首页|Human CD56+CD39+dNK cells support fetal survival through controlling trophoblastic cell fate:immune mechanisms of recurrent early pregnancy loss

Human CD56+CD39+dNK cells support fetal survival through controlling trophoblastic cell fate:immune mechanisms of recurrent early pregnancy loss

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Decidual natural killer(dNK)cells are the most abundant immune cells at the maternal-fetal interface during early pregnancy in both mice and humans,and emerging single-cell transcriptomic studies have uncovered various human dNK subsets that are disrupted in patients experiencing recurrent early pregnancy loss(RPL)at early gestational stage,suggesting a connection between abnormal proportions or characteristics of dNK subsets and RPL pathogenesis.However,the functional mechanisms underlying this association remain unclear.Here,we established a mouse model by adoptively transferring human dNK cells into pregnant NOG(NOD/Shi-scid/IL-2Rynul1)mice,where human dNK cells predominantly homed into the uteri of recipients.Using this model,we observed a strong correlation between the properties of human dNK cells and pregnancy outcome.The transfer of dNK cells from RPL patients(dNK-RPL)remarkably worsened early pregnancy loss and impaired placental trophoblast cell differentiation in the recipients.These adverse effects were effectively reversed by transferring CD56+CD39+dNK cells.Mechanistic studies revealed that CD56+CD39+dNK subset facilitates early differentiation of mouse trophoblast stem cells(mTSCs)towards both invasive and syncytial pathways through secreting macrophage colony-stimulating factor(M-CSF).Administration of recombinant M-CSF to NOG mice transferred with dNK-RPL efficiently rescued the exacerbated pregnancy outcomes and fetal/placental development.Collectively,this study established a novel humanized mouse model featuring functional human dNK cells homing into the uteri of recipients and uncovered the pivotal role of M-CSF in fetal-supporting function of CD56+CD39+dNK cells during early pregnancy,highlighting that M-CSF may be a previously unappreciated therapeutic target for intervening RPL.

recurrent pregnancy lossCD56+CD39+dNK subsetNOG miceadoptive transferplacental trophoblast cell fateM-CSF

Wentong Jia、Liyang Ma、Xin Yu、Feiyang Wang、Qian Yang、Xiaoye Wang、Mengjie Fan、Yan Gu、Ran Meng、Jian Wang、Yuxia Li、Rong Li、Xuan Shao、Yan-Ling Wang

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State Key Laboratory of Stem cell and Reproductive Biology,Key Laboratory of Organ Regeneration and Reconstruction,Institute of Zoology,Chinese Academy of Sciences,Beijing 100101,China

Beijing Institute for Stem Cell and Regenerative Medicine,Beijing 100101,China

University of the Chinese Academy of Sciences,Beijing 101408,China

NHC Key Lab of Reproduction Regulation,Shanghai Engineering Research Center of Reproductive Health Drug and Devices,Shanghai Institute for Biomedical and Pharmaceutical Technologies,Shanghai 200237,China

National Clinical Center for Obstetrics and Gynecology,Peking University Third Hospital,Beijing 100191,China

Department of Family Planning,The Second Hospital of Tianjin Medical University,Tianjin 300211,China

Department of Prenatal Screening,Haidian Maternal and Child Health Hospital,Beijing 100080,China

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National Key Research and Development Program of ChinaNational Key Research and Development Program of ChinaNational Key Research and Development Program of ChinaNational Key Research and Development Program of ChinaNational Natural Science Foundation of China

2022YFC27024002021YFC27003032022YFC27025002022YFA110360182192872

2024

10.1093/nsr/nwae142

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ISSN：
年,卷(期)：2024.11(6)
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