Department of Animal Genetics, Breeding and Reproduction, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China.
J Agric Food Chem. 2024 Oct 2;72(39):21635-21649. doi: 10.1021/acs.jafc.4c06178. Epub 2024 Sep 18.
Follicle development, a crucial process in reproductive biology, hinges upon the dynamic proliferation of granulosa cells (GCs). Growth differentiation factor-8 (GDF8) is well-known as myostatin for inhibiting skeletal muscle growth, and it also exists in ovarian GCs and follicle fluid. However, the relationship between GCs proliferation and GDF8 remains elusive. Sulforaphane (SFN) is a potent bioactive compound, which in our study has been demonstrated to induce the expression of GDF8 in GCs. Meanwhile, we discover a novel role of SFN in promoting the proliferation of porcine GCs. Specifically, SFN enhances GCs proliferation by accelerating the progression of the cell cycle through the G1 phase to the S phase. By performing gene expression profiling, we showed that the promoting proliferative effects of SFN are highly correlated with the TGF-β signaling pathways and cell cycle. Among the ligand factors of TGF-β signaling, we identify GDF8 as a critical downstream effector of SFN, which acts through ALK5 to mediate SFN-induced proliferation and G1/S transition. In addition, we identify a noncanonical downstream pathway by which GDF8 induces the activation of MAPK/ERK to facilitate the cell cycle progression in GCs. Moreover, we reveal that the expression of GDF8 is regulated by SFN through epigenetic modifications of H3K27 acetylation. These findings not only provide mechanistic insights into the regulation of GCs proliferation but also establish a previously unrecognized role of GDF8 in follicle development, which have significant implications for developing strategies to improve female fertility.
卵泡发育是生殖生物学中的一个关键过程，依赖于颗粒细胞（GCs）的动态增殖。生长分化因子 8（GDF8）作为抑制骨骼肌生长的肌肉生长抑制素而闻名，它也存在于卵巢 GCs 和卵泡液中。然而，GCs 增殖与 GDF8 之间的关系仍然难以捉摸。萝卜硫素（SFN）是一种有效的生物活性化合物，在我们的研究中已被证明可以诱导 GCs 中 GDF8 的表达。同时，我们发现 SFN 在促进猪 GCs 增殖方面具有新的作用。具体而言，SFN 通过加速细胞周期从 G1 期到 S 期的进程来增强 GCs 的增殖。通过进行基因表达谱分析，我们表明 SFN 的促进增殖作用与 TGF-β 信号通路和细胞周期高度相关。在 TGF-β 信号通路的配体因子中，我们确定 GDF8 是 SFN 的关键下游效应因子，它通过 ALK5 介导 SFN 诱导的增殖和 G1/S 期转换。此外，我们确定了 GDF8 通过 MAPK/ERK 的非经典下游途径诱导激活，以促进 GCs 中的细胞周期进程。此外，我们揭示了 GDF8 的表达受 SFN 通过 H3K27 乙酰化的表观遗传修饰调节。这些发现不仅为 GCs 增殖的调控提供了机制见解，而且确立了 GDF8 在卵泡发育中的先前未被认识的作用，这对于开发提高女性生育力的策略具有重要意义。
