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bioRxiv · 10.64898/2026.03.25.714293

Hormonal stimulation induces broader decidualization responses than cAMP alone in 3D human endometrial organoids

Liu, S.·Zhang, J.·Zhan, T.·Zhang, Q.·Douglas, N.·Ye, X.·Xiao, S.
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Abstract

The human endometrium undergoes cyclic, hormone-driven remodeling that establishes a transient window of receptivity required for embryo implantation, placentation, and maintenance of pregnancy. Decidualization of endometrial stromal cells is a central component of this process and can be induced in vitro using cAMP alone or in combination with ovarian steroid hormones (EPC: estradiol, progesterone, and cAMP). Although cAMP activates the core decidual transcriptional program, whether hormone supplementation induces a more physiologically relevant response remains unclear, particularly in 3D endometrial organoid (Endo-organoid) models which have emerged as a new alternative methodology (NAM). Here, we compared morphological and transcriptomic responses of human endometrial stromal cell-derived Endo-organoids undergoing decidualization induced by cAMP or EPC stimulation. EPC-treated Endo-organoids exhibited enhanced structural remodeling and more advanced morphological transformation compared with cAMP-treated organoids. RNA-seq analysis revealed substantial overlap in canonical decidual gene expression between the two conditions, but EPC induced broader transcriptional and pathway-level changes, including enrichment of metabolic, stress-response, and differentiation-related processes. Together, these findings demonstrate that while cAMP activates the core decidual program, EPC elicits a broader and more physiologically relevant decidualization response in 3D human Endo-organoids, providing guidance for optimizing Endo-organoids to study endometrial receptivity, implantation, and early pregnancy success.

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Liu, S., Zhang, J., Zhan, T., Zhang, Q., Douglas, N., Ye, X., Xiao, S.. 2026-03-28. Hormonal stimulation induces broader decidualization responses than cAMP alone in 3D human endometrial organoids. https://doi.org/10.64898/2026.03.25.714293

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