Jang Chloe, Iosef Cristiana, Renaud Stephen J, Han Victor K M
Department of Biochemistry, Western University, London, Canada.
Department of Anatomy and Cell Biology, Western University, London, Canada.
J Cell Mol Med. 2025 Sep;29(18):e70821. doi: 10.1111/jcmm.70821.
Decidualization is a critical process for successful pregnancy. It is characterised by the transformation of endometrial stromal cells into decidual cells that support embryo implantation and placental development. Maternal amino acid deficiency is linked to impaired decidualization, which can lead to pregnancy complications such as miscarriage, preeclampsia and fetal growth restriction. Halofuginone (HF), a synthetic alkaloid, induces nutritional stress by triggering the amino acid starvation response. This study investigated the effects of HF-induced nutritional stress and amino acid supplementation on decidualization of human endometrial stromal cells (HESCs). Exposure of HESCs to decidualization agents caused distinct morphological changes and expression of insulin-like growth factor binding protein-1 (IGFBP-1), indicative of successful decidualization. Treatment of HESCs with HF or leucine-deprived media inhibited the expression of key decidualization markers. Interestingly, supplementation with proline, but not leucine, rescued the inhibitory effects of HF on decidualization of HESCs. HF inhibited the expression of genes encoding growth factors crucial for decidualization, highlighting their sensitivity to amino acid availability, and disrupted transforming growth factor β-SMAD signalling, which was restored by proline supplementation. These findings highlight the essential role of amino acids, particularly proline, for proper decidualization and suggest potential therapeutic strategies for improved reproductive health.
蜕膜化是成功妊娠的关键过程。其特征在于子宫内膜基质细胞转化为支持胚胎着床和胎盘发育的蜕膜细胞。母体氨基酸缺乏与蜕膜化受损有关,这可能导致诸如流产、先兆子痫和胎儿生长受限等妊娠并发症。常山酮(HF)是一种合成生物碱,通过触发氨基酸饥饿反应诱导营养应激。本研究调查了HF诱导的营养应激和氨基酸补充对人子宫内膜基质细胞(HESC)蜕膜化的影响。将HESC暴露于蜕膜化剂会引起明显的形态变化和胰岛素样生长因子结合蛋白-1(IGFBP-1)的表达,这表明蜕膜化成功。用HF或亮氨酸缺乏的培养基处理HESC会抑制关键蜕膜化标志物的表达。有趣的是,补充脯氨酸而非亮氨酸可挽救HF对HESC蜕膜化的抑制作用。HF抑制了对蜕膜化至关重要的生长因子编码基因的表达,突出了它们对氨基酸可用性的敏感性,并破坏了转化生长因子β-SMAD信号通路,脯氨酸补充可恢复该信号通路。这些发现突出了氨基酸尤其是脯氨酸对正常蜕膜化的重要作用,并提出了改善生殖健康的潜在治疗策略。