MMP14 Regulates Cranial Neural Crest Epithelial‐to‐Mesenchymal Transition and Migration

Garmon, Taylor; Wittling, Megen; Nie, Shuyi

doi:10.1002/dvdy.24661

Cited by 37 publications

(40 citation statements)

References 66 publications

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“…This conclusion is supported by the identification of ERG + SMA + cells with active SMAD2 signaling within the infarct and by the results with in vitro experiments showing that addition of neutralizing anti-TGFβ1 antibody to EC-Mφ co-cultures abolished EndMT. Our findings are in line with the role of MT1-MMP as an activator of epithelial to mesenchymal transition (EMT) in other pathophysiological contexts such as development, cancer, and lung fibrosis ( Garmon et al, 2018 ; Nguyen et al, 2016 ; Xiong et al, 2017 ). Interestingly, a recent scRNAseq study carried out on healthy and post-infarcted hearts identified a subset of post-MI Mφs with a HIF1α-dependent signature, which specifically upregulated Mmp14 expression ( Dick et al, 2019 ).…”

Section: Discussionsupporting

confidence: 88%

Macrophages promote endothelial-to-mesenchymal transition via MT1-MMP/TGFβ1 after myocardial infarction

Alonso-Herranz

Sahún-Español

Paredes

et al. 2020

eLife

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Macrophages (Mφs) produce factors that participate in cardiac repair and remodeling after myocardial infarction (MI); however, how these factors crosstalk with other cell types mediating repair is not fully understood. Here, we demonstrated that cardiac Mφs increased expression of Mmp14 (MT1-MMP) 7 days post-MI. We selectively inactivated the Mmp14 gene in Mφs using a genetic strategy (Mmp14f/f:Lyz2-Cre). This conditional KO (MAC-Mmp14 KO) resulted in attenuated post-MI cardiac dysfunction, reduced fibrosis, and preserved cardiac capillary network. Mechanistically, we showed that MT1-MMP activates latent TGFβ1 in Mφs, leading to paracrine SMAD2-mediated signaling in endothelial cells (ECs) and endothelial-to-mesenchymal transition (EndMT). Post-MI MAC-Mmp14 KO hearts contained fewer cells undergoing EndMT than their wild-type counterparts, and Mmp14-deficient Mφs showed a reduced ability to induce EndMT in co-cultures with ECs. Our results indicate the contribution of EndMT to cardiac fibrosis and adverse remodeling post-MI and identify Mφ MT1-MMP as a key regulator of this process.

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Section: Discussionsupporting

confidence: 88%

Macrophages promote endothelial-to-mesenchymal transition via MT1-MMP/TGFβ1 after myocardial infarction

Alonso-Herranz

Sahún-Español

Paredes

et al. 2020

eLife

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“…This conclusion is further supported by the identification of ERG + SMA + cells with active SMAD2 signaling pathway within the infarction and by the results obtained in in vitro experiments. Our findings are in line with the role of MT1-MMP as an activator of epithelial to mesenchymal transition (EMT) in other pathophysiological contexts such as development, cancer, and lung fibrosis (Garmon et al, 2018;Nguyen et al, 2016;Xiong et al, 2017). Interestingly, a recent scRNAseq study carried out on healthy and post-infarcted hearts identified a subset of post-MI Mφs with a HIF1α-dependent signature, which specifically upregulated Mmp14 expression (Dick et al, 2019).…”

Section: Mφ-derived Mt1-mmp Induces Endmt After MIsupporting

confidence: 86%

Macrophages promote endothelial-to-mesenchymal transition via MT1-MMP/TGFβ1 after myocardial infarction

Alonso-Herranz

Sahún-Español

Gonzalo

et al. 2020

Preprint

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Macrophages produce factors that participate in cardiac repair and remodeling after myocardial infarction (MI); however, how these factors crosstalk with other cell types mediating repair is not fully understood. In this study, we demonstrated that cardiac macrophages increased expression of Mmp14 (MT1-MMP) 7 days post-MI. Specific macrophage-targeting of MT1-MMP (MT1-MMPΔLysM mice) attenuates post-MI cardiac dysfunction, reduces fibrosis, and preserves the cardiac capillary network. Mechanistically, we showed that MT1-MMP activates latent TGFβ1 in macrophages, leading to paracrine SMAD2-mediated signaling in endothelial cells and endothelial-to-mesenchymal transition (EndMT). Post-MI MT1-MMPΔLysM hearts contained fewer cells undergoing EndMT than their wild-type counterparts, and MT1-MMP-deficient macrophages showed a reduced ability to induce EndMT in co-cultures with endothelial cells. Our results demonstrate the contribution of EndMT to cardiac fibrosis and adverse remodeling post-MI and identify macrophage MT1-MMP as a key regulator of this process. The identified mechanism has potential as a therapeutic target in ischemic heart disease.

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“…1G). This result was verified with an in vitro degradation assay, where neural tubes (transfected with AQP-1 FL or pMES) were plated on top of fluorescently labeled gelatin (Garmon et al, 2018). After 40 hours of incubation, the assays were imaged, and average fluorescent intensity of the gelatin was quantified as a read out of degradation (Fig.…”

Section: Resultsmentioning

confidence: 75%

“…The protocol was slightly modified by heating all the gelatin to 60 degrees Celsius so that there was no issue in room temperature and warm gelatin not mixing fully. To optimize cell adhesion, fibronectin was then added over the gelatin as previously described (Garmon et al, 2018). 15 neural tubes (transfected with either pMES or AQP-1 FL) were plated into each well with 500ul of media and incubated for 40 hours.…”

Section: Methodsmentioning

confidence: 99%

Neural crest cells bulldoze through the microenvironment using Aquaporin-1 to stabilize filopodia

McLennan

McKinney

Teddy

et al. 2019

Preprint

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2Neural crest migration requires cells to move through an environment filled with dense 3 extracellular matrix and mesoderm to reach targets throughout the vertebrate embryo. 4 Here, we use high-resolution microscopy, computational modeling, and in vitro and in 5 vivo cell invasion assays to investigate the function of Aquaporin-1 (AQP-1) signaling. 6 We find that migrating lead cranial neural crest cells express AQP-1 mRNA and protein, 7 implicating a biological role for water channel protein function during invasion. 8 Differential AQP-1 levels affect neural crest cell speed, direction, and the length and 9 stability of cell filopodia. Further, AQP-1 enhances matrix metalloprotease (MMP) 10 activity and colocalizes with phosphorylated focal adhesion kinases (pFAK). Co-11 localization of AQP-1 expression with EphB guidance receptors in the same migrating 12 neural crest cells raises novel implications for the concept of guided bulldozing by lead 13 cells during migration. 14 15 3 1 INTRODUCTION 2 Cell migration is essential during embryogenesis to gastrulate, elongate the vertebrate 3 axis, and distribute cells into the periphery to contribute to organ development. Despite 4 the importance of cell migration to human development and disease, it is still unclear 5 what mechanisms enable cells to invade the dense ECM, mesoderm and other cell 6 types characteristic of the embryonic microenvironment. The complexity of the 7 embryonic microenvironment means that invading cells must rapidly change cell shape 8 and volume, form and sustain protrusions that penetrate different sized gaps, and attach 9 to and remodel the ECM. Thus, there is a tremendous need to identify and test the 10 function of molecules critical to embryonic cell migration and better understand their 11 mechanistic basis.12 13 Neural crest cell migration is one of the most prevalent examples of how cells efficiently 14 distribute throughout the growing vertebrate embryo to precise targets. In the head, 15 cranial neural crest cells must invade through dense ECM, loosely connected 16 mesoderm, and migrating endothelial cells. Yet, it has remained unclear how the 17 migrating neural crest cells that first encounter the embryonic microenvironment 18 penetrate small gaps between mesodermal cells and degrade the ECM to move in a 19 directed manner to peripheral targets. By combining dynamic in vivo imaging and super 20 resolution microscopy with gain-and loss-of-function experiments, we are poised to 21 examine the function of genes presumed critical to neural crest cell migration. Thus, the 22 embryonic neural crest is an attractive in vivo model to study the function of cell 23 invasion genes in mechanistic detail. 4 1 Using single cell RT-qPCR and transcriptome profiling, we discovered the enhanced 2 expression of several genes in the most invasive chick cranial neural crest cells, 3 including AQP-1 (McLennan et al., 2015a; Morrison et al., 2017a). AQP-1 is a 4 transmembrane channel protein that facilitates the flux of water across the plasma 5 5 ...

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MMP14 Regulates Cranial Neural Crest Epithelial‐to‐Mesenchymal Transition and Migration

Abstract: The results demonstrate that MMP14 is critical for neural crest EMT and migration, partially through regulating the levels of cadherins. Developmental Dynamics 247:1083-1092, 2018. © 2018 Wiley Periodicals, Inc.

Cited by 37 publications

References 66 publications

Macrophages promote endothelial-to-mesenchymal transition via MT1-MMP/TGFβ1 after myocardial infarction

Macrophages promote endothelial-to-mesenchymal transition via MT1-MMP/TGFβ1 after myocardial infarction

Macrophages promote endothelial-to-mesenchymal transition via MT1-MMP/TGFβ1 after myocardial infarction

Neural crest cells bulldoze through the microenvironment using Aquaporin-1 to stabilize filopodia

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