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Maternal obesity drives functional alterations in uterine NK cells
Sofie Perdu, … , Lauren DeLuca, Alexander G. Beristain
Sofie Perdu, … , Lauren DeLuca, Alexander G. Beristain
Published July 21, 2016
Citation Information: JCI Insight. 2016;1(11):e85560. https://doi.org/10.1172/jci.insight.85560.
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Research Article Immunology Reproductive biology

Maternal obesity drives functional alterations in uterine NK cells

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Abstract

Over one-fifth of North American women of childbearing age are obese, putting these women at risk for a variety of detrimental chronic diseases. In addition, obesity increases the risk for developing major complications during pregnancy. The mechanisms by which obesity contributes to pregnancy complications and loss remain unknown. Increasing evidence indicates that obesity results in major changes to adipose tissue immune cell composition and function; whether or not obesity also affects immune function in the uterus has not been explored. Here we investigated the effect of obesity on uterine natural killer (uNK) cells, which are essential for uterine artery remodeling and placental development. Using a cohort of obese or lean women, we found that obesity led to a significant reduction in uNK cell numbers accompanied with impaired uterine artery remodeling. uNK cells isolated from obese women had altered expression of genes and pathways associated with extracellular matrix remodeling and growth factor signaling. Specifically, uNK cells were hyper-responsive to PDGF, resulting in overexpression of decorin. Functionally, decorin strongly inhibited placental development by limiting trophoblast survival. Together, these findings establish a potentially new link between obesity and poor pregnancy outcomes, and indicate that obesity-driven changes to uterine-resident immune cells critically impair placental development.

Authors

Sofie Perdu, Barbara Castellana, Yoona Kim, Kathy Chan, Lauren DeLuca, Alexander G. Beristain

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Figure 2

Maternal obesity is linked with reduced numbers of uterine NK (uNK) cells and delayed artery remodeling.

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Maternal obesity is linked with reduced numbers of uterine NK (uNK) cell...
(A) Flow cytometry gating strategy to identify and quantify uNK cells in control and obese women. Live decidual leukocytes were selected by excluding nonviable cells and CD3+ lymphocytes. uNK cell proportions within the CD45+ fraction were quantified by their surface expression of CD56 and CD16 and are presented as proportion of cells. SSC, side scatter. (B) Representative flow cytometry plots of uNK cell proportions in control (n = 16) and obese (n = 16) women. Median values of CD56bright cells are shown within plots. IQR, interquartile range. (C) Scatter plots depicting CD56bright cell proportions in control and obese women; horizontal line indicates group median. (D) Representative immunofluorescence images of first trimester decidual tissue (11–13 weeks of gestation) from control (n = 10) and obese (n = 10) women immunostained with antibodies directed against CD56 (green), smooth muscle actin (SMA; red), and CD31 (red); DAPI-stained nuclei are labeled blue. Scale bars: 50 μm. The perforated white box indicates enlarged image. Quantification of (E) absolute uNK cell numbers, (F) arterial smooth muscle thickness, (G) arterial vessel:lumen ratios and (H) numbers of small (< 100-μm diameter) and large (≥ 100-μm diameter) arteries per field of view from decidual specimens of control (C) and obese (O) women. Representative immunofluorescence images (I) and quantification of proportions of apoptosing uNK cells (J) in decidual tissue from control (n = 10) and obese (n = 10) women. Sections were immunostained with antibodies directed against CD56 (red) and cleaved caspase-3 (cl-CASP3; green); DAPI-stained nuclei are labeled blue. White arrowheads highlight apoptosing uNK cells. Scale bars: 50 μm. Statistical analyses were performed using a nonparametric 2-tailed Mann-Whitney t test.

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