Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
Sci Adv. 2022 Sep 2;8(35):eabq1475. doi: 10.1126/sciadv.abq1475.
Ovarian fibrosis is a pathological condition associated with aging and is responsible for a variety of ovarian dysfunctions. Given the known contributions of tissue fibrosis to tumorigenesis, it is anticipated that ovarian fibrosis may contribute to ovarian cancer risk. We recently reported that diabetic postmenopausal women using metformin had ovarian collagen abundance and organization that were similar to premenopausal ovaries from nondiabetic women. In this study, we investigated the effects of aging and metformin on mouse ovarian fibrosis at a single-cell level. We discovered that metformin treatment prevented age-associated ovarian fibrosis by modulating the proportion of fibroblasts, myofibroblasts, and immune cells. Senescence-associated secretory phenotype (SASP)-producing fibroblasts increased in aged ovaries, and a unique metformin-responsive subpopulation of macrophages emerged in aged mice treated with metformin. The results demonstrate that metformin can modulate specific populations of immune cells and fibroblasts to prevent age-associated ovarian fibrosis and offers a new strategy to prevent ovarian fibrosis.
卵巢纤维化是一种与衰老相关的病理状态，可导致多种卵巢功能障碍。鉴于组织纤维化已知可促进肿瘤发生，预计卵巢纤维化可能会增加卵巢癌的风险。我们最近报道称，使用二甲双胍的糖尿病绝经后女性的卵巢胶原含量和组织与非糖尿病绝经前女性的卵巢相似。在这项研究中，我们在单细胞水平上研究了衰老和二甲双胍对小鼠卵巢纤维化的影响。我们发现，二甲双胍通过调节成纤维细胞、肌成纤维细胞和免疫细胞的比例来预防与年龄相关的卵巢纤维化。衰老相关分泌表型（SASP）产生的成纤维细胞在衰老的卵巢中增加，并且在接受二甲双胍治疗的衰老小鼠中出现了一种独特的对二甲双胍有反应的巨噬细胞亚群。这些结果表明，二甲双胍可以调节特定的免疫细胞和成纤维细胞群体，以预防与年龄相关的卵巢纤维化，并为预防卵巢纤维化提供了一种新策略。
