MT1-MMP–dependent neovessel formation within the confines of the three-dimensional extracellular matrix

Chun, Tae Hwa; Sabeh, Farideh; Ota, Ichiro; Murphy, Hedwig S.; McDonagh, Kevin T.; Holmbeck, Kenn; Birkedal‐Hansen, Henning; Allen, Edward; Weiss, Stephen J.

doi:10.1083/jcb.200405001

Cited by 311 publications

(346 citation statements)

References 62 publications

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“…RT-PCR analysis of their upregulation and downregulation revealed that only gelatinase MMP-2 was constantly active, whereas MMP-9 and MMP-19 genes were active in the first days of perfused culture, but silenced at day 12, when tubular network was formed ( Figure 4B). Since MT1-MMP proteolyzes the pro-MMP-2 to its active form that can activate MMP-9, these three MMPs would form a collaborative network to drive the vasculogenic response [27]. The data presented here shows that PEGylated fibrin matrix supports the vasculogenic proteolytic program of HUVEChASC co-culture.…”

Section: Discussionmentioning

confidence: 61%

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Hydrogel-based microfluidics for vascular tissue engineering

Koroleva

Deiwick

Nguyen³

et al. 2016

BioNanoMaterials

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Abstract:In this work, we have explored 3-D co-culture of vasculogenic cells within a synthetically modified fibrin hydrogel. Fibrinogen was covalently linked with PEG-NHS in order to improve its degradability resistance and physico-optical properties. We have studied influences of the degree of protein PEGylation and the concentration of enzyme thrombin used for the gel preparation on cellular responses. Scanning electron microscopy analysis of prepared gels revealed that the degree of PEGylation and the concentration of thrombin strongly influenced microstructural characteristics of the protein hydrogel. Human umbilical vein endothelial cells (HUVECs) and human adipose-derived stem cells (hASCs), used as vasculogenic co-culture, could grow in 5:1 PEGylated fibrin gels prepared using 1:0.2 protein to thrombin ratio. This gel formulation supported hASCs and HUVECs spreading and the formation of cell extensions and cell-to-cell contacts. Expression of specific ECM proteins and vasculogenic process inherent cellular enzymatic activity were investigated by immunofluorescent staining, gelatin zymography, western blot and RT-PCR analysis. After evaluation of the optimal gel composition and PEGylation ratio, the hydrogel was utilized for investigation of vascular tube formation within a perfusable microfluidic system. The morphological development of this co-culture within a perfused hydrogel over 12 days led to the formation of interconnected HUVEC-hASC network. The demonstrated PEGylated fibrin microfluidic approach can be used for incorporating other cell types, thus representing a unique experimental platform for basic vascular tissue engineering and drug screening applications.

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Section: Discussionmentioning

confidence: 61%

“…Invasion and tubulogenesis only takes place if a full-length membrane-associated form of type-1 matrix metalloproteinase (MT1-MMP) is expressed [27]. Recently published analyses revealed a combinatorial MT1-MMP proteolytic program that governs endothelial cell chemotaxis, motility, and adhesion, which ultimately leads to angiogenesis [28].…”

Section: Discussionmentioning

confidence: 99%

Hydrogel-based microfluidics for vascular tissue engineering

Koroleva

Deiwick

Nguyen³

et al. 2016

BioNanoMaterials

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“…Membrane type-1 matrix metalloproteinase has been implicated in the pericellular proteolysis in events ranging from normal development to malignant progression (Hotary et al, 2003;Chun et al, 2004;Holmbeck et al, 2004). MT1-MMP requires proteolytic activation and the removal of the N-terminal prodomain sequence in order to be converted into the catalytically active species (Murphy et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Furin regulates the intracellular activation and the uptake rate of cell surface-associated MT1-MMP

et al. 2006

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Invasion-promoting membrane type-1 matrix metalloproteinase (MT1-MMP) functions in cancer cells as an oncogene and as a mediator of proteolytic events on the cell surface. To exert its functional activity, MT1-MMP requires proteolytic removal of the prodomain sequence. There are two potential furin cleavage motifs, R 89 -R-P-R-C 93 and R 108 -R-K-R-Y 112 , in the prodomain sequence of MT1-MMP. Our data suggest an important role of furin and related proprotein convertases (PCs) in mediating both the activation of MT1-MMP and the levels of functionally active MT1-MMP at the surface of cancer cells. We have determined that the peptide sequence that spans the first cleavage site is susceptible to furin and PC5/6, whereas the second sequence is susceptible to furin and also to PC5/6, PC7 and PACE4. In the structure of the MT1-MMP proenzyme, the R 89 -R-P-R-C 93 site, however, is inaccessible to PCs. Our studies also demonstrated a direct functional link between the activation and the uptake rate of the proenzyme and the enzyme of MT1-MMP. Thus, the uptake rate of the latent MT1-MMP proenzyme noticeably exceeded that of the active enzyme. We conclude that furin and related PCs are the essential components of the specialized cellular machinery that controls the levels of the functionally active, mature, MT1-MMP enzyme on the cell surface to continually support the potency of pericellular proteolysis.

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“…MMP9 and MMP14 have another effect on the vasculature: the perivascular (or smooth muscle) cells that ensheath the endothelial cells of the blood vessels are missing or their density is significantly decreased in normal vessels and during tumour neoangiogenesis [57][58][59] . This defect is especially evident in the smaller arterioles of the brain, and many of the remaining perivascular cells have irregular morphology.…”

Section: Mmps In Blood-vessel Remodellingmentioning

confidence: 99%

Matrix metalloproteinases and the regulation of tissue remodelling

Page-McCaw

Ewald

Werb

2007

Nat Rev Mol Cell Biol

2,554

2,180

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Matrix metalloproteinases (MMPs) were discovered because of their role in amphibian metamorphosis, yet they have attracted more attention because of their roles in disease. Despite intensive scrutiny in vitro, in cell culture and in animal models, the normal physiological roles of these extracellular proteases have been elusive. Recent studies in mice and flies point to essential roles of MMPs as mediators of change and physical adaptation in tissues, whether developmentally regulated, environmentally induced or disease associated.The founding member of the matrix metalloproteinase (MMP) family, collagenase, was identified in 1962 by Gross and Lapiere, who found that tadpole tails during metamorphosis contained an enzyme that could degrade fibrillar collagen 1,2 . Subsequently, an interstitial collagenase, collagenase-1 or MMP1, was found in diseased skin and synovium 3 . In vitro, MMP1 initiates degradation of native fibrillar collagens, crucial components of vertebrate extracellular matrix (ECM), by cleaving the peptide bond between Gly775-Ile776 or Gly775-Lys776 in native type I, II or III collagen molecules 3,4 . Further research led to the discovery of a family of structurally related proteinases (23 in human, 24 in mice), now referred to as the MMP family.Interest in MMPs increased in the late 1960s and early 1970s following observations that MMPs are upregulated in diverse human diseases including rheumatoid arthritis and cancer. Importantly, high levels of MMPs often correlated with poor prognosis in human patients (reviewed in REF. 5 ). However, recent clinical data indicate that the relationship between § These authors contributed equally to this paper. Competing interests statementThe authors declare no competing financial interests. DATABASESThe following terms in this article are linked online to: Entrez Genome: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene DmMmp1 | DmMmp2 NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptMMPs and disease is not simple; for example, increased MMP activity can enhance tumour progression or can inhibit it (reviewed in REF. 6 ). This complex relationship between MMP expression and cancer has increased the basic and clinical interest in understanding MMP function in vivo, but it has also focused attention on MMPs and pathology, and relatively less attention has been focused on the normal roles of these enzymes. MMP proteolysisMMPs are members of the metzincin group of proteases, which are named after the zinc ion and the conserved Met residue at the active site 11,12 . Recent work has generated a unified peptidase nomenclature 13 Functions of MMP proteolysisHistorically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. However, MMP proteolysis can create space for cells to migrate, can produce specific substrate-cleavage fragments with independent biological activity, can MMPs in bone modelling and remodellingBone is an important site of ongoing tissue remodelling during development...

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MT1-MMP–dependent neovessel formation within the confines of the three-dimensional extracellular matrix

Cited by 311 publications

References 62 publications

Hydrogel-based microfluidics for vascular tissue engineering

Hydrogel-based microfluidics for vascular tissue engineering

Furin regulates the intracellular activation and the uptake rate of cell surface-associated MT1-MMP

Matrix metalloproteinases and the regulation of tissue remodelling

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