Amino Acid Restriction Impairs Human Endometrial Stromal Cell Decidualization and Is Rescued by Proline Supplementation

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.