Human Myometrial Cell Fate under Chronic Oxidative Stress for Leiomyomagenesis

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.