Endometrial stromal fibroblasts from women with polycystic ovary syndrome have impaired progesterone-mediated decidualization, aberrant cytokine profiles and promote enhanced immune cell migration in vitro

Piltonen, Terhi; Chen, J.C.; Khatun, Masuma; Kangasniemi, Marika; Liakka, Annikki; Spitzer, Trimble L; Tran, Nguyen; Huddleston, Heather G.; Irwin, Juan C.; Giudice, Linda C.

doi:10.1093/humrep/dev055

Cited by 114 publications

(94 citation statements)

References 62 publications

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“…Primers were designed by Fluidigm and optimized for SYBR-based qRT-PCR following the Fluidigm Biomark guidelines on mRNA amplification, including primer amplification efficiency, amplicon size, and appropriate dissociation temperatures governing mRNA amplification. These amplification conditions are compliant with the Minimum Information for Publication of Quantitative Real-Time PCR Experiments (MIQE)(24) and thermo-cycling conditions were similar to those previously reported (25). The comparative (delta-delta) Ct method was used to measure relative gene expression for each cell type (ABI User bulletin 2).…”

Section: Methodssupporting

confidence: 56%

Cryopreservation and recovery of human endometrial epithelial cells with high viability, purity, and functional fidelity

Chen

Hoffman

Arora

et al. 2016

Fertility and Sterility

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Objective To develop a protocol for cryopreservation and recovery of human endometrial epithelial cells (eEC) retaining molecular and functional characteristics of endometrial epithelium in vivo. Design This is an in vitro study using human endometrial cells. Setting University research laboratory. Patients Endometrial biopsies were obtained from premenopausal women undergoing benign gynecological procedures. Interventions Primary eEC were cryopreserved in 1% fetal bovine serum (FBS)/10% dimethyl sulfoxide (DMSO) in Defined Keratinocyte Serum Free Medium (KSFM). Recovered cells were observed for endometrial stromal fibroblast (eSF) contamination and subsequently evaluated for morphology, gene expression, and functional characteristics of freshly cultured eECs and in vivo endometrial epithelium. Main Outcome Measures Analysis of eEC morphology and the absence of eSF contamination; evaluation of epithelial-specific gene and protein expression; assessment of epithelial polarity. Results eEC recovered after cryopreservation (n=5) displayed epithelial morphology and expressed E-cadherin (CDH1), occludin (OCLN), claudin1 (CLDN1), and keratin18 (KRT18). Compared to eSF, recovered eEC displayed increased (P<0.05) expression of epithelial-specific genes AREG, CDH1, DEFB4A, MMP7, and WNT7A, while exhibiting low-to-undetectable (P<0.05) stromal-specific genes COL6A3, HOXA11, MMP2, PDGFRB, and WNT5A. Recovered eEC secrete levels of cytokines and growth factors comparable to freshly cultured eEC. Recovered eEC can formed a polarized monolayer with high transepithelial electrical resistance (TER) and impermeability to small molecules, and expressed apical/basolateral localization of CDH1 and apical localization of OCLN. Conclusion We have developed a protocol for cryopreservation of eEC in which recovered cells after thawing demonstrate morphological, transcriptomic, and functional characteristics of human endometrial epithelium in vivo.

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Section: Methodssupporting

confidence: 56%

Cryopreservation and recovery of human endometrial epithelial cells with high viability, purity, and functional fidelity

Chen

Hoffman

Arora

et al. 2016

Fertility and Sterility

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“…For instance, uterine TNFα and Il-6 gene expression is increased in PCOS-like rats, confirming that TNFα and Il-6 play inflammatory roles in the endometrial function in PCOS patients (Orostica et al, 2016, Piltonen et al, 2013, 2015). We also show that the anti-inflammatory effect of metformin is via the PI3k-Akt-NFκB signaling pathway.…”

Section: Discussionmentioning

confidence: 61%

Metformin Ameliorates Uterine Defects in a Rat Model of Polycystic Ovary Syndrome

Zhang

Meng

et al. 2017

EBioMedicine

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Adult rats treated concomitantly with insulin and human chorionic gonadotropin exhibit endocrine, metabolic, and reproductive abnormalities that are very similar to those observed in polycystic ovary syndrome (PCOS) patients. In this study, we used this rat model to assess the effects of metformin on PCOS-related uterine dysfunction. In addition to reducing androgen levels, improving insulin sensitivity, and correcting the reproductive cycle, metformin treatment induced morphological changes in the PCOS-like uterus. At the molecular and cellular levels, metformin normalized the androgen receptor-mediated transcriptional program and restored epithelial–stromal interactions. In contrast to glucose transport, uterine inflammatory gene expression was suppressed through the PI3K–Akt–NFκB network, but without affecting apoptosis. These effects appeared to be independent of AMPK subunit and autophagy-related protein regulation. We found that when metformin treatment partially restored implantation, several implantation-related genes were normalized in the PCOS-like rat uterus. These results improve our understanding of how metformin rescues the disruption of the implantation process due to the uterine defects that result from hyperandrogenism and insulin resistance. Our data provide insights into the molecular and functional clues that might help explain, at least in part, the potential therapeutic options of metformin in PCOS patients with uterine dysfunction.

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“…The fact that some outcomes were worsened in hyperandrogenic PCOS phenotypes may relate to the reciprocal relationship between HA and IR (either intrinsic or extrinsic related to obesity) 4,107 in PCOS. This likely aggravates sex hormone imbalances that contribute to adverse pregnancy and birth outcomes through endometrial abnormalities like thickening the endometrium, 108 dysregulating angiogenesis, 92 and inducing a state of inflammation in endometrium 94,[109][110][111] and consequently impacting on implantation and placentation. 25,92,108 The prevalence of outcomes did not significantly change on exclusion of studies using metformin during pregnancy, which is consistent with prior literature on miscarriage, 112 GDM, 113 and PE.…”

Section: Discussionmentioning

confidence: 99%

Increased maternal pregnancy complications in polycystic ovary syndrome appear to be independent of obesity—A systematic review, meta‐analysis, and meta‐regression

et al. 2019

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Summary Polycystic ovary syndrome (PCOS) is associated with an increased risk of maternal pregnancy and delivery complications. However, the impact of clinical features of PCOS and other potential risk factors in PCOS is still unknown. We aimed to investigate the association of PCOS with maternal pregnancy and delivery complications with consideration of risk factors and potential confounders. The meta‐analysis included 63 studies. PCOS was associated with higher miscarriage, gestational diabetes mellitus, gestational hypertension, pre‐eclampsia, induction of labour, and caesarean section. The association of PCOS with these outcomes varied by geographic continent, PCOS phenotypes, and study quality. Pre‐eclampsia and induction of labour were not associated with PCOS on body mass index‐matched studies. No outcome was associated with PCOS on assisted pregnancies. Age was significantly associated with higher miscarriage on meta‐regression. There were no studies assessing perinatal depression. We confirm that PCOS is associated with an increased risk of maternal pregnancy and delivery complications. The association of PCOS with the outcomes is worsened in hyperandrogenic PCOS phenotypes, in specific geographic continents, and in the highest quality studies but disappears in assisted pregnancies. Future studies in PCOS are warranted to investigate proper timing for screening and prevention of maternal pregnancy and delivery complications with consideration of clinical features of PCOS.

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Endometrial stromal fibroblasts from women with polycystic ovary syndrome have impaired progesterone-mediated decidualization, aberrant cytokine profiles and promote enhanced immune cell migration in vitro

Cited by 114 publications

References 62 publications

Cryopreservation and recovery of human endometrial epithelial cells with high viability, purity, and functional fidelity

Cryopreservation and recovery of human endometrial epithelial cells with high viability, purity, and functional fidelity

Metformin Ameliorates Uterine Defects in a Rat Model of Polycystic Ovary Syndrome

Increased maternal pregnancy complications in polycystic ovary syndrome appear to be independent of obesity—A systematic review, meta‐analysis, and meta‐regression

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