Center of Reproduction and Genetics, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou 215002, China; Department of Obstetrics and Gynaecology, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, British Columbia V6H 3V5, Canada.
Department of Obstetrics and Gynaecology, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, British Columbia V6H 3V5, Canada.
Cell Signal. 2019 Nov;63:109392. doi: 10.1016/j.cellsig.2019.109392. Epub 2019 Aug 19.
Hyaluronan serves as a structural component of ovarian follicles, and hyaluronan-mediated signaling cascades lead to follicular development, oocyte maturation, and ovulation. Transforming growth factor-β (TGF-β1) is highly expressed in human oocytes and granulosa cells and involved in the regulation of follicular development and ovulation. Previous studies have shown the imperative role for TGF-β signaling in the regulation of hyaluronan-mediated cumulus expansion and ovulation in human granulosa-lutein (hGL) cells. However, the detailed underlying molecular mechanisms by which TGF-β regulates the synthesis of hyaluronan in hGL cells are not fully elucidated. Using both primary and immortalized hGL cells as study models, we provide the first data showing that TGF-β1 significantly promoted the synthesis of hyaluronan by upregulating the expression of hyaluronan synthase 2 in these cells. Additionally, using dual inhibition approaches, we show that the TGF-β type II (TβRII) receptor and TGF-β type I (ALK5) receptor are functional receptors that mediate stimulatory effects in response to TGF-β1. Moreover, we found that the canonical SMAD2/SMAD3-SMAD4 signaling pathway is the principal intracellular signaling pathway that upregulates the expressionhyaluronan synthase and subsequent hyaluronan synthesis. Notably, we showed that SNAIL transcription factor is a critical molecule mediating the TGF-β signaling, which contributes to the increase in hyaluronan synthesis. These results of our in vitro studies suggest that intraovarian TGF-β1 plays a functional role in the local regulation of hyaluronan synthesis in hGL cells.
透明质酸作为卵泡的结构成分，透明质酸介导的信号级联反应导致卵泡发育、卵母细胞成熟和排卵。转化生长因子-β（TGF-β1）在人卵母细胞和颗粒细胞中高度表达，并参与卵泡发育和排卵的调节。先前的研究表明，TGF-β信号在调节人颗粒细胞黄体（hGL）细胞中透明质酸介导的卵丘扩展和排卵中起着至关重要的作用。然而，TGF-β调节 hGL 细胞中透明质酸合成的详细潜在分子机制尚未完全阐明。使用原代和永生化的 hGL 细胞作为研究模型，我们提供了第一个数据，表明 TGF-β1 通过上调这些细胞中透明质酸合酶 2 的表达，显著促进了透明质酸的合成。此外，通过双重抑制方法，我们表明 TGF-β 型 II（TβRII）受体和 TGF-β 型 I（ALK5）受体是功能性受体，可介导对 TGF-β1 的刺激作用。此外，我们发现经典的 SMAD2/SMAD3-SMAD4 信号通路是上调透明质酸合酶表达和随后透明质酸合成的主要细胞内信号通路。值得注意的是，我们表明 SNAIL 转录因子是介导 TGF-β信号的关键分子，有助于增加透明质酸的合成。这些体外研究结果表明，卵巢内的 TGF-β1 在 hGL 细胞中透明质酸合成的局部调节中发挥功能作用。
