2. Academic Validation
  3. An active glutamine/α-ketoglutarate/HIF-1α axis prevents pregnancy loss by triggering decidual IGF1+GDF15+NK cell differentiation

An active glutamine/α-ketoglutarate/HIF-1α axis prevents pregnancy loss by triggering decidual IGF1+GDF15+NK cell differentiation

  • Cell Mol Life Sci. 2022 Nov 30;79(12):611. doi: 10.1007/s00018-022-04639-x.
Shao-Liang Yang # 1 2,  Hai-Xia Tan # 3,  Zhen-Zhen Lai 1,  Hai-Yan Peng 4,  Hui-Li Yang 1,  Qiang Fu 5,  Hai-Yan Wang 6,  Da-Jin Li 7 8,  Ming-Qing Li 9 10 11
Affiliations

Affiliations

  • 1 Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, China.
  • 2 Department of Gynecology of Integrated Traditional Chinese and Western Medicine, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, China.
  • 3 Department of Obstetrics and Gynecology, Zhangye People's Hospital of HeXi College, Zhangye, Gansu, China.
  • 4 Department of Gynecology and Obstetrics, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China.
  • 5 School of Pharmacy, Binzhou Medical University, Yantai, Shandong, China.
  • 6 Department of Gynecology of Integrated Traditional Chinese and Western Medicine, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, China. [email protected].
  • 7 Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, China. [email protected].
  • 8 Key Laboratory of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Fudan University, Shanghai, China. [email protected].
  • 9 Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, China. [email protected].
  • 10 Key Laboratory of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Fudan University, Shanghai, China. [email protected].
  • 11 Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 36449080 DOI: 10.1007/s00018-022-04639-x
Abstract

Deficiency of decidual NK (dNK) cell number and function has been widely regarded as an important cause of spontaneous abortion. However, the metabolic mechanism underlying the crosstalk between dNK cells and embryonic trophoblasts during early pregnancy remains largely unknown. Here, we observed that enriched glutamine and activated glutaminolysis in dNK cells contribute to trophoblast invasion and embryo growth by insulin-like growth factor-1 (IGF-1) and growth differentiation factor-15 (GDF-15) secretion. Mechanistically, these processes are dependent on the downregulation of EGLN1-HIF-1α mediated by α-ketoglutarate (α-KG). Blocking glutaminolysis with the GLS inhibitor BPTES or the glutamate dehydrogenase inhibitor EGCG leads to early embryo implantation failure, spontaneous abortion and/or fetal growth restriction in pregnant mice with impaired trophoblast invasion. Additionally, α-KG supplementation significantly alleviated pregnancy loss mediated by defective glutaminolysis in vivo, suggesting that inactivated glutamine/α-ketoglutarate metabolism in dNK cells impaired trophoblast invasion and induced pregnancy loss.

Keywords

Decidual NK cells; GDF-15; Glutamine metabolism; IGF-1; Spontaneous abortion; α-Ketoglutarate.

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