NRP1 and MMP9 are dual targets of RNA‐binding protein QKI5 to alter VEGF‐R/ NRP1 signalling in trophoblasts in preeclampsia

Yang, Xingyu; Chen, Dan; He, Biwei; Cheng, Weiwei

doi:10.1111/jcmm.16580

Cited by 14 publications

(17 citation statements)

References 46 publications

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“…Whether the same is true in human trophoblast cells remains unclear and needs to be further defined. Interestingly, NPR1 expression is downregulated in PE trophoblast cells 42 , 43 . Collectively, these results support our conclusion that downregulation of ANGPTL4 results in insufficient trophoblast cell invasion in PE.…”

Section: Discussionmentioning

confidence: 99%

G protein-coupled estrogen receptor stimulates human trophoblast cell invasion via YAP-mediated ANGPTL4 expression

Cheng

Fang

et al. 2021

Commun Biol

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Insufficient invasion of trophoblast cells into the uterine decidua is associated with preeclampsia (PE). G protein-coupled estrogen receptor (GPER) is a membrane estrogen receptor involved in non-genomic estrogen signaling. GPER is expressed in human trophoblast cells and downregulated GPER levels are noted in PE. However, to date, the role of GPER in trophoblast cells remains largely unknown. Here, we applied RNA sequencing (RNA-seq) to HTR-8/SVneo human trophoblast cells in response to G1, an agonist of GPER, and identified angiopoietin-like 4 (ANGPTL4) as a target gene of GPER. Treatment of trophoblast cells with G1 or 17β-estradiol (E2) activated Yes-associated protein (YAP), the major downstream effector of the Hippo pathway, via GPER but in a mammalian STE20-like protein kinase 1 (MST1)-independent manner. Using pharmacological inhibitors as well as loss- and gain-of-function approaches, our results revealed that YAP activation was required for GPER-stimulated ANGPTL4 expression. Transwell invasion assays demonstrated that activation of GPER-induced ANGPTL4 promoted cell invasion. In addition, the expression levels of GPER, YAP, and ANGPTL4 were downregulated in the placenta of patients with PE. Our findings reveal a mechanism by which GPER exerts its stimulatory effect on human trophoblast cell invasion by upregulating YAP-mediated ANGPTL4 expression.

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Section: Discussionmentioning

confidence: 99%

G protein-coupled estrogen receptor stimulates human trophoblast cell invasion via YAP-mediated ANGPTL4 expression

Cheng

Fang

et al. 2021

Commun Biol

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“…Cardiomyocyte specific NRP1 depletion in mice is accompanied by the upregulation of cardiac remodeling genes, including ANF, BNP βMHC 17 . Positive regulation of MMP9 by NRP1 in trophoblast cell proliferation and migration is known 32 . NRP1 ablation results in decreased protein and mRNA levels of MMP9 32 .…”

Section: Discussionmentioning

confidence: 99%

Conditional, tissue-specific CRISPR/Cas9 vector system in zebrafish reveal the role of neuropilin-1b in heart regeneration

Mukhopadhyay

Angom

Wang

et al. 2023

Preprint

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CRISPR/Cas9 technology-mediated genome editing has significantly improved the targeted inactivation of genes in vitro and in vivo in many organisms. In this study, we have reported a novel CRISPR-based vector system for conditional tissue-specific gene ablation in zebrafish. Specifically, the cardiac-specific cardiac myosins light chain 2 (cmlc2) promoter drives Cas9 expression to silence the neuropilin-1(nrp1) gene in cardiomyocytes in a heat-shock inducible manner. This vector system establishes a unique tool to regulate the gene knockout in both the developmental and adult stages and hence, widens the possibility of loss-of-function studies in zebrafish at different stages of development and adulthood. Using this approach, we investigated the role of neuropilin isoforms nrp1a and nrp1b in response to cardiac injury and regeneration in adult zebrafish hearts. We observed that both the isoforms (nrp1a and nrp1b) are upregulated after the cryoinjury. Interestingly, the nrp1b-knockout significantly altered heart regeneration and impaired cardiac function in the adult zebrafish, demonstrated by reduced heart rate (ECG), ejection fractions, and fractional shortening. In addition, we show that the knockdown of nrp1b but not nrp1a induces activation of the cardiac remodeling genes in response to cryoinjury. To our knowledge, this is the first study where we have reported a heat shock-mediated conditional knockdown of nrp1a and nrp1b isoforms using CRISPR/Cas9 technology in the cardiomyocyte in zebrafish, and furthermore have identified a crucial role for nrp1b isoform in zebrafish cardiac remodeling and eventually heart function in response to injury.

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“…Absent from this list is MMP9, a matrix metalloprotease often described as an EVT marker important in controlling trophoblast invasion [55]. It should be noted that the majority of (if not all) studies describing MMP9 expression specificity to invasive trophoblast subsets characterized and tested MMP9 function in immortalized trophoblastic cell lines [56] or inadequately described primary trophoblast cultures [57]. This latter example is especially important as primary cultures of CTB and EVT are challenging to establish and experiment on.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic mapping of the metzincin landscape in human trophoblasts

Wächter

Shannon

Castellana

et al. 2022

Preprint

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The metzincin family of metalloproteases coordinates cell and tissue developmental processes through regulation of growth factor availability, receptor signaling, and cell-cell/cell-matrix adhesion. During placental development, while distinct roles for metzincin proteases in controlling specific trophoblast functions have been described, a comprehensive assessment of metzincins during discrete stages of trophoblast differentiation has yet to be performed. Here we provide a comprehensive single cell transcriptomic resource of metzincin protease expression in diverse states of human trophoblasts from first trimester placental and decidual tissues. In the 8 distinct trophoblasts states categorized [four progenitor cytotrophoblast (CTB), one syncytiotrophoblast precursor (SCTp), two column CTB (cCTB), and one extravillous trophoblast (EVT) state], we identified 24 metzincin genes. These included 12 adamalysins, 2 pappalysins, 3 astacins and 7 matrixins. Cell trajectory modeling shows that expression of most (19/24) metzincins increases across CTB to EVT differentiation, though select proteases also increase as CTB fuse into syncytiotrophoblast. Within the CTB niche, single-cell velocity ordering identified 11 metzincins (ADAM10, -17, MMP14, -15, -19, -23B, ADAMTS1, -6, -19, TLL-1, -2) expressed in progenitors proximal to the predicted origin. Analysis of metzincin-substrate interactions within the CTB niche revealed ~150 substrates and binding partners, including FBN2 as an ADAMTS6-specific substrate preferentially expressed in trophoblast progenitors. Together, this work characterizes the metzincin transcriptomic landscape in human first trimester trophoblasts and establishes insight into the roles specific proteases perform within distinct trophoblast niches and across differentiation. This resource serves as a guide for future investigations into the roles of metzincin proteases in human placental development.

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NRP1 and MMP9 are dual targets of RNA‐binding protein QKI5 to alter VEGF‐R/ NRP1 signalling in trophoblasts in preeclampsia

Cited by 14 publications

References 46 publications

G protein-coupled estrogen receptor stimulates human trophoblast cell invasion via YAP-mediated ANGPTL4 expression

G protein-coupled estrogen receptor stimulates human trophoblast cell invasion via YAP-mediated ANGPTL4 expression

Conditional, tissue-specific CRISPR/Cas9 vector system in zebrafish reveal the role of neuropilin-1b in heart regeneration

Transcriptomic mapping of the metzincin landscape in human trophoblasts

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