Bone morphogenetic protein 2 promotes human trophoblast cell invasion and endothelial‐like tube formation through ID1‐mediated upregulation of IGF binding protein‐3

Zhao, Hongjin; Klausen, Christian; Zhu, Hua; Li, Yan

doi:10.1096/fj.201902168rr

Cited by 25 publications

(34 citation statements)

References 76 publications

(178 reference statements)

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“…Several studies have shown that ID1 is a downstream target of BMP, 25‐27 and the administration of IGFBP 3 could reverse the dysregulated expression of vascular and fibroblastic genes in heart tissue with Id conditionally knocked out 28 . Notably, our previous studies also showed that BMP2 promotes cell invasion and endothelial‐like tube formation via the ID1‐mediated upregulation of IGFBP3 expression in human trophoblast cells 11 . Although the essential roles of IGFBP3 induced by BMP2 in trophoblast cell invasion have been confirmed during placentation, 11 there is no evidence showing the functional roles of BMP2‐induced IGFBP3 signaling in the process of endometrial remodeling.…”

Section: Introductionmentioning

confidence: 87%

“…Among the BMP subfamily members, BMP2 is expressed in both human secretory endometrial stromal and decidual cells, and this growth factor plays critical roles in regulating the processes of decidualization [7][8][9] and trophoblast cell invasion. [10][11][12] Although numerous BMP subfamily members (BMP2, BMP4, BMP5, BMP6, BMP7, and BMP8) are expressed in the uterus of pregnant mice, only the expression of BMP2 is spatiotemporally correlated with decidualization and embryo implantation. 13 Conditional ablation of Bmp2 in the mouse uterus resulted in complete infertility because the uterine stroma was incapable of undergoing the decidual reaction.…”

Section: Introductionmentioning

confidence: 99%

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The regulation of IGFBP3 by BMP2 has a role in human endometrial remodeling

et al. 2020

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In mammals, bone morphogenetic protein 2 (BMP2) is a critical regulator of endometrial decidualization and early implantation. Insulin-like growth factor-binding protein 3 (IGFBP3) is highly expressed in the endometrium and at the maternal-fetal interface in multiple species, including humans. BMP2-induced IGFBP3 signaling has been confirmed to have a role in trophoblast cell invasion; however, the involvement of this signaling pathway in endometrial remodeling remains poorly understood. To determine the roles of BMP2 in regulating IGFBP3 expression during the How to cite this article:

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Section: Introductionmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

The regulation of IGFBP3 by BMP2 has a role in human endometrial remodeling

et al. 2020

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“…The same group extended these studies and showed that BMP2 promotes TB cell invasion by upregulating N-cadherin via non-canonical ALK2/3/4-SMAD2/3-SMAD4 signaling [78]. They also revealed the role of BMP2 in promoting TB invasion and tube-like formation by ID1-mediated insulin-like growth factor binding protein-3 (IGFBP3) upregulation in primary and HTR8/SVneo cell cultures [47]. Indeed, it is becoming more evident that the TGFβ family uses combinatorial signaling via both SMAD cascades to induce EMT [79].…”

Section: Bmp Cascadementioning

confidence: 86%

“…ID1 is strongly expressed in EVTs of human first trimester placenta compared to CTBs, suggesting that ID1 contributes to the differentiation of CTBs into EVTs [88]. BMP2 promotes TB cell invasion and endothelial-like tube formation by ID1-mediated IGFBP-3 upregulation, as demonstrated both in primary TBs and the HTR8/SVneo TB cell line [47]. ID2 downregulation is essential for CTB differentiation, but in cases of abnormal differentiation from TB in PE women, ID2 expression was constitutive [89].…”

Section: Tgfβ Family-associated Factorsmentioning

confidence: 90%

The TGFβ Family in Human Placental Development at the Fetal-Maternal Interface

2020

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Emerging data suggest that a trophoblast stem cell (TSC) population exists in the early human placenta. However, in vitro stem cell culture models are still in development and it remains under debate how well they reflect primary trophoblast (TB) cells. The absence of robust protocols to generate TSCs from humans has resulted in limited knowledge of the molecular mechanisms that regulate human placental development and TB lineage specification when compared to other human embryonic stem cells (hESCs). As placentation in mouse and human differ considerably, it is only with the development of human-based disease models using TSCs that we will be able to understand the various diseases caused by abnormal placentation in humans, such as preeclampsia. In this review, we summarize the knowledge on normal human placental development, the placental disease preeclampsia, and current stem cell model systems used to mimic TB differentiation. A special focus is given to the transforming growth factor-beta (TGFβ) family as it has been shown that the TGFβ family has an important role in human placental development and disease.

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“…The establishment of trophoblast lineage and differentiation into distinct trophoblast subtypes that exert various functions is tightly regulated by signaling cascades integrating with transcription factor networks 3 . Previous work has identified transcription factor ID1 as a mediator of BMP2‐induced IGFBP3 expression as well as trophoblast invasion and endothelial‐like tube formation 2 . Whether other transcription factors are involved in BMP2‐regulated trophoblast functions and the molecular mechanisms underlying transcriptional regulation of these factors has yet to be elucidated.…”

Section: Introductionmentioning

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 promotes human trophoblast cell invasion and endothelial‐like tube formation through ID1‐mediated upregulation of IGF binding protein‐3

Abstract: Extravillous cytotrophoblasts (EVTs) invade into the uterine wall and remodel spiral arteries for proper placentation. Studies from us and others have demonstrated that the transforming growth factor-β superfamily member bone morphogenetic protein

Cited by 25 publications

References 76 publications

The regulation of IGFBP3 by BMP2 has a role in human endometrial remodeling

The regulation of IGFBP3 by BMP2 has a role in human endometrial remodeling

The TGFβ Family in Human Placental Development at the Fetal-Maternal Interface

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

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