2. Academic Validation
  3. TNFSF14+ natural killer cells prevent spontaneous abortion by restricting leucine-mediated decidual stromal cell senescence

TNFSF14+ natural killer cells prevent spontaneous abortion by restricting leucine-mediated decidual stromal cell senescence

  • EMBO J. 2024 Sep 11. doi: 10.1038/s44318-024-00220-3.
Jia-Wei Shi 1 2 3,  Zhen-Zhen Lai 2,  Wen-Jie Zhou 4,  Hui-Li Yang 2,  Tao Zhang 5,  Jian-Song Sun 6,  Jian-Yuan Zhao 7,  Ming-Qing Li 8 9 10
Affiliations

Affiliations

  • 1 Department of Reproductive Immunology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, People's Republic of China.
  • 2 Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Shanghai Medical School, Fudan University, Shanghai, 200080, People's Republic of China.
  • 3 Department of Obstetrics and Gynecology, The first affiliated Hospital of Ningbo University, Ningbo, 315021, People's Republic of China.
  • 4 Reproductive Medical Center, Department of Obstetrics and Gynecology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China.
  • 5 Assisted Reproductive Technology Unit, Department of Obstetrics and Gynecology, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, People's Republic of China.
  • 6 School of Life Science and Health Engineering, Jiangnan University, Wuxi, 214122, People's Republic of China.
  • 7 Institute for Developmental and Regenerative Cardiovascular Medicine, MOE-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, People's Republic of China. zhaojianyuan1508@xinhuamed.com.cn.
  • 8 Department of Reproductive Immunology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, People's Republic of China. mqli@sjtu.edu.cn.
  • 9 Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Shanghai Medical School, Fudan University, Shanghai, 200080, People's Republic of China. mqli@sjtu.edu.cn.
  • 10 Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, People's Republic of China. mqli@sjtu.edu.cn.
PMID: 39261664 DOI: 10.1038/s44318-024-00220-3
Abstract

In preparation for a potential pregnancy, the endometrium of the uterus changes into a temporary structure called the decidua. Senescent decidual stromal cells (DSCs) are enriched in the decidua during decidualization, but the underlying mechanisms of this process remain unclear. Here, we performed single-cell RNA transcriptomics on ESCs and DSCs and found that cell senescence during decidualization is accompanied by increased levels of the branched-chain amino acid (BCAA) transporter SLC3A2. Depletion of leucine, one of the branched-chain Amino acids, from cultured media decreased senescence, while high leucine diet resulted in increased senescence and high rates of embryo loss in mice. BCAAs induced senescence in DSCs via the p38 MAPK pathway. In contrast, TNFSF14+ decidual natural killer (dNK) cells were found to inhibit DSC senescence by interacting with its ligand TNFRSF14. As in mice fed high-leucine diets, both mice with NK cell depletion and Tnfrsf14-deficient mice with excessive uterine senescence experienced adverse pregnancy outcomes. Further, we found excessive uterine senescence, SLC3A2-mediated BCAA intake, and insufficient TNFRSF14 expression in the decidua of patients with recurrent spontaneous abortion. In summary, this study suggests that dNK cells maintain senescence homeostasis of DSCs via TNFSF14/TNFRSF14, providing a potential therapeutic strategy to prevent DSC senescence-associated spontaneous abortion.

Keywords

Abortion; Aging; Decidualization; Leucine; TNFRSF14.

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