Dual Regulation of Natural Killer Cells by the Decidualization Milieu: Stromal Cell-Independent and Stromal Cell-Dependent Mechanisms Publisher Pubmed



Vanaki N ; Tavangar B ; Darzi M ; Mirzadegan E ; Aghazadeh Z ; Shokri F ; Zarnani A H
Source: Reproduction Published:2026

Abstract

In brief: In brief Decidualization of endometrial stromal cells is essential for embryo implantation and modulates endometrial immunity, ­especially natural killer cells, while the potential of menstrual blood stromal cells is unclear. This study shows that decidualization reshapes the immunomodulatory effects of endometrial stromal cells and menstrual blood stromal cells, shifting peripheral natural killer cells to a pregnancy-supportive phenotype, advancing knowledge in reproductive immunology. Decidualization of endometrial stromal cells (EnSCs) is essential for implantation in part by modulating the endometrial ­immune network. Although menstrual blood-derived stromal cells (MenSCs) are considered as EnSC surrogates, little is known about their impact on regulation of the endometrial immune system. Here, we compared how decidualization affects the ability of EnSCs and MenSCs to modulate natural killer (NK) cells. EnSCs and MenSCs were isolated and those cell sources with good decidualization capacity were selected. The expression of HLA-ABC and HLA-DR before and after decidualization was assessed. The impact of EnSCs and MenSCs, either in the presence or absence of the decidualization cocktail, on NK cell markers, and NK cell-mediated cytotoxicity against EnSCs, MenSCs, and K562 cells, was evaluated. IFN-γ pretreatment and decidualization increased HLA-ABC expression in MenSCs. Decidualization in both EnSCs and MenSCs led to a marked reduction in the expression CD16 and NKG2D while increasing CD9+ and CD56bright NK cell frequency. Decidualization, caused a significant decrease in the perforin and IFN-γ levels of NK cells and significantly diminished NK cell cytotoxicity toward K562 cells. We observed that certain aspects of NK cells are modulated solely by the decidualization cocktail, while other aspects are actively regulated by stromal cells beyond the cocktail’s effects. This study demonstrates that the immunoregulatory functions of EnSCs and MenSCs are profoundly altered by the decidualization milieu, with certain aspects being further modulated through direct involvement of the stromal cells themselves. © The Author(s) 2026. Published by Oxford University Press on behalf of the Society for Reproduction and Fertility. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/pages/standard-publication-reuse-rights)