Dysregulation of Decidual NK Cell Proliferation by Impaired Decidual Cells: A Potential Contributor to Excessive Trophoblast Invasion in Placenta Accreta Spectrum

Background Abnormal interactions among decidual cells, decidual natural killer (dNK) cells, and trophoblasts are implicated in contributing to the placenta accreta spectrum (PAS). However, the specific details of these interactions remain unclear. Methods Normal human placental maternal decidua-mesenchymal stem cells (MD-MSCs) and pathological MD-MSCs from PAS patients (PAs) were isolated and cultured in serum-free conditions. Decidualization was induced using hormonal cocktails: estradiol (E2)/ progesterone (P4) and chemical agents 8-br-cAMP/ medroxyprogesterone acetate (MPA) for both MD-MSCs and PAs. dNK-like cells were generated from peripheral natural killer (pNK) cells through MD-MSCs induction. Interactions among decidual cells, dNK cells, and trophoblasts were studied using a transwell co-culture system. Bulk RNA-seq analysis was performed to identify differential genes between MD-MSCs and PAs and explored their potential role in immune tolerance regulation of decidual NK cells and trophoblast invasion. Results This study aims to explore the correlation between defective decidualization of endometrial stromal cells and dysregulated dNK cell proliferation, leading to excessive trophoblast invasion and the development of PAS. Decidualization defects were confirmed in PAs, characterized by reduced morphological changes and altered expression levels of decidual biomarkers at both mRNA and protein levels, potentially associated with overexpression of estrogen receptor (ER). Furthermore, both PAs and normal MD-MSCs exhibited similar patterns in regulating trophoblast invasion, suggesting an indirect impact of impaired decidual cells on trophoblast behavior. Interestingly, decidualized MD-MSCs (De-MD-MSCs) showed the potential to induce conversion of pNK cells into dNK-like cells, which displayed reduced cytotoxicity on trophoblasts and enhanced KIR2DL4 expression, possibly through upregulated Csf3 , Il1β , and Tgfb1 . Additionally, dNK-like cells exhibited increased proliferation when co-cultured with PAs, regulated by Cxcl12 , Il33 , Tgfb1 , Vegfa , and Vegfc , enhancing trophoblast invasion and spiral artery remodeling. Conditioned medium derived from PAs-induced dNK-like cells demonstrated a higher capacity to promote trophoblast invasion in a dose-dependent manner. Conclusion Abnormal proliferation of dNK cells induced by impaired decidual cells may contribute to the pathogenesis of PAS, providing valuable insights into its mechanisms and potential therapeutic interventions.