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HMGB1 Modulates Decidualization Through PGC1α and Mitochondrial Bioenergetics

ABSTRACT: Endometrial decidualization is pivotal for embryo implantation and pregnancy. This study explores the role of HMGB1 in endometrial stromal cells (hESCs) during decidualization. We found that HMGB1 expression increased during decidualization in normal tissues but decreased in recurrent spontaneous abortion (RSA) cases. HMGB1 knockdown in hESCs disrupted decidualization by impairing cell differentiation, reducing the expression of prolactin (PRL) and IGFBP1, and increasing abnormal cell proliferation. RNA-seq identified 1,838 differentially expressed genes, among which multiple genes involved in mitotic cell division, reproductive process and oxidative phosphorylation. Mitochondrial dysfunction was evident, with reduced oxidative phosphorylation, ATP production, and mitochondrial fission/fusion balance in HMGB1-deficient cells. CUT&RUN analysis revealed that HMGB1 binds to the PGC1α promoter, a key regulator of mitochondrial biogenesis, suggesting that HMGB1 controls cellular bioenergetics. Finally, PGC1α downregulation in RSA decidua implies that HMGB1 exerts its effects on decidualization through mitochondrial regulation. These findings highlight HMGB1’s critical role in orchestrating mitochondrial function and cellular energy homeostasis during decidualization, offering new insights into the molecular mechanisms behind decidual dysfunction and pregnancy disorders.

ORGANISM(S): Homo sapiens

PROVIDER: GSE279402 | GEO | 2025/10/01

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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HMGB1 Modulates Decidualization Through PGC1α and Mitochondrial Bioenergetics

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