Bone morphogenetic protein 2 induces the activation of WNT/β-catenin signaling and human trophoblast invasion through up-regulating BAMBI

Zhao, Hongjin; Chang, Hsun‐Ming; Klausen, Christian; Li, Yan

doi:10.1016/j.cellsig.2019.109489

Cited by 19 publications

(19 citation statements)

References 46 publications

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“…Trophoblast cells are closely associated with placenta formation, which could conceivably promote PE progression through effects on cellular biological function, and indeed, impaired invasion and migration of trophoblast cells are linked to PE development [ 21 ]. The HTR8/SVneo trophoblast cells used in the present study are immortalized human extravillous trophoblasts [ 22 ]. Furthermore, we collected and analyzed clinical placenta samples.…”

Section: Discussionmentioning

confidence: 99%

miR-519d downregulates LEP expression to inhibit preeclampsia development

Cai

et al. 2021

Open Medicine

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The purpose of the current study was to characterize role of microRNA (miR)-519d in trophoblast cells and preeclampsia (PE) development and its potential underlying mechanism. Regulation of leptin (LEP) by miR-519d was verified using a dual-luciferase reporter gene assay. Loss- and gain-of-function assays were conducted to detect the roles of miR-519d and LEP in proliferation, migratory ability, and invasive capacity of HTR-8/SVneo cells by means of CCK-8 assay, scratch test, and Transwell invasion assay, respectively. The cell apoptosis rate and cycle distribution were analyzed by flow cytometry. LEP expression was elevated, whereas miR-519d level was suppressed in the PE placenta samples compared with those from normal pregnancy. Depletion of LEP promoted proliferation, migratory ability, and invasive capacity and repressed apoptosis. miR-519d could bind 3′ untranslated regions (3′UTRs) of LEP, the extent of which correlated negatively with LEP expression. miR-519d suppressed the expression of LEP in HTR-8/SVneo cells. Moreover, overexpression of miR-519d promoted survival and migratory ability of HTR-8/SVneo cells. Taken together, we find that miR-519d targeted LEP and downregulated its expression, which could likely inhibit the development of PE.

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Section: Discussionmentioning

confidence: 99%

miR-519d downregulates LEP expression to inhibit preeclampsia development

Cai

et al. 2021

Open Medicine

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“…TWIST1, which is a negative regulator of trophoblast cell invasion [68][69][70] , was uniquely downregulated 2.9-fold in control-iPSC-derived trophoblast under hypoxia. BAMBI, which mediates BMP2-induced activation of WNT/β-catenin pathway and trophoblast invasion in human primary EVT and immortalized human EVT cell lines 71 , was uniquely upregulated 3.1-fold in control-iPSC-derived trophoblast under hypoxia.…”

Section: Assessment Of the Epigenome In Mscs And Ipscs From Pe And Nomentioning

confidence: 98%

Modeling preeclampsia using human induced pluripotent stem cells

Horii

Morey

Bui

et al. 2021

Sci Rep

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Preeclampsia (PE) is a pregnancy-specific hypertensive disorder, affecting up to 10% of pregnancies worldwide. The primary etiology is considered to be abnormal development and function of placental cells called trophoblasts. We previously developed a two-step protocol for differentiation of human pluripotent stem cells, first into cytotrophoblast (CTB) progenitor-like cells, and then into both syncytiotrophoblast (STB)- and extravillous trophoblast (EVT)-like cells, and showed that it can model both normal and abnormal trophoblast differentiation. We have now applied this protocol to induced pluripotent stem cells (iPSC) derived from placentas of pregnancies with or without PE. While there were no differences in CTB induction or EVT formation, PE-iPSC-derived trophoblast showed a defect in syncytialization, as well as a blunted response to hypoxia. RNAseq analysis showed defects in STB formation and response to hypoxia; however, DNA methylation changes were minimal, corresponding only to changes in response to hypoxia. Overall, PE-iPSC recapitulated multiple defects associated with placental dysfunction, including a lack of response to decreased oxygen tension. This emphasizes the importance of the maternal microenvironment in normal placentation, and highlights potential pathways that can be targeted for diagnosis or therapy, while absence of marked DNA methylation changes suggests that other regulatory mechanisms mediate these alterations.

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“…SOX4 can directly interact with and stabilize β‐catenin protein to enhance WNT signaling in colon cancer cells 31 . Our previous study has demonstrated that BMP2 activates WNT signaling by inducing GSK3β phosphorylation and thus increasing β‐catenin accumulation 32 . It would be interesting to examine whether SOX4 is involved in BMP2‐induced WNT/β‐catenin activation in human trophoblast.…”

Section: Discussionmentioning

confidence: 99%

Transcription factor SOX4 facilitates BMP2‐regulated gene expression during invasive trophoblast differentiation

Zhu

Klausen

et al. 2021

The FASEB Journal

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The interplay between growth factors, signaling pathways and transcription factors during placental development is key to controlling trophoblast differentiation. Bone morphogenetic protein 2 (BMP2) has been implicated in trophoblast invasion and spiral artery remodeling during early placental development. However, the molecular mechanisms by which these are accomplished have not been fully elucidated, particularly for transcriptional regulation of key transcription factors. Here, we identified SOX4 as a direct target gene induced by BMP2 in first‐trimester placental trophoblasts. Analysis of single‐cell RNA‐seq data from first‐trimester placentas and decidua tissues revealed that SOX4 expression is mainly localized in extravillous trophoblast and decidual stromal cells. Moreover, gain‐ and loss‐of‐function approaches demonstrated that SOX4 exerts a pro‐invasive role in human trophoblasts, and this effect contributes to BMP2‐enhanced trophoblast invasion. Importantly, we found that SOX4 was required for BMP2‐induced regulation of a subset of genes associated with cell migration and extracellular matrix organization. We also show that SOX4‐dependent regulation of the BMP2 target SERPINE2 occurs via binding of SOX4 to regulatory elements such as enhancers, thereby promoting BMP2‐induced trophoblast invasion. In conclusion, these findings uncover a novel mechanism involving SOX4 that shapes the BMP2‐regulated transcriptional network during invasive trophoblast development.

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Bone morphogenetic protein 2 induces the activation of WNT/β-catenin signaling and human trophoblast invasion through up-regulating BAMBI

Cited by 19 publications

References 46 publications

miR-519d downregulates LEP expression to inhibit preeclampsia development

miR-519d downregulates LEP expression to inhibit preeclampsia development

Modeling preeclampsia using human induced pluripotent stem cells

Transcription factor SOX4 facilitates BMP2‐regulated gene expression during invasive trophoblast differentiation

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