Decreased STAT3 in human idiopathic fetal growth restriction contributes to trophoblast dysfunction

Borg, Anthony J.; Yong, Hannah Ee Juen; Lappas, Martha; Degrelle, Séverine A.; Keogh, Rosemary; Silva-Costa, F. Da; Fournier, Thierry; Abumaree, Mohamed; Keelan, Jeffrey A.; Kalionis, Bill; Murthi, Padma

doi:10.1530/rep-14-0622

Cited by 29 publications

(29 citation statements)

References 55 publications

(68 reference statements)

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“…22, 23, 24 In accordance with a function of p45 NF-E2 in regulating trophoblast differentiation, we observed increased caspase-3 activation and cell death in association with reduced p45 NF-E2 expression in vitro and in vivo . This finding is congruent with the increased frequency of syncytial knots in IUGR.…”

Section: Discussionsupporting

confidence: 80%

“…22, 23, 24 These processes are physiologically tightly regulated but may be increased in placental diseases. Therefore, we investigated whether p45 NF-E2 deficiency enhances syncytiotrophoblast differentiation and activation of apoptosis regulators.…”

Section: Resultsmentioning

confidence: 99%

“…This finding is congruent with the increased frequency of syncytial knots in IUGR. 24, 33, 34 Further experiments are required to ascertain the mechanistic link between reduced p45 NF-E2 expression, increased activation of pro-apoptotic regulators and altered trophoblast differentiation.…”

Section: Discussionmentioning

confidence: 99%

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p45 NF-E2 regulates syncytiotrophoblast differentiation by post-translational GCM1 modifications in human intrauterine growth restriction

et al. 2017

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Placental insufficiency jeopardizes prenatal development, potentially leading to intrauterine growth restriction (IUGR) and stillbirth. Surviving fetuses are at an increased risk for chronic diseases later in life. IUGR is closely linked with altered trophoblast and placental differentiation. However, due to a paucity of mechanistic insights, suitable biomarkers and specific therapies for IUGR are lacking. The transcription factor p45 NF-E2 (nuclear factor erythroid derived 2) has been recently found to regulate trophoblast differentiation in mice. The absence of p45 NF-E2 in trophoblast cells causes IUGR and placental insufficiency in mice, but mechanistic insights are incomplete and the relevance of p45 NF-E2 for human syncytiotrophoblast differentiation remains unknown. Here we show that p45 NF-E2 negatively regulates human syncytiotrophoblast differentiation and is associated with IUGR in humans. Expression of p45 NF-E2 is reduced in human placentae complicated with IUGR compared with healthy controls. Reduced p45 NF-E2 expression is associated with increased syncytiotrophoblast differentiation, enhanced glial cells missing-1 (GCM1) acetylation and GCM1 desumoylation in IUGR placentae. Induction of syncytiotrophoblast differentiation in BeWo and primary villous trophoblast cells with 8-bromo-adenosine 3′,5′-cyclic monophosphate (8-Br-cAMP) reduces p45 NF-E2 expression. Of note, p45 NF-E2 knockdown is sufficient to increase syncytiotrophoblast differentiation and GCM1 expression. Loss of p45 NF-E2 using either approach resulted in CBP-mediated GCM1 acetylation and SENP-mediated GCM1 desumoylation, demonstrating that p45 NF-E2 regulates post-translational modifications of GCM1. Functionally, reduced p45 NF-E2 expression is associated with increased cell death and caspase-3 activation in vitro and in placental tissues samples. Overexpression of p45 NF-E2 is sufficient to repress GCM1 expression, acetylation and desumoylation, even in 8-Br-cAMP exposed BeWo cells. These results suggest that p45 NF-E2 negatively regulates differentiation and apoptosis activation of human syncytiotrophoblast by modulating GCM1 acetylation and sumoylation. These studies identify a new pathomechanism related to IUGR in humans and thus provide new impetus for future studies aiming to identify new biomarkers and/or therapies of IUGR.

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Section: Discussionsupporting

confidence: 80%

Section: Resultsmentioning

confidence: 99%

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p45 NF-E2 regulates syncytiotrophoblast differentiation by post-translational GCM1 modifications in human intrauterine growth restriction

et al. 2017

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“…The STAT3 signaling pathway is involved in the process of cell division, migration and invasion of various cell types. Moreover, STAT3 is detected in primary trophoblast cells isolated from first-trimester placenta and the activity is essential for implantation and pregnancy progression as STAT3 - / - knockout embryos degenerate and die [41]. Our data showed that STAT3 activation in trophoblasts was remarkably inhibited after exposure to THC.…”

Section: Discussionmentioning

confidence: 79%

Suppression of STAT3 Signaling by Δ9-Tetrahydrocannabinol (THC) Induces Trophoblast Dysfunction

Chang¹,

Bian²,

He³

et al. 2017

Cell Physiol Biochem

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Aims: Marijuana is a widely used illicit drug and its consumption during pregnancy has been associated with adverse reproductive outcomes. The purpose of this study was to determine the effects of chronic intake of Δ⁹-tetrahydrocannabinol (THC), the major component of marijuana, on trophoblast function, placental development, and birth outcomes. Methods: The pathological characteristics and distribution of cannabinoid receptors in placenta were observed by immunohistochemical (IHC) staining. Cell migration in response to THC was measured by transwell assays. The levels of cannabinoid receptors and Signal Transducer and Activator of Transcription 3 (STAT3) were detected by western blot. Results: We found the placenta expressed two main cannabinoid receptors, suggesting that THC induced biological responses in placental cells. Supporting this hypothesis, we observed dramatic alterations of placental morphology in marijuana users. Using THC and inhibitors of cannabinoid receptors, we demonstrated that THC impaired trophoblast cell migration and invasion partly via cannabinoid receptors. Additionally, pregnant mice injected with THC showed adverse reproductive events including reduced number of fetuses, lower maternal and placental weights. Mechanistically, STAT3 signaling pathway was involved in the THC-induced suppression of trophoblast cell motility and pregnancy outcomes. Conclusion: Our study indicates that the STAT3 signaling pathway plays a critical role in THC-induced trophoblast dysfunction.

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“…Previous reports have shown that the STAT3 signaling pathway plays an important role in regulating trophoblast cell growth, proliferation, migration and invasion 28 29 30 31 32 33 . Recent studies demonstrated that the inhibition of STAT3 phosphorylation resulted in the suppression of proliferation, migration, invasion and increased apoptosis of HTR-8/SVneo cells 31 32 33 . Certain cytokines and other molecules enhance HTR-8/SVneo cell invasion through STAT3 phosphorylation 34 35 36 .…”

Section: Discussionmentioning

confidence: 99%

Dysregulated expression of IDO may cause unexplained recurrent spontaneous abortion through suppression of trophoblast cell proliferation and migration

Zong

Luo

et al. 2016

Sci Rep

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In pregnancy, trophoblast proliferation, migration and invasion are important for the establishment and maintenance of a successful pregnancy. Impaired trophoblast function has been implicated in recurrent spontaneous abortion (RSA), a major complication of pregnancy, but the underlying mechanisms remain unclear. Indoleamine 2,3-dioxygenase (IDO), an enzyme that catabolizes tryptophan along the kynurenine pathway, is highly expressed in the placenta and serum during pregnancy. Here, we identified a novel function of IDO in regulating trophoblast cell proliferation and migration. We showed that IDO expression and activity were decreased in unexplained recurrent spontaneous abortion (URSA) compared to normal pregnancy. Furthermore, blocking IDO in human trophoblast cells led to reduced proliferation and migration, along with decreased STAT3 phosphorylation and MMP9 expression. Increased STAT3 phosphorylation reversed the IDO knockdown-suppressed trophoblast cell proliferation and migration. In addition, the overexpression of IDO promoted cell proliferation and migration, which could be abolished by the STAT3 signaling inhibitor (AG490). Finally, we observed similar reductions of STAT3 phosphorylation and MMP9 expression in URSA patients. These results indicate that the level of IDO expression may be associated with pregnancy-related complications, such as URSA, by affecting trophoblast cell proliferation and migration via the STAT3 signaling pathway.

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Decreased STAT3 in human idiopathic fetal growth restriction contributes to trophoblast dysfunction

Cited by 29 publications

References 55 publications

p45 NF-E2 regulates syncytiotrophoblast differentiation by post-translational GCM1 modifications in human intrauterine growth restriction

p45 NF-E2 regulates syncytiotrophoblast differentiation by post-translational GCM1 modifications in human intrauterine growth restriction

Suppression of STAT3 Signaling by Δ9-Tetrahydrocannabinol (THC) Induces Trophoblast Dysfunction

Dysregulated expression of IDO may cause unexplained recurrent spontaneous abortion through suppression of trophoblast cell proliferation and migration

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