by promoting oxidative DNA damage leading to mutations in MED12 and leiomyoma growth. We hypothesize that chronic oxidative stress in human myometrial cells induces cellular remodeling and genomic alterations that promote adaptation and contribute to early events in leiomyoma development. To test this hypothesis, we generated stable human myometrial cell lines (Myo-hTERT) of wild type, MnSOD68K and mutant MnSOD68Q that impairs MnSOD antioxidant activity thereby imposing sustained oxidative stress. Experiments were performed both in vitro using three-dimensional spheroid cultures and in vivo using xenograft models in immunocompromised mice, with some studies extending up to 10 months to model chronic oxidative stress. Cells were exposed to the oxidative inducer paraquat (PQ) and analyzed using cellular and molecular approaches including spatial transcriptomics and MED12 mutational analysis. Cells expressing MnSOD68Q exhibited increased intracellular ROS and oxidative DNA damage, as indicated by accumulation of 8-hydroxy-deoxyguanosine (8-OHdG). Transcriptomic analysis revealed activation of pathways associated with oxidative stress responses including collagen/extracellular matrix, cellular senescence and IGF/AKT signaling. Xenografts of primary myometrial cells subjected to prolonged oxidative stress demonstrated similar molecular responses and showed an increased frequency of MED12 mutations. These changes were accompanied by modest increases in cell proliferation with minimal induction of cell death. Together, these findings provide mechanistic evidence that sustained oxidative stress can drive molecular and genomic changes in myometrial cells and support a causal role for chronic redox imbalance in the initiation of uterine leiomyomas.

ORGANISM(S): Homo sapiens

PROVIDER: GSE330163 | GEO | 2026/06/09

REPOSITORIES: GEO

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Project description:Background and objective: Uterine leiomyomas may arise from somatic stem or progenitor cells, leading to abnormal activation, proliferation, and clonal expansion. In organ cultures of myometrium and leiomyoma, differentiated cells decline after 7 days, whereas resident stem cells may persist within their niches and subsequently become activated, proliferate, and repopulate tissue slices. This study investigated gene expression programs that regulate the proliferation and differentiation of myometrial and MED12-mutant leiomyoma stem cells during long-term organ culture. Results: Comparison of normal and tumor tissues at baseline and after culture revealed several fibroid transcriptional signatures that were preserved during prolonged ex vivo culture. The MED12 mutation persisted in the repopulated fibroid slices, supporting the hypothesis that fibroids originate from stem or progenitor cells harboring MED12 mutation. Both tissues activated hypoxia and stemness-associated programs, including robust induction of HMGA1, HMGA2, and PLAG1. Myometrium induced KITLG/KIT expression, a limited number of CD49b (ITGA2)-stem-positive and Ki67-positive proliferating cells, indicating restrained proliferation, likely mediated by upregulation of ITGA2-AS1. Additionally, myometrial slice cultures were enriched for immune and endothelial/vascular programs, including several SOX family members. In contrast, leiomyoma cultures exhibited widespread CD24/CD73 expression, focal CD49b clusters, high Ki67 positivity, metabolic reprogramming toward complex carbohydrate degradation, SLC-mediated transport, and a low-PLIN2/high-ACLY signature. Uterine leiomyoma cultures repressed genes involved in vascular homeostasis (e.g., PLPP3) and preferentially activated pathways related to smooth muscle excitability and vesicle secretion. Extracellular matrix (ECM) remodeling was strongly pro-fibrotic in leiomyomas, with significant upregulation of several TGFB-regulated and related genes, a disrupted balance of KLF regulators, including loss of the anti-fibrotic repressor KLF10 and induction of the pro-fibrotic KLF5 factor, and broad upregulation of integrins. Differential expression of multiple HOX genes further distinguished ECM regulation between tissues. From niche survival to pro-fibrotic expansion, the study delineates checkpoints primed for intervention, highlighting potential therapeutic opportunities targeting profibrotic signaling, metabolic dependencies, and integrin-mediated ECM interactions. Conclusion: Long-term organ culture recapitulates key molecular features of fibroids and reveals tissue-specific mechanisms governing stem cell activation and differentiation. These findings identify potential therapeutic opportunities and establish long-term organ culture as a robust, physiologically relevant platform for investigating normal and tumor biology.

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Human Myometrial Cell Fate under Chronic Oxidative Stress for Leiomyomagenesis

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