Repository logo

Human uterine natural killer cells regulate differentiation of extravillous trophoblast early in pregnancy.

Accepted version



Change log


Li, Qian 
Sharkey, Andrew 
Sheridan, Megan 
Magistrati, Elisa 
Arutyunyan, Anna 


In humans, balanced invasion of trophoblast cells into the uterine mucosa, the decidua, is critical for successful pregnancy. Evidence suggests that this process is regulated by uterine natural killer (uNK) cells, but how they influence reproductive outcomes is unclear. Here, we used our trophoblast organoids and primary tissue samples to determine how uNK cells affect placentation. By locating potential interaction axes between trophoblast and uNK cells using single-cell transcriptomics and in vitro modeling of these interactions in organoids, we identify a uNK cell-derived cytokine signal that promotes trophoblast differentiation at the late stage of the invasive pathway. Moreover, it affects transcriptional programs involved in regulating blood flow, nutrients, and inflammatory and adaptive immune responses, as well as gene signatures associated with disorders of pregnancy such as pre-eclampsia. Our findings suggest mechanisms on how optimal immunological interactions between uNK cells and trophoblast enhance reproductive success.



KIR-HLA-C interactions, cytokines, extravillous trophoblast, human pregnancy, organoids, placentation, pre-eclampsia, reproductive disorders, single-cell RNA sequencing, uterine natural killer cells, Pregnancy, Female, Humans, Extravillous Trophoblasts, Uterus, Placentation, Trophoblasts, Killer Cells, Natural

Journal Title

Cell Stem Cell

Conference Name

Journal ISSN


Volume Title


Elsevier BV
Wellcome Trust (101602/Z/13/Z)
Medical Research Council (MR/P001092/1)
Wellcome Trust (200841/Z/16/Z)
European Commission (629785)
Wellcome Trust (204464/Z/16/Z)
European Commission Horizon 2020 (H2020) ERC (853546)
EU Horizon 2020