Natural killer-cell deficiency alters placental development in rats†

Abstract

Natural killer (NK) cells are the most prevalent leukocyte population in the uterus during early pregnancy. Natural killer cells contribute to uterine vascular (spiral artery) remodeling in preparation for the increased demand on these vessels later in pregnancy. A second wave of spiral artery modification is directed by invasive trophoblast cells. The significance of the initial wave of NK-cell-mediated vascular remodeling in species exhibiting deep trophoblast invasion such as humans and rats is not known. The purpose of this study was to generate a genetic model of NK-cell deficiency in rats, and determine the consequences of NK-cell deficiency on spiral artery remodeling and reproductive outcomes. To accomplish this task, we utilized zinc finger nuclease-mediated genome editing of the rat interleukin-15 (Il15) gene. Il15 encodes a cytokine required for NK-cell lineage development. Using this strategy, a founder rat was generated containing a frameshift deletion in Il15. Uteri of females harboring a homozygous mutation at the Il15 locus contained no detectable NK cells. NK-cell deficiency did not impact fetal growth or viability. However, NK-cell deficiency caused major structural changes to the placenta, including expansion of the junctional zone and robust, early-onset activation of invasive trophoblast-guided spiral artery remodeling. In summary, we successfully generated an NK-cell-deficient rat and showed, using this model, that NK cells dampen the extent of trophoblast invasion and delay trophoblast-directed spiral artery remodeling. This study furthers our understanding of the role of NK cells on uterine vascular remodeling, trophoblast invasion, and placental development.

Uterine Natural Killer Cell Heterogeneity: Lessons From Mouse Models

“…In this model, a deficiency in the signaling adaptor molecule Grb2-associated binding protein 3 (Gab3) was important for trNK cell proliferation in response to local cytokine (IL15) stimulation. A similar outcome of dysregulated trophoblast invasion occurs in a rat model of IL15 deficient NK cells (69). These results suggest that defects in trNK cell proliferation lead to interstitial trophoblast hyperinvasion and provide insights into placenta accreta.…”

Evolutionary transcriptomics implicates HAND2 in the origins of implantation and regulation of gestation length

“…In the context of pregnancy, it is important for the recruitment of uterine natural killer (uNK) cells to the endometrium ( Kitaya et al, 2000 ; Verma et al, 2000 ; Ashkar et al, 2003 ; Barber and Pollard, 2003 ; Kitaya et al, 2005 ; Laskarin et al, 2006 ). The roles of uNK cells in the remodeling of uterine spiral arteries and regulating trophoblast invasion are well known ( Zygmunt et al, 1998 ; Hanna et al, 2006 ; Smith et al, 2009b ; Burke et al, 2010 ; Hazan et al, 2010 ; Lash et al, 2010 ; Bany et al, 2012 ; Robson et al, 2012 ; Zhang et al, 2013 ; Lima et al, 2014 ; Fraser et al, 2015 ; Felker and Croy, 2016 ; Renaud et al, 2017 ). Endometrial stromal cell-derived IL15 is also necessary for the selective targeting and clearance of senescent endometrial stromal cells from the implantation site by uNK cells, which is essential for endometrial rejuvenation and remodeling at embryo implantation ( Brighton et al, 2017 ).…”

Advances in Genome Editing and Application to the Generation of Genetically Modified Rat Models

“…NK cells could play a role in placenta generation, and IL-15 KO rats showed an absence of NK cells and several abnormal placental characteristics, supporting a role for NK cells (Renaud et al, 2017).…”