Expression and Significance of WNT4 in Ectopic and Eutopic Endometrium of Human Endometriosis

Liang, Yanming; Li, Yan; Liu, Kuiran; Chen, Peng; Wang, Danbo

doi:10.1177/1933719115602763

Cited by 22 publications

(15 citation statements)

References 25 publications

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“…Interestingly, the proliferation of eutopic endometrial MSCs was elevated by endometriotic PF much remarkably than ectopic endometrial MSCs derived from the same patients, while the proliferation of normal endometrial MSCs was inhibited in the same condition. These data suggest that there are some inherent differences between endometrial MSCs from patients with and without endometriosis facilitating the proliferation of eutopic but not normal endometrial MSCs in the presence of endometriotic PF, which is consistent with the theory of “eutopic endometrium determinism” [44].…”

Section: Discussionsupporting

confidence: 86%

Endometriotic Peritoneal Fluid Promotes Myofibroblast Differentiation of Endometrial Mesenchymal Stem Cells

Zhang

Suo

Chen

et al. 2019

Stem Cells International

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During the development of endometriosis, the presence of fibrotic tissues in and surrounding endometriotic lesions may lead to subsequent adhesion, anatomic distortion, and chronic pain. Therefore, studies aimed at clarifying the underlying mechanisms of fibrogenesis in endometriosis could potentially provide a novel strategy for effective treatment. Mesenchymal stem cells (MSCs) play a key role in fibrotic diseases by differentiating into myofibroblasts in appropriate microenvironment. In this study, we collected endometrial and endometriotic tissues from patients with endometriosis (n=32) and control patients without endometriosis (n=20) to compare the expression of fibrotic proteins and investigate the effect of endometriotic peritoneal fluid (PF) on myofibroblast differentiation of endometrial MSCs. We found that the expression of fibrotic proteins, including alpha-smooth muscle actin (α-SMA), type I collagen (collagen I), connective tissue growth factor (CTGF), and fibronectin, and the extent of fibrosis extremely enhanced in ectopic endometria compared with eutopic endometria from the same patients with endometriosis and normal endometria from patients without endometriosis. We next isolated and identified endometrial MSCs and found that treatment with endometriotic PF strongly induced endometrial MSCs to differentiate into myofibroblasts concomitant with the activation of Smad2/3. Moreover, ectopic endometrial MSCs expressed elevated collagen I, α-SMA, fibronectin, and CTGF. Sushi domain containing-2 (SUSD2), a marker of endometrial MSCs, and α-SMA, a well-recognized marker for myofibroblasts, colocalized extensively in ectopic endometria while seldom in normal and eutopic endometria. These findings suggest that ectopic endometrial MSCs are probably more susceptible to myofibroblast differentiation because of the long-term influence of endometriotic PF. All together, we report for the first time that endometriotic PF promotes myofibroblast differentiation of endometrial MSCs. This understanding will greatly improve our understanding of the pathophysiology of endometriosis and help design better therapeutics.

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Section: Discussionsupporting

confidence: 86%

Endometriotic Peritoneal Fluid Promotes Myofibroblast Differentiation of Endometrial Mesenchymal Stem Cells

Zhang

Suo

Chen

et al. 2019

Stem Cells International

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“…In a histological comparison of IHH expression in endometrial biopsy samples from women with endometriosis and healthy controls, IHH expression was decreased in secretory phase endometrium from endometriosis patients [155]. Correspondingly, later studies found COUPTFII [131] and WNT4 [132] expression levels decreased in both endometrial samples from women with endometriosis and endometriotic lesions. These findings identified a major pathway downstream of P4 signaling that is disrupted in women with endometriosis and may lead to endometrial non-receptivity in these patients by interfering with regulation of uterine epithelial proliferation and stromal decidualization.…”

Section: Dysregulation Of Progesterone and Estrogen Signaling In Ementioning

confidence: 99%

“…Several other steroid hormone-regulated pathways we have discussed are both implicated in endometriosis and closely involved in pregnancy establishment. Proteins involved in regulation and mediation of the P4-responsive IHH pathway including GATA2, SOX17, IHH, COUPTFII, and WNT4 are required for successful implantation in mice [29,30,34,65,67] but are reduced in the endometrium of women with endometriosis [68,131,132,136,155], revealing a potential large-scale molecular connection between P4 resistance and fertility problems in endometriosis. The transcriptional regulators FOXO1, ARID1A, and HDAC3 are three additional factors associated with P4 signaling that are required for uterine receptivity in mice and down-regulated in the endometrium of women with endometriosis, further corroborating the association between the P4 resistance of endometriosis with infertility [55,69,119,144,157].…”

Section: Pathologies Related To Steroid Hormone Signaling Dysregulmentioning

confidence: 99%

Progesterone and Estrogen Signaling in the Endometrium: What Goes Wrong in Endometriosis?

Marquardt

Kim

Shin

et al. 2019

IJMS

284

203

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In the healthy endometrium, progesterone and estrogen signaling coordinate in a tightly regulated, dynamic interplay to drive a normal menstrual cycle and promote an embryo-receptive state to allow implantation during the window of receptivity. It is well-established that progesterone and estrogen act primarily through their cognate receptors to set off cascades of signaling pathways and enact large-scale gene expression programs. In endometriosis, when endometrial tissue grows outside the uterine cavity, progesterone and estrogen signaling are disrupted, commonly resulting in progesterone resistance and estrogen dominance. This hormone imbalance leads to heightened inflammation and may also increase the pelvic pain of the disease and decrease endometrial receptivity to embryo implantation. This review focuses on the molecular mechanisms governing progesterone and estrogen signaling supporting endometrial function and how they become dysregulated in endometriosis. Understanding how these mechanisms contribute to the pelvic pain and infertility associated with endometriosis will open new avenues of targeted medical therapies to give relief to the millions of women suffering its effects.

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“…The Wnt family protein Wnt-4 is essential for the development of the female reproductive tract (Vainio et al 1999), and acts as a signalling molecule in cell-cell interactions, proliferation and migration (Liang et al 2016). Expression levels of WNT4 in the eutopic endometrium appear to be higher in a group of women with endometriosis than in a control group (Liang et al 2016). Moreover, a GWAS found that a SNP located close to the WNT4 gene (rs7521902) was associated with the endometriosis risk (Pagliardini et al 2013).…”

mentioning

confidence: 99%

Polymorphisms and endometriosis: a systematic review and meta-analyses

Méar

Herr

Fauconnier

et al. 2019

Human Reproduction Update

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BACKGROUND Endometriosis is an estrogen-dependent gynecological disorder that affects at least 10% of women of reproductive age. It may lead to infertility and non-specific symptoms such as chronic pelvic pain. Endometriosis screening and diagnosis are difficult and time-consuming. Late diagnosis (with a delay ranging from 3.3 to 10.7 years) is a major problem and may contribute to disease progression and a worse response to treatment once initiated. Efficient screening tests might reduce this diagnostic delay. As endometriosis is presumed to be a complex disease with several genetic and non-genetic pathogenic factors, many researchers have sought to identify polymorphisms that predispose to this condition. OBJECTIVE AND RATIONALE We performed a systematic review and meta-analysis of the most regularly reported polymorphisms in order to identify those that might predispose to endometriosis and might thus be of value in screening. SEARCH METHODS The MEDLINE database was searched for English-language publications on DNA polymorphisms in endometriosis, with no date restriction. The PubTator text mining tool was used to extract gene names from the selected publications’ abstracts. We only selected polymorphisms reported by at least three studies, having applied strict inclusion and exclusion criteria to their control populations. No stratification based on ethnicity was performed. All steps were carried out according to PRISMA guidelines. OUTCOMES The initial selection of 395 publications cited 242 different genes. Sixty-two genes (corresponding to 265 different polymorphisms) were cited at least in three publications. After the application of our other selection criteria (an original case-control study of endometriosis, a reported association between endometriosis and at least one polymorphism, data on women of reproductive age and a diagnosis of endometriosis in the cases established by surgery and/or MRI and confirmed by histology), 28 polymorphisms were eligible for meta-analysis. Only five of the 28 polymorphisms were found to be significantly associated with endometriosis: interferon gamma (IFNG) (CA) repeat, glutathione S-transferase mu 1 (GSTM1) null genotype, glutathione S-transferase pi 1 (GSTP1) rs1695 and wingless-type MMTV integration site family member 4 (WNT4) rs16826658 and rs2235529. Six others showed a significant trend towards an association: progesterone receptor (PGR) PROGINS, interCellular adhesion molecule 1 (ICAM1) rs1799969, aryl-hydrocarbon receptor repressor (AHRR) rs2292596, cytochrome family 17 subfamily A polypeptide 1 (CYP17A1) rs743572, CYP2C19 rs4244285 and peroxisome proliferator-activated receptor gamma (PPARG) rs1801282), and 12 showed a significant trend towards the lack of an association: tumor necrosis factor (TNF) rs1799964, interleukin 6 (IL6) rs1800796, transforming growth factor beta 1 (TGFB1) rs1800469, estrogen receptor 1 (ESR1) rs2234693, PGR rs10895068, FSH receptor (FSHR) rs6166, ICAM1 rs5498, CYP1A1 rs4646903, CYP19A1 rs10046, tumor protein 53 (TP53) rs1042522, X-ray repair complementing defective repair in Chinese hamster cells 1 (XRCC1) rs25487 and serpin peptidase inhibitor clade E member 1 (SERPINE1) rs1799889; however, for the 18 polymorphisms identified in the latter two groups, further studies of the potential association with the endometriosis risk are needed. The remaining five of the 28 polymorphisms were not associated with endometriosis: glutathione S-transferase theta 1 (GSTT1) null genotype, vascular endothelial growth factor alpha (VEGFA) rs699947, rs833061, rs2010963 and rs3025039. WIDER IMPLICATIONS By carefully taking account of how the control populations were defined, we identified polymorphisms that might be candidates for use in endometriosis screening and polymorphisms not associated with endometriosis. This might constitute the first step towards identifying polymorphism combinations that predispose to endometriosis (IFNG (CA) repeat, GSTM1 null genotype, GSTP1 rs1695, WNT4 rs16826658 and WNT4 rs2235529) in a large cohort of patients with well-defined inclusion criteria. In turn, these results might improve the diagnosis of endometriosis in primary care. Lastly, our present findings may enable a better understanding of endometriosis and improve the management of patients with this disease.

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Expression and Significance of WNT4 in Ectopic and Eutopic Endometrium of Human Endometriosis

Cited by 22 publications

References 25 publications

Endometriotic Peritoneal Fluid Promotes Myofibroblast Differentiation of Endometrial Mesenchymal Stem Cells

Endometriotic Peritoneal Fluid Promotes Myofibroblast Differentiation of Endometrial Mesenchymal Stem Cells

Progesterone and Estrogen Signaling in the Endometrium: What Goes Wrong in Endometriosis?

Polymorphisms and endometriosis: a systematic review and meta-analyses

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