ORIGINAL RESEARCH article
Front. Cell Dev. Biol.
Sec. Stem Cell Research
Volume 13 - 2025 | doi: 10.3389/fcell.2025.1618461
This article is part of the Research TopicAdvancements in Stem Cell Differentiation and Disease ApplicationsView all 7 articles
Dysregulation of Decidual NK Cell Proliferation by Impaired Decidual Cells: A Potential Contributor to Excessive Trophoblast Invasion in Placenta Accreta Spectrum Authors
Provisionally accepted
- 1Department and Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan
- 2Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei, Taiwan
- 3VitaSpring Biomedical Co. Ltd., USA, New Taipei, Taiwan
- 4MediDiamond Inc., Taiwan, Taipei, Taiwan
- 5LuminX Biotech Co. Ltd., Taiwan, Taipei, Taiwan
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Aberrant interactions among decidual stromal cells, decidual natural killer (dNK) cells, and trophoblasts are implicated in placenta accreta spectrum (PAS) pathogenesis, though the underlying mechanisms remain unclear. This study investigates the relationship between defective decidualization of endometrial stromal cells and dysregulated dNK cell proliferation, which may contribute to excessive trophoblast invasion and the development of PAS. We established an in vitro system that mimics the decidual microenvironment to investigate these interactions. Maternal decidua-derived mesenchymal stem cells (MD-MSCs) from healthy pregnancies and PAS patients (PA-MSCs) were isolated and induced to undergo decidualization using hormonal and chemical stimuli. Peripheral natural killer (pNK) cells were then co-cultured with these MSCs to generate dNK-like cells. Cellular interactions among MSCs, dNK-like cells, and trophoblasts were evaluated using an in vitro co-culture system. Decidualization defects in PA-MSCs were marked by reduced morphological changes and dysregulated expression of decidual markers, potentially associated with estrogen receptor (ER) overexpression. Furthermore, both PA-MSCs and normal MD-MSCs similarly regulated 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 the conversion of pNK cells into dNK-like cells, which displayed reduced cytotoxicity on trophoblasts and elevated KIR2DL4 expression. These dNK-like cells exhibited increased proliferation when co-cultured with PA-MSCs, enhancing trophoblast invasion and spiral artery remodeling. Conditioned medium derived from PA-MSCs-induced dNK-like cells demonstrated a higher capacity to promote trophoblast invasion in a dosedependent manner. The 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.
Keywords: decidualization, Placenta accreta spectrum (PAS), trophoblast invasion, decidual natural killer cell, Immune tolerace
Received: 26 Apr 2025; Accepted: 27 Jun 2025.
Copyright: © 2025 Liu, Shih, Wu, Lin and Ling. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Hsin-Hung Lin, Department and Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, 10051, Taiwan
Thai-Yen Ling, Department and Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, 10051, Taiwan
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