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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 3

Maternal obesity instructs gene expression-informed uterine NK (uNK) cell clustering.

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Maternal obesity instructs gene expression-informed uterine NK (uNK) cel...
(A) Schema of experimental pipeline starting from NK cell purification, RNA extraction, microarray hybridization, data preprocessing, and computational analyses. (B) Dendrogram depicts hierarchical clustering of control and obese uNK cell samples generated by the 200 high coefficient of variation (high-CV) gene signature where the 24 samples (n = 13 control; n = 11 obese) were separated into 4 groups (G1, G2, G3, and G4). The heatmap displays expression profiles of the top 200 genes with highest CV; the 200 high-CV genes are clustered into 11 gene clusters depicted by different colored bars (C1–C11). Within the heatmap, blue = low expression; black = mid-level expression; yellow = high expression. For each sample, patient BMI and C-reactive protein (CRP) status is indicated above the heatmap (control = black; obese = green; low CRP = white; high CRP = red). (C) Principal component analysis (PCA) of top 200 high-CV genes across 24 uNK cell samples. Control samples are indicated by black type while obese samples are indicated by green. (D) Dotmap depiction of significant pathways enriched in the 154 C3 probe signature determined by ToppGene analyses. FDR values (q value; Bonferroni) are represented by the color of boxes, and percentage of genes in the GO annotated list are indicated by the size of the circle within each box. Statistical analyses were performed in the R statistical environment using limma library beadarray packages. ECM, extracellular matrix.

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