Department of Obstetrics and Gynecology, E-Da Hospital, Kaohsiung, Taiwan.
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, 100, Tzyou 1st Rd., Kaohsiung, 807, Taiwan.
Reprod Sci. 2020 Sep;27(9):1698-1706. doi: 10.1007/s43032-020-00139-0. Epub 2020 Apr 6.
Adenomyosis is defined as the presence of endometrial glands and stroma in the myometrium. The mechanisms associated with the pathogenesis of adenomyosis remain unclear. Epithelial-mesenchymal transition (EMT) is characterized by losing cell polarity and cell-cell adhesion together with gaining migratory and invasive properties of stromal cells to become mesenchymal stem cells. Transforming growth factor-β1 (TGF-β1), an anti-inflammatory cytokine secreted by multiple cell types, plays a crucial role in embryogenesis and tissue homeostasis. The induction of EMT and ultimate fibrosis by TGF-β1 is suggested to play a critical role in the pathogenesis of adenomyosis. Thus, this study aims to demonstrate the occurrence of EMT in and the effects of anti-TGF-β1 on the pathogenesis of adenomyosis. ICR mice were fed with 1 μg/g body weight of tamoxifen (TAM) by in the first 4 postnatal days (PNDs). Subsequently, the right and left uterine horns were correspondingly injected with or without 10 μg of anti-TGF-β1 neutralizing antibody on PND42 followed by sacrifice on PND64. E-cadherin, vimentin, and α-smooth muscle actin (α-SMA) expression in the uteri was evaluated by qRT-PCR, Western blot, and immunohistochemistry. Clusters of endometrial glands and increased numbers of vimentin-positive stromal cells in the disrupted α-SMA-positive myometrium were observed in the uteri from TAM-treated mice. Numbers of stromal cells in the myometrium and the disrupted myometrial continuity were reduced by anti-TGF-β1. Moreover, uterine expression of E-cadherin and vimentin/α-SMA was increased and decreased by anti-TGF-β1 treatment, respectively. Anti-TGF-β1 successfully inhibits EMT and the development of adenomyosis in mouse uteri.
子宫腺肌病定义为子宫内膜腺体和基质存在于子宫肌层中。与子宫腺肌病发病机制相关的机制仍不清楚。上皮-间充质转化 (EMT) 的特征是失去细胞极性和细胞-细胞黏附，同时获得间质细胞的迁移和侵袭特性，成为间充质干细胞。转化生长因子-β1 (TGF-β1) 是一种由多种细胞类型分泌的抗炎细胞因子，在胚胎发生和组织稳态中发挥关键作用。TGF-β1 诱导 EMT 和最终纤维化被认为在子宫腺肌病的发病机制中起关键作用。因此，本研究旨在证明 EMT 的发生以及抗 TGF-β1 对子宫腺肌病发病机制的影响。在出生后的第 4 天（PND），ICR 小鼠通过喂食 1μg/g 体重的他莫昔芬 (TAM)。随后，在 PND42 时分别用或不用 10μg 的抗 TGF-β1 中和抗体注射右侧和左侧子宫角，并在 PND64 时处死。通过 qRT-PCR、Western blot 和免疫组织化学评估子宫中 E-钙黏蛋白、波形蛋白和α-平滑肌肌动蛋白 (α-SMA) 的表达。在 TAM 处理的小鼠子宫中观察到子宫内膜腺体簇和破坏的 α-SMA 阳性子宫肌层中增加的波形蛋白阳性间质细胞数量。抗 TGF-β1 减少了子宫肌层中的间质细胞数量和破坏的子宫肌层连续性。此外，抗 TGF-β1 处理分别增加和减少了子宫中 E-钙黏蛋白和波形蛋白/α-SMA 的表达。抗 TGF-β1 成功抑制了 EMT 和小鼠子宫腺肌病的发展。
