Abstract
Decidual NK (dNK) cells, a distinct type of NK cell, are thought to regulate uterine spiral artery remodeling, a process that allows for increased blood delivery to the fetal-placental unit. Impairment of uterine spiral artery remodeling is associated with decreased placental perfusion, increased uterine artery resistance, and obstetric complications such as preeclampsia and intrauterine growth restriction. Ex vivo manipulation of human peripheral blood NK (pNK) cells by a combination of hypoxia, TGFß-1 and 5-aza-2’-deoxycytidine yields cells with phenotypic and in vitro functional similarities to dNK cells, called idNK cells. Here, gene expression profiling shows that CD56Bright idNK cells derived ex vivo from human pNK cells, and to a lesser extent CD56Dim idNK cells, are enriched in the gene expression signature that distinguishes dNK cells from pNK cells. When injected into immunocompromised pregnant mice with elevated uterine artery resistance, idNK cells homed to the uterus and reduced the uterine artery resistance index, suggesting improved placental perfusion.
Highlights
Abnormal placentation sets the stage for the development of pregnancy complications that may present with devastating maternal and fetal outcomes
CD56Bright idNK cells express a panel of molecules and chemokine receptors in a pattern similar to Decidual Natural killer (NK) (dNK) cells and distinct from CD56Bright peripheral blood NK (pNK) as evaluated by flow cytometry
Conversion of pNK cells to idNK cells is marked by the acquisition of CD9 and Killer cell Immunoglobulin-like Receptors (KIRs) expression[36], only CD9+ KIR+ cells were collected from the CD56Bright idNK and CD56Dim idNK cell populations for gene expression profiling (Fig 2A)
Summary
Abnormal placentation sets the stage for the development of pregnancy complications that may present with devastating maternal and fetal outcomes. Defective spiral artery remodeling leads to decreased placental perfusion and has been associated with pregnancy complications such as preeclampsia, intrauterine growth restriction (IUGR), and miscarriages [18,19,20] These pathological conditions lead to significant maternal and fetal morbidity and mortality [21,22] and to date, there are no effective treatments. Rag2-/-γc-/- mice do not present with hypertension or growth restriction as noted in severe preeclampsia [21,32,33], they constitute a representative model to examine the early stages of preeclampsia development Because these immunodeficient mice are good recipients for xenogeneic cells, they are a good model to test the ability of human cells to remodel uterine spiral arteries. That differentiates dNK and pNK cells, and that idNK cell injection into pregnant immunocompromised mice reduces uterine artery resistance
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