Sensory nerve-derived neuropeptides accelerate the development and fibrogenesis of endometriosis

Liu, Xishi; Yan, Dingmin; Guo, Sun‐Wei

doi:10.1093/humrep/dey392

Cited by 40 publications

(32 citation statements)

References 87 publications

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“…Granted, while almost all past research focus has fixated on endometriotic epithelial and stromal cells nearly exclusively, there are many other cells in its microenvironment. Platelets 21,23 , neutrophils 69 , macrophages 19,24 , and recently nerve fibers 25,26 all have been identified to be accessories to aid and abet the lesional development. Indeed, these cells are known to be irreplaceable partners in a successful wound healing 70 .…”

Section: Discussionmentioning

confidence: 99%

“…As we showed previously, however, the vast heterogeneity of endometriosis appears to be determined mostly by the lesional microenvironments 80 . Namely, regardless of subtypes, all endometriotic lesions appear to undergo identical molecular processes such as epithelial-mesenchymal transition (EMT), fibroblast-to-myofibroblast transdifferentiation (FMT), smooth muscle metaplasia (SMM), and fibrogenesis 25,26,53 , even in adenomyotic lesions 81,82 . Moreoever, increased local production of estrogen is common to all subtypes of endometriosis 83 and even to adenomyosis 84 .…”

Section: Discussionmentioning

confidence: 99%

“…Rather, its development and the subsequent manifestation of various symptomology require, by necessity, aid and assistance from many aiders and abettors. Indeed, accumulating evidence suggests that endometriotic lesions are essentially wounds undergoing repeated tissue injury and repair (ReTIAR) [19][20][21][22] , and, as such, many non-endometriotic cells in the lesional microenvironment, such as platelets 21,23 , macrophages 19,24 , and now nerve fibers 25,26 , are actively involved in facilitating lesional development.…”

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confidence: 99%

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Platelets induce increased estrogen production through NF-κB and TGF-β1 signaling pathways in endometriotic stromal cells

Liu

Zhang

et al. 2020

Sci Rep

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Endometriosis is estrogen-dependent disorder. Two theories provide the explanations for the increased estrogen production. One is the feed-forward loop model linking inflammation and estrogen production. The more recent model evokes the tissue hypoxia resulting from endometrial debris detached and then regurgitated to the peritoneal cavity. Both models tacitly assume that everything occurs within the endometriotic stromal cells, seemingly without the need for exogenous factors. This study was undertaken to investigate as whether platelets may be responsible for local estrogen overproduction. We employed in vitro experimentation that evaluated the 17β-estradiol (e 2) levels in endometriotic stromal cells treated with activated platelets, and the genes and protein expression levels of StAR, HSD3B2, aromatase, and HSD17B1, as well as their upstream genes/proteins such as nf-κB, TGF-β1, HIF-1α, SF-1 and phosphorylated CREB. In addition, we conducted 2 animal experimentations using platelet depletion/infusion and also neutralization of NF-κB and tGf-β1, followed by immunohistochemistry analysis of involved in StAR, HSD3B2, aromatase, and HSD17B1, as well as SF-1 and p-CREB. We found that treatment of endometriotic stromal cells by activated platelets increase the e 2 production by 4.5 fold, and concomitant with increased gene and protein expression of StAR, HSD3B2, aromatase, and HSD17B1, the four genes/enzymes important to estrogen synthesis, along with their upstream genes HIF-1α, SF-1 and phosphorylated CREB. Moreover, platelets activate these genes through the activation of NF-κB and/or TGF-β1, and antagonism of either signaling pathway can abolish the induction of the 4 genes and thus increased estrogen production. The two animal experimentations confirmed these changes. Thus, platelets increase the E 2 production in endometriotic stromal cells through upregulation of StAR, HSD3B2, aromatase, and HSD17B1 via the activation of NF-κB and/or TGF-β1. These findings provide a yet another compelling piece of evidence that endometriotic lesions are indeed wounds undergoing repeated tissue injury and repair. They strongly indicate that non-hormonal therapeutics for endometriosis is theoretically viable, with antiplatelet therapy being one promising avenue. Endometriosis, defined as the deposition and growth of endometrium-like tissues outside the uterine cavity, is a common disorder affecting about 6-10% of women of reproductive age 1. As a major contributor to pelvic pain and infertility 2 impacting negatively on women's quality of life 3 , a source of anxiety and depression 4 and a leading cause of gynecological hospitalization in the United States 5 and likely in many other parts of the world, endometriosis is frequently viewed as an enigmatic disease due to its elusive pathogenesis and pathophysiology 6,7. Consequently, its effective treatment remains a challenge 2,8. Endometriosis has been viewed as a ultimate hormonal disease 9 , featuring estrogen-dependent growth and maintenance of ectopic endometrium as well as ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Platelets induce increased estrogen production through NF-κB and TGF-β1 signaling pathways in endometriotic stromal cells

Liu

Zhang

et al. 2020

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“…Furthermore, platelets activated by excessive hemorrhaging drive SMM and fibrogenesis in endometriosis through EMT and FMT (52). SP, a neuropeptide expressed in peripheral sensory neurons, can stimulate the development EMT, FMT, SMM and ultimately, fibrosis, in endometriotic lesions, indicating that the main clinical features are chronic pelvic pain (53).…”

Section: Endometriosis As a Fibrotic Conditionmentioning

confidence: 99%

Somatic driver mutations in endometriosis as possible regulators of fibrogenesis (Review)

Kobayashi

2019

Wrld Acd Sci

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The aim of this review article was to assess the potential link between somatic driver mutations in endometriosis and the pathogenesis of fibrotic processes in other organ systems. This review presents the results of a PubMed literature search for publications dealing with the association between the endometriosis susceptibility driver gene mutations and pathological gene alterations related to fibrosis in the liver, kidney and lung. Genetic studies have demonstrated that endometriosis has somatic mutations in driver genes, including AT-rich interaction domain 1A (ARID1A), phosphatase and tensin homolog (PTEN), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), KRAS, tumor protein P53 (TP53), P16 or B-Raf proto-oncogene, serine/threonine kinase (BRAF), directly related to neoplasms. Tissue injury and repair induce inflammation and oxidative stress, which induces (epi)genetic DNA damage and mutations, promotes epithelial-mesenchymal transition (EMT) and fibroblast-to-myofibroblast transdifferentiation (FMT) through the induction of fibrogenic signaling pathways regulated by transforming growth factor (TGF)-β/Smad and these driver genes, resulting in α-smooth muscle actin (α-SMA) and collagen production and increased cellular contractility, leading to increased smooth muscle metaplasia (SMM) and fibrosis. Elevated levels of reactive oxygen species may lead to increased damage to DNA and may induce cell cycle arrest accompanied by the acquisition of replication stress, senescence-associated characteristics and carcinogenesis, at least to a certain extent. This process may be a major hallmark of fibrogenesis of the liver, kidney and lung. Given that somatic driver mutations occur frequently in benign endometriosis and the physiologically normal endometrium, there may be at least 2 distinct phases of epigenetic and genetic modifications in endometriosis: The initial wave of hemoglobin-induced oxidative stress and (epi)genetic DNA damages and mutations would be followed by the second big wave of cellular senescence, fibrogenesis and finally, carcinogenesis. Thus, it can be concluded that endometriosis may represent a hemorrhageinduced fibrotic and low-grade pre-neoplastic lesion that may be a precursor lesion of a subset of malignant transformation. Contents 1. Introduction 2. Data collection methods 3. The driver genes in endometriosis as a major hallmark of fibrosis in other organ systems 4. Endometriosis as a fibrotic condition 5. Endometriosis as a premalignant condition 6. Conclusions and future considerations

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“…Thus, we investigated the effects of varying doses of IL-1β and/or TNFα (supplementary Note, supplementary Methods, supplementary Results, supplementary Fig. S1) on cell proliferation, cell migration, collagen gel contraction, mRNA and/or protein expression of collagen type I (Col I), matrix metalloproteinase-1 (MMP-1), and alpha smooth muscle actin (αSMA), which are commonly used methods for evaluating fibrosis [4][5][6][7][8][9][10][11][12] , in endometriotic and menstrual endometrial stromal cells of patients with endometriosis. We included menstrual endometrial stromal cells of healthy fertile women for comparison.…”

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Dose-dependent pro- or anti-fibrotic responses of endometriotic stromal cells to interleukin-1β and tumor necrosis factor α

Matsuzaki

Pouly

Canis

2020

Sci Rep

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Endometriosis are characterized by dense fibrous tissue. Numerous studies have investigated roles of inflammation on the pathophysiology of endometriosis. However, the interplay of inflammation and fibrosis remains to be clarified. Here we show that low levels of interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNFα) promoted a fibrotic phenotype, whereas high levels of IL-1β and tnfα inactivated the fibrotic phenotype of endometriotic stromal cells (Ectopic-ES). IL-1β 10 pg/mL and TNFα 100 and 1,000 pg/mL had minimal effects, whereas the highest dose of IL-1β (100 pg/mL) significantly decreased collagen gel contraction in Ectopic-ES. Furthermore, in Ectopic-ES, low levels of IL-1β (1 pg/mL) and/or tnfα 10 pg/mL significantly increased Col I mRNA expression, whereas higher doses of IL-1β (10 and/ or 100 pg/mL) and/or TNFα (100 and/or 1,000 pg/mL) significantly decreased Col I and/or αSMA mRNA expression and the percentage of cells with Col I + and/or αSMA + stress fibers. In contrast, in either menstrual endometrial stromal cells of patients with endometriosis or those of healthy women, varying doses of IL-1β and/or TNFα had no significant effects on either Col I or αSMA mRNA/protein expression. The present findings bring into question whether we should still continue to attempt anti-inflammatory treatment strategies for endometriosis. Endometriosis, particularly deep infiltrating endometriosis and ovarian endometriosis, is histologically characterized by the presence of dense fibrous tissue 1-3. Previous studies including those from our group demonstrated that knowledge of the cellular and molecular mechanisms of fibrosis is indispensable for the development of strategies to prevent and treat this condition 4-12. Acute inflammatory reactions play an important part in triggering fibrosis in many different organ systems 13. Low-grade but persistent inflammation is also thought to contribute to the progression of fibrosis 13. In many fibrotic disorders, a persistent inflammatory trigger is crucial to the activation of the wound-healing process that leads to fibrosis 13. Endometriosis has been considered to be an immune-mediated chronic inflammatory disorder 14,15. Numerous studies have investigated the role of immune-mediated chronic inflammation on the pathophysiology of endometriosis 14,15 and attempted to evaluate various anti-inflammatory drugs, including tumor necrosis factor-alpha TNFα inhibitors 16-18 and cyclooxygenase-2 (Cox-2) inhibitors 19-21 , in endometriosis. However, the interplay between inflammation and fibrosis at the cellular and molecular levels in endometriosis pathophysiology remains to be clarified. Studies have suggested that repeated tissue injury and repair caused by recurrent menstrual bleeding induce inflammation, resulting in fibrosis in endometriosis 8,9. However, endometrial repair is normally scarless 22. It is not clear why repeated tissue injury and repair caused by recurrent menstrual bleeding do not induce fibrosis in the endometrium, whereas they do in endometriosis. Acco...

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Sensory nerve-derived neuropeptides accelerate the development and fibrogenesis of endometriosis

Cited by 40 publications

References 87 publications

Platelets induce increased estrogen production through NF-κB and TGF-β1 signaling pathways in endometriotic stromal cells

Platelets induce increased estrogen production through NF-κB and TGF-β1 signaling pathways in endometriotic stromal cells

Somatic driver mutations in endometriosis as possible regulators of fibrogenesis (Review)

Dose-dependent pro- or anti-fibrotic responses of endometriotic stromal cells to interleukin-1β and tumor necrosis factor α

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