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

作　　者：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 

机构地区：[1]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 [2]Beijing Institute for Stem Cell and Regenerative Medicine,Beijing 100101,China [3]University of the Chinese Academy of Sciences,Beijing 101408,China [4]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 [5]National Clinical Center for Obstetrics and Gynecology,Peking University Third Hospital,Beijing 100191,China [6]Department of Family Planning,The Second Hospital of Tianjin Medical University,Tianjin 300211,China [7]Department of Prenatal Screening,Haidian Maternal and Child Health Hospital,Beijing 100080,China

出　　处：《National Science Review》2024年第6期122-138,共17页国家科学评论（英文版）

基　　金：supported by grants from the National Key Research and Development Program of China(2022YFC2702400,2021YFC2700303,2022YFC2702500 and2022YFA1103601);the National Natural Science Foundation of China(82192872).

摘　　要：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-2Rγ^(null))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.

关 键 词：recurrent pregnancy loss CD56^(+)CD39^(+)dNK subset NOG mice adoptive transfer placental trophoblast cell fate M-CSF 

分 类 号：R329.2[医药卫生—人体解剖和组织胚胎学]