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

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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.

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All data generated or analyzed during this study are included in this published article and its supplementary information files.

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Abbreviations

α-KG:

α-Ketoglutarate

ACTB:

β-Actin

BPTES:

Inhibitor of glutaminase

dNK:

Decidual NK cells

DIC:

Decidual immune cells

DMKG:

Dimethyl alpha-ketoglutarate

DMOG:

Dimethyloxallyl glycine, inhibitor of HIF prolyl-hydroxylase

DSC:

Decidual stromal cells

eNK:

Endometrial NK cells

EGCG:

Epigallocatechin gallate sulfate, inhibitor of glutamate dehydrogenase

EGLN1:

Egl nine homolog 1

EP300:

E1A binding protein p300

ESC:

Endometrial stromal cells

ESR1:

Estrogen receptor 1

FGF-19:

Fibroblast growth factor-19

GABA:

γ-Aminobutyric acid

GDF15:

Growth differentiation factor-15

GLS:

Glutaminase

GLUD:

Glutamate dehydrogenase

HIF-1α:

Hypoxia inducible factor-1α

IGF1:

Insulin-like growth factor-1

IUGR:

Intrauterine growth restriction

OXPHOS:

Oxidative phosphorylation

PBMC:

Peripheral blood mononuclear cells

pNK:

Peripheral NK cells

TCA:

Tricarboxylic acid

TET:

Ten-eleven translocation methylcytosine dioxygenase

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Acknowledgements

We are grateful to Prof. Shi-Min Zhao from Institute of Metabolism and Integrative Biology (IMIB), School of Life Sciences, Fudan University, for guidance and help. This study supported by the National Natural Science Foundation of China (NSFC) (No. 92057119, 31970798, 32070915), the National Key Research and Development Program of China (2017YFC1001404), the Program for Zhuoxue of Fudan University (JIF157602), the Support Project for Original Personalized Research of Fudan University, and the Yantai Science and Technology Innovation Plan (2021XDHZ082).

Funding

Funding was provided by National Natural Science Foundation of China (92057119, 31970798, 32070915), National Key Research and Development Program of China (2017YFC1001404), Program for Zhuoxue of Fudan University (JIF157602), Support Project for Original Personalized Research of Fudan University, Yantai Science and Technology Innovation Plan (2021XDHZ082).

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Author notes

  1. Shao-Liang Yang and Hai-Xia Tan contributed equally.

Authors and Affiliations

  1. Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, China

    Shao-Liang Yang, Zhen-Zhen Lai, Hui-Li Yang, Da-Jin Li & Ming-Qing Li

  2. Department of Gynecology of Integrated Traditional Chinese and Western Medicine, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, China

    Shao-Liang Yang & Hai-Yan Wang

  3. Department of Obstetrics and Gynecology, Zhangye People’s Hospital of HeXi College, Zhangye, Gansu, China

    Hai-Xia Tan

  4. Department of Gynecology and Obstetrics, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China

    Hai-Yan Peng

  5. School of Pharmacy, Binzhou Medical University, Yantai, Shandong, China

    Qiang Fu

  6. Key Laboratory of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Fudan University, Shanghai, China

    Da-Jin Li & Ming-Qing Li

  7. Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, China

    Ming-Qing Li

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Contributions

SLY and HXT conducted all experiments and prepared the figures and the manuscript. ZZL, HYP and HLY assisted with cell sorting, in vivo experiments, prepared the figures and the manuscript. QF edited the manuscript. MQL, DJL and HYW initiated and supervised the project and edited the manuscript. All the authors were involved in writing the manuscript.

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Correspondence to Hai-Yan Wang, Da-Jin Li or Ming-Qing Li.

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Yang, SL., Tan, HX., Lai, ZZ. et al. An active glutamine/α-ketoglutarate/HIF-1α axis prevents pregnancy loss by triggering decidual IGF1+GDF15+NK cell differentiation. Cell. Mol. Life Sci. 79, 611 (2022). https://doi.org/10.1007/s00018-022-04639-x

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