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. 2013 Sep;98(9):3765-75.
doi: 10.1210/jc.2013-1923. Epub 2013 Jul 3.

Mesenchymal stem/progenitors and other endometrial cell types from women with polycystic ovary syndrome (PCOS) display inflammatory and oncogenic potential

T T Piltonen  1 , J Chen, D W Erikson, T L B Spitzer, F Barragan, J T Rabban, H Huddleston, J C Irwin, L C Giudice
Affiliations

Mesenchymal stem/progenitors and other endometrial cell types from women with polycystic ovary syndrome (PCOS) display inflammatory and oncogenic potential

T T Piltonen et al. J Clin Endocrinol Metab. 2013 Sep.

Abstract

Context: Endometrium in polycystic ovary syndrome (PCOS) presents altered gene expression indicating progesterone resistance and predisposing to reduced endometrial receptivity and endometrial cancer.

Objective: We hypothesized that an altered endocrine/metabolic environment in PCOS may result in an endometrial "disease phenotype" affecting the gene expression of different endometrial cell populations, including stem cells and their differentiated progeny.

Design and setting: This was a prospective study conducted at an academic medical center.

Patients and main outcome measures: Proliferative-phase endometrium was obtained from 6 overweight/obese PCOS (National Institutes of Health criteria) and 6 overweight/obese controls. Microarray analysis was performed on fluorescence-activated cell sorting-isolated endometrial epithelial cells (eEPs), endothelial cells, stromal fibroblasts (eSFs), and mesenchymal stem cells (eMSCs). Gene expression data were validated using microfluidic quantitative RT-PCR and immunohistochemistry.

Results: The comparison between eEP(PCOS) and eEP(Ctrl) showed dysregulation of inflammatory genes and genes with oncogenic potential (CCL2, IL-6, ORM1, TNAIFP6, SFRP4, SPARC). eSF(PCOS) and eSF(Ctrl) showed up-regulation of inflammatory genes (C4A/B, CCL2, ICAM1, TNFAIP3). Similarly, in eMSC(PCOS) vs eMSC(Ctrl), the most up-regulated genes were related to inflammation and cancer (IL-8, ICAM1, SPRR3, LCN2). Immunohistochemistry scoring showed increased expression of CCL2 in eEP(PCOS) and eSF(PCOS) compared with eEP(Ctrl) and eSF(Ctrl) and IL-6 in eEP(PCOS) compared with eEP(Ctrl).

Conclusions: Isolated endometrial cell populations in women with PCOS showed altered gene expression revealing inflammation and prooncogenic changes, independent of body mass index, especially in eEP(PCOS) and eMSC(PCOS), compared with controls. The study reveals an endometrial disease phenotype in women with PCOS with potential negative effects on endometrial function and long-term health.

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Figures

Figure 1.
Figure 1.
Isolation of the different cell types by FACS from human endometrium. A–C, FACS analysis of live single-cell fraction. D, EPCAM+ epithelial cells (eEPa) and CD45+ lymphocytes isolated from the cell population. E, Cells sorted into 3 populations according to the label for MCAM (CD146, eENs), PDGFRB (eSFs), or MCAM (CD146) and PDGFRB (eMSCs). SSC, side scatter; FSC, forward scatter; APC, allophycocyanin, FITC, fluorescein isothiocyanate; PE, phycoerythrin.
Figure 2.
Figure 2.
A, Endometrial cell populations of overweight/obese women with PCOS and overweight/obese controls clustered in PCA by cell type and disease. B, Hierarchical clustering analysis of the differentially expressed genes (≥2 FC, P < .05) between eMSCs, eSFs, eENs, and eEPs in overweight/obese women with PCOS (yellow) and overweight/obese controls (white).
Figure 3.
Figure 3.
Immunohistochemical localization of CCL2 (monocyte chemoattractant protein-1) and IL-6 protein in human endometrium. Representative paraffin-embedded endometrial sections in anovulatory overweight/obese women with PCOS (n = 4) and overweight/obese controls (n = 4) are shown. A, CCL2 was highly expressed in LE and GE PCOS epithelium and ST compared with the control tissue. The Quick Score showed increased immunostaining for LE, GE, and ST in PCOS endometrium (*, P < .05). B, IL-6 showed increased expression in LE and GE in the PCOS endometrium compared with control (Quick Score; LE and GE, P < .05) (nonimmune rabbit IgG, negative control; ×200 magnification).
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