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Effects of Amino Acid Restriction on Decidualization of Human Endometrial Stromal Cells

ABSTRACT: This study aimed to evaluate the effects of amino acid restriction, as mimicked by Halofuginone (HF), and amino acid supplementation on decidualization of human endometrial stromal cells (HESCs). When HESCs were exposed to decidualization agents, distinct morphological changes and increased insulin-like growth factor binding protein 1 (IGFBP-1) production were observed, indicative of successful decidualization. HF treatment inhibited IGFBP-1 secretion and expression of key decidualization markers in a dose-dependent manner. Supplementation with proline, but not leucine, rescued the inhibitory effects of HF on decidualization of HESCs. RNA-sequencing analysis revealed that several growth factors crucial for decidualization were inhibited by HF, suggesting their sensitivity to amino acid availability. HF disrupted transforming growth factor β (TGFβ)-SMAD signaling, which was restored by proline supplementation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE294481 | GEO | 2025/09/24

REPOSITORIES: GEO

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Project description:Decidualization of human endometrial stromal cells (hESCs), a critical process for embryo implantation and successful pregnancy, begins during the secretory phase of the menstrual cycle. We evaluated 25 established in vitro decidualization markers in hESCs using in vivo single-cell transcriptomic data. Most markers, including PRL and IGFBP1, did not reliably distinguish between proliferative and secretory phase hESCs, nor between decidualized and non-decidualized hESCs. Only 8 genes (STAT3, CEBPB, WNT4, IL-15, TIMP3, HAND2, FOXO1 and MMP19) showed differential expression between the menstrual phase and decidualization status in vivo. We hypothesized that the difference between in vitro and in vivo marker expression might result from the absence of endometrial glands in the in vitro decidualization model. While endometrial glands are known to secrete factors critical for uterine receptivity, their specific role in decidualization is not well understood. To investigate this, we examined the influence of the glandular secretome on ESC decidualization using an in vitro co-culture model of human endometrial organoids (hEOs) and hESCs. Decidualization was induced in hESCs, and the effects of hEO co-culture or exposure to hEO secretome were assessed by morphological analysis, molecular marker expression, and transcriptomic profiling. Unexpectedly, both hEO co-culture and exposure to the hEO secretome significantly reduce the up-regulation of canonical decidualization markers and the mesenchymal-epithelial transition typically induced during hESC decidualization. Transcriptomic analysis further revealed downregulation of decidualization regulators, CEBPA and EDN1, in ESCs exposed to the hEO secretome compared to decidualized controls. These findings were corroborated in an estradiol-stimulated mouse model, where increased endometrial gland formation correlated with reduced decidualization and lower expression of CEBPA and EDN1. Collectively, our results reveal a previously unrecognized homeostatic role for the endometrial gland secretome in regulating ESC decidualization. These insights highlight the limitations of current in vitro decidualization models and underscore the importance of glandular-stromal interactions in endometrial function and reproductive health.

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Effects of Amino Acid Restriction on Decidualization of Human Endometrial Stromal Cells

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