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Single-cell RNA Sequencing Reveals a Pro-fibrotic Epithelial Subpopulation Contributing to Endometrial Dysfunction in Polycystic Ovary Syndrome

ABSTRACT: Endometrial dysfunction in women with polycystic ovary syndrome (PCOS) significantly contributes to adverse pregnancy outcomes, including recurrent implantation failure and high miscarriage rates. However, the specific roles of individual cell types in this dysfunction, particularly in non-obese and obese PCOS patients, remain unclear. This study utilized single-cell RNA sequencing to comprehensively examine cellular heterogeneity in the proliferative-phase endometrium of non-obese PCOS, obese PCOS, and healthy controls. Notably, we identified a distinct subpopulation of endometrial epithelial cells (EC) exhibiting a predisposition for epithelial-mesenchymal transition, characterized by elevated expression of decorin (DCN) and extracellular matrix 1 (ECM1) (DCNhighECM1high EC2). The proportion of these cells was significantly higher in PCOS patients, potentially disrupting normal epithelial function and reducing endometrial receptivity. Analysis of cell-cell communication revealed a notable decrease in anti-fibrotic bone morphogenetic protein (BMP) signaling in fibroblasts targeting DCNhighECM1high EC2, coupled with a marked increase in pro-fibrotic transforming growth factor beta (TGFβ) signaling in immune cells targeting DCNhighECM1high EC2. This imbalance between the two pathways likely drives the fibrotic transformation of endometrial epithelial cells in both non-obese and obese PCOS patients. Collectively, our findings highlight potential therapeutic targets for managing endometrial dysfunction in PCOS.

ORGANISM(S): Homo sapiens

PROVIDER: GSE338479 | GEO | 2026/09/23

REPOSITORIES: GEO

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Project description: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 M-bM-^@M-^\disease phenotypeM-bM-^@M-^] affecting the gene expression of different endometrial cell populations, including stem cells and their differentiated progeny. Design and setting: A prospective study conducted at an academic medical center. Patients and Main Outcome Measures: Proliferative phase endometrium was obtained from 6 overweight/obese PCOS (NIH criteria) and 6 overweight/obese controls. Microarray analysis was performed on fluorescence-activated cell sorting (FACS)-isolated endometrial epithelial cells (eEP), endothelial cells (eEN), stromal fibroblasts (eSF) and mesenchymal stem cells (eMSC). Gene expression data were validated using microfluidic Q-RT-PCR and immunohistochemistry (IHC). Results: The comparison between eEPPCOS and eEPCtrl showed dysregulation of inflammatory genes and genes with oncogenic potential (CCL2, IL-6, ORM1, TNAIFP6, SFRP4, SPARC). eSFPCOS and eSFCtrl showed upregulation of inflammatory genes (C4A/B, CCL2, ICAM1, TNFAIP3). Similarly, in eMSCPCOS vs. eMSCCtrl the most upregulated genes were related to inflammation and cancer (IL-8, ICAM1, SPRR3, LCN2). IHC scoring showed increased expression of CCL2 in eEPPCOS and eSFPCOS compared to eEPCtrl and eSFCtrl and IL-6 in eEPPCOS compared to eEPCtrl. Conclusions: Isolated endometrial cell populations in women with PCOS showed altered gene expression revealing inflammation and pro-oncogenic changes, independent of BMI, especially in eEPPCOS and eMSCPCOS, compared to controls. The study reveals an endometrial M-bM-^@M-^\disease phenotypeM-bM-^@M-^] in women with PCOS with potential negative effects on endometrial function and long-term health. Proliferative phase endometrium was obtained from 6 overweight/obese PCOS (NIH criteria) and 6 overweight/obese controls. Microarray analysis was performed on fluorescence-activated cell sorting (FACS)-isolated endometrial epithelial cells (eEP), endothelial cells (eEN), stromal fibroblasts (eSF) and mesenchymal stem cells (eMSC). Tissue samples were obtained through the National Institute of Health (NIH)/University of California, San Francisco (UCSF), Human Endometrial Tissue and DNA Bank in accordance with the guidelines of the Declaration of Helsinki. Informed consent was obtained from all participants in the UCSF Center for Reproductive Health, and the study was approved by the UCSF Committee on Human Research. The clinical summary of the study participants is shown in Table 1. Eleven proliferative phase endometrial biopsies (Pipelle, Cooper Surgical Shelton, Connecticut) and one curettage specimen were collected from over-weight (Body Mass Index [BMI, kg/m2] M-bM-^IM-% 27 < 29.9; n=1) and obese (BMI M-bM-^IM-% 30; n=5) women with PCOS (age 30.5M-BM-1 2.1 yrs, BMI 34.13M-BM-1 2.2, NIH criteria (17) and overweight (n=2) and obese (n=4) control women (age 36.50M-BM-11.70 yrs, BMI 35.73M-BM-13.96). All PCOS subjects had normal 17-hydroxyprogesterone, prolactin and thyroid hormone levels. Control samples were obtained from healthy volunteer and women undergoing benign gynecological surgery. All controls reported menstrual cycles with regular interval (25-35 days) and no clinical evidence of having PCOS. Neither PCOS nor control subjects were exposed to hormonal medications for at least 2 months prior to tissue sampling and were confirmed not pregnant.

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Single-cell RNA Sequencing Reveals a Pro-fibrotic Epithelial Subpopulation Contributing to Endometrial Dysfunction in Polycystic Ovary Syndrome

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