Platelets drive smooth muscle metaplasia and fibrogenesis in endometriosis through epithelial–mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation

Zhang, Qi; Duan, Jie; Liu, Xishi; Guo, Sun‐Wei

doi:10.1016/j.mce.2016.03.015

Cited by 150 publications

(176 citation statements)

References 106 publications

Supporting

Mentioning

151

Contrasting

Order By: Relevance

“…Activated platelets also release significant amounts of serotonin, which activates TGF-β in inducing fibrosis, and antagonists of 5HT2A receptors ameliorate fibrosis in rodent models 16 , 17 . In addition, platelets have been shown to drive epithelial-to-mesenchymal and fibroblast-to-myofibroblast transition in models of endometriosis 18 . In our retrospective study, platelet-to-albumin ratios ≥125, independent of small bowel dilation or anti-TNF exposure, doubled the hazard of surgery within 2 years.…”

Section: Discussionmentioning

confidence: 99%

Intestinal Dilation and Platelet:Albumin Ratio Are Predictors of Surgery in Stricturing Small Bowel Crohn’s Disease

Stidham

Guentner

Ruma³

et al. 2016

Clinical Gastroenterology and Hepatology

View full text Add to dashboard Cite

BACKGROUND & AIMS It is a challenge to predict how patients with small bowel Crohn’s disease (CD) will respond to intensified medical therapy. We aimed to identify factors that predicted surgery within 2 years of hospitalization for CD, to guide medical vs surgical management decisions. METHODS We performed a retrospective review of adults hospitalized for small bowel CD from 2004 through 2012 at a single academic referral center. Subjects underwent abdominal computed tomography or magnetic resonance imaging within 3 weeks of hospitalization. Imaging characteristics of small bowel dilation, bowel wall thickness, and disease activity were assessed by a single, blinded radiologist. Multivariate analysis by Cox proportional hazard regression techniques were used to generate a prediction model of intestinal resection within 2 years. RESULTS A total of 221 subjects met selection criteria, with 32.6% undergoing surgery within 2 years of index admission. Bivariate analysis showed high-dose steroid use (>40 mg), ongoing treatment with anti-tumor necrosis factor agents at admission, platelet count, platelet:albumin ratio, small bowel dilation (≥35 mm), and bowel wall thickness to predict surgery (P≤.01). Multivariate modeling demonstrated small bowel dilation greater than 35 mm (hazard ratio [HR], 2.92; 95% confidence interval [CI], 1.73–4.94) and a platelet:albumin ratio ≥125 (HR, 2.13; 95% CI, 1.15–3.95) to predict surgery. Treatment with anti-tumor necrosis factor agents at admission conferred a non-significant increased trend for risk of surgery (HR, 1.61; 95% CI, 0.994–2.65). CONCLUSIONS Small bowel dilation greater than 35 mm and high platelet:albumin ratios are independent and synergistic risk factors for future surgery in patients with structuring small bowel CD. Platelet:albumin ratios may capture the relationship between acute inflammation and cumulative damage and serve as markers of intestines that cannot be salvaged with medical therapy.

show abstract

Section: Discussionmentioning

confidence: 99%

Intestinal Dilation and Platelet:Albumin Ratio Are Predictors of Surgery in Stricturing Small Bowel Crohn’s Disease

Stidham

Guentner

Ruma³

et al. 2016

Clinical Gastroenterology and Hepatology

View full text Add to dashboard Cite

show abstract

“…TGF-β is a major driver of fibrosis in endometriosis and can promote fibroblast to myofibroblast transdifferentiation via the Smad-dependent and Smad-independent signaling pathways [139]; it also promotes epithelial–mesenchymal transition (EMT) of endometrial cells and increases their migration ability [140,141]. Blockade of TGF-β and its affiliated targets reverses EMT and myofibroblast transdifferentiation in endometriosis and offers a potential therapeutic target [142,143]. Additionally, an in vivo study using an experimental endometriosis model showed that the presence of IL-1β in the peritoneal fluid of endometriosis patients could contribute to surgery-related adhesion, and inhibiting IL-1β with IL-1 receptor antagonist could significantly reduce postoperative adhesion [144].…”

Section: Targeting Inflammation For Treatment Of Endometriosis-assmentioning

confidence: 99%

Chronic Niche Inflammation in Endometriosis-Associated Infertility: Current Understanding and Future Therapeutic Strategies

Lin

Chen

Chang

et al. 2018

IJMS

130

View full text Add to dashboard Cite

Endometriosis is an estrogen-dependent inflammatory disease that affects up to 10% of women of reproductive age and accounts for up to 50% of female infertility cases. It has been highly associated with poorer outcomes of assisted reproductive technology (ART), including decreased oocyte retrieval, lower implantation, and pregnancy rates. A better understanding of the pathogenesis of endometriosis-associated infertility is crucial for improving infertility treatment outcomes. Current theories regarding how endometriosis reduces fertility include anatomical distortion, ovulatory dysfunction, and niche inflammation-associated peritoneal or implantation defects. This review will survey the latest evidence on the role of inflammatory niche in the peritoneal cavity, ovaries, and uterus of endometriosis patients. Nonhormone treatment strategies that target these inflammation processes are also included. Furthermore, mesenchymal stem cell-based therapies are highlighted for potential endometriosis treatment because of their immunomodulatory effects and tropism toward inflamed lesion foci. Potential applications of stem cell therapy in treatment of endometriosis-associated infertility in particular for safety and efficacy are discussed.

show abstract

“…We have recently demonstrated that, because of this hallmark, endometriotic lesions are essentially wounds that undergo repeated tissue injury and repair (ReTIAR), resulting in platelet-driven epithelial-mesenchymal transition (EMT), fibroblast-to-myofibroblast transdifferentiation (FMT), smooth muscle metaplasia (SMM) and ultimately fibrosis 7, 8 .…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, to date several factors have been shown to regulate EMT in endometriosis and adenomyosis, including estrogen 11 , Wnt/β-catenin 2 , lipocalin 2 12 , hepatocyte growth factor (HGF) 2, 13, 14 , lysyl oxidase 15 , periostin 16 , hypoxia 17 , microRNA-200b (miR-200b) 18 , platelets 7 and possibly Myc 19 and LSD1 20 . It becomes clear that EMT not only increases cellular invasiveness but also promotes fibrogenesis 7, 21 .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Enhancer of Zeste homolog 2 (EZH2) induces epithelial-mesenchymal transition in endometriosis

Zhang

Dong

Liu

et al. 2017

Sci Rep

Self Cite

View full text Add to dashboard Cite

EZH2, a subunit of the polycomb repressive complex 2 (PRC2) catalyzing trimethylation of histone H3 lysine 27 (H3K27), induces epithelial-mesenchymal transition (EMT) in cancers. However, whether EZH2 regulates EMT in endometriosis is unclear. Here, we show that EZH2 expression, along with its associated PRC2 proteins, is significantly elevated in ectopic and eutopic endometrium from women with endometriosis as compared with control endometrium. EZH2 knockdown or inhibition restored the epithelial phenotypes of endometriotic epithelial cells, concomitant with the upregulation of E-cadherin and downregulation of vimentin and transcription factors (Snail and Slug) as well as reduced cellular migratory and invasive propensity. Conversely, overexpression of EZH2 induced the expression of Snail, Slug and vimentin and suppresses E-cadherin expression. In vivo administration of 3-Deazaneplanocin A (DZNep), an EZH2 inhibitor, significantly inhibited the growth of endometriotic lesions and improved generalized hyperalgesia, along with attenuated EMT and reduced fibrosis in endometriosis. Notably, platelets induced EZH2 upregulation and increased H3K27 and H3K9 trimethylation levels in endometriotic epithelial cells. These data identify EZH2 as a novel driver of EMT in endometriosis, implicates the link between wound healing and epigenetic changes in the context of endometriosis, and underscore the role of platelets in the development of endometriosis.

show abstract

Platelets drive smooth muscle metaplasia and fibrogenesis in endometriosis through epithelial–mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation

Cited by 150 publications

References 106 publications

Intestinal Dilation and Platelet:Albumin Ratio Are Predictors of Surgery in Stricturing Small Bowel Crohn’s Disease

Intestinal Dilation and Platelet:Albumin Ratio Are Predictors of Surgery in Stricturing Small Bowel Crohn’s Disease

Chronic Niche Inflammation in Endometriosis-Associated Infertility: Current Understanding and Future Therapeutic Strategies

Enhancer of Zeste homolog 2 (EZH2) induces epithelial-mesenchymal transition in endometriosis

Contact Info

Product

Resources

About