Del Valle Julieta S, Van Helden Ruben W, Moustakas Ioannis, Wei Fu, Asseler Joyce D, Metzemaekers Jeroen, Pilgram Gonneke S K, Mummery Christine L, van der Westerlaken Lucette A J, van Mello Norah M, Chuva de Sousa Lopes Susana M
Department of Anatomy and Embryology, Leiden University Medical Center, 2333 ZC Leiden, the Netherlands.
The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center, Leiden 2333 ZC, the Netherlands.
iScience. 2025 Feb 13;28(3):112020. doi: 10.1016/j.isci.2025.112020. eCollection 2025 Mar 21.
Tissue fibrosis, with the excessive accumulation of extracellular matrix, leads to organ dysfunction. The ovary shows signs of fibrosis from an early age, creating a permissive environment for ovarian cancer. A robust culture-platform to study human ovarian fibrosis would enable screens for antifibrotic drugs to prevent or even reverse this process. Based on previous results showing that androgen therapy can induce ovarian fibrosis, we characterized the fibrotic state of ovaries from transmasculine donors of reproductive age. Anti-inflammatory and antioxidant drugs, such as Pirfenidone, Metformin, and Mitoquinone, could reduce and revert the excess collagen content of the ovarian cortical tissue during culture. We demonstrated that Metformin exerts an antioxidant role and prevents a glycolytic metabolic shift in non-immune ovarian stromal cells in the human ovary, while promoting early folliculogenesis during culture. These results may contribute to develop strategies to manage pro-tumorigenic fibrotic ovarian stroma in advanced age and metabolic disorders.
组织纤维化伴随着细胞外基质的过度积累，会导致器官功能障碍。卵巢从幼年起就显示出纤维化迹象，为卵巢癌创造了一个适宜的环境。一个强大的用于研究人类卵巢纤维化的培养平台将能够筛选抗纤维化药物，以预防甚至逆转这一过程。基于先前显示雄激素疗法可诱导卵巢纤维化的结果，我们对育龄期跨性别供体的卵巢纤维化状态进行了表征。抗炎和抗氧化药物，如吡非尼酮、二甲双胍和米托醌，可在培养过程中减少并逆转卵巢皮质组织中过量的胶原蛋白含量。我们证明，二甲双胍发挥抗氧化作用，可防止人类卵巢中非免疫性卵巢基质细胞发生糖酵解代谢转变，同时在培养过程中促进早期卵泡发生。这些结果可能有助于制定策略，以管理老年和代谢紊乱中促肿瘤性纤维化卵巢基质。
