Microvesicles shed from fibroblasts act as metalloproteinase carriers in a 3-D collagen matrix

Abstract

This study shows that fibroblasts migrating into a collagen matrix release numerous microvesicles into the surrounding medium. By spreading in regions of the matrix far distant from cells of origin, microvesicles carry metalloproteinase 9 (MMP-9) to act upon the collagen fibrils. As a result, the collagen matrix is gradually transformed from a laminar to a fibrillar type of architecture. As shown by western blots and gelatin zymography, MMP-9 is secreted as a 92 kDa precursor and activated upon release of 82 kDa product into the culture medium. Activation is more efficient under three-dimensional than in two-dimensional culturing conditions. While MMP-9 labeling is associated with intraluminal vesicles clustered inside the microvesicles, the microvesicle’s integrin β1 marker is bound to the outer membrane. The intraluminal vesicles are recruited from the cortical cytoplasm and eventually released following uploading inside the microvesicle. Here, we propose that fusion of the intraluminal vesicles with the outer microvesicle’s membrane could work as a mechanism controlling the extent to which MMP-9 is first activated and then released extracellularly.

Matrix Metalloproteinases as Biomarkers of Atherosclerotic Plaque Instability

“…Angiogenesis is promoted at low levels of endothelial-derived microvesicles containing active MMP-2 and MMP-9, while high levels of these MVs inhibit plaque angiogenesis which reduces the risk of rupture [35]. In addition, Lozito et al demonstrated that EVs secreted from endothelial cells are involved in the activation of MMP-2 initiating remodeling of the vascular matrix [36,37]. MMP-2 present in EC-derived vesicles also participates in neovascularization, promoting capillary structure formation and plaque rupture [25,38].…”

Extracellular Vesicles and Matrix Remodeling Enzymes: The Emerging Roles in Extracellular Matrix Remodeling, Progression of Diseases and Tissue Repair

“…In addition to the Rab GTPases, the kinesins could also drive cell surface exposure of MT1-MMP and promote CD44 shedding in primary macrophages [ 51 ]. Masci and colleagues propose that EVs dispersed along the fibroblast cell periphery contain abundance of MMPs [ 52 ]. The authors also demonstrate that the fusion of intraluminal vesicles with the outer membrane microvesicles (MVs) could act as a controlling mechanism during which MMP-9 is first activated (i.e., cleaved) and then released extracellularly.…”

“…The regulation of EV-associated proteolytic activities plays active roles in physiological processes such as reproduction [ 52 ]. The gelatinases such as MMP-2 and MMP-9 found in the seminal vesicles and ventral prostate of Meriones libycus are involved in the seasonal reproductive cycle.…”

“…The gelatinases such as MMP-2 and MMP-9 found in the seminal vesicles and ventral prostate of Meriones libycus are involved in the seasonal reproductive cycle. In fact, the immunosuppression of MMP-2 and MMP-9 in seminal vesicles has been observed during seasonal cycle of reproduction [ 52 ].…”

Characterization of Collagen/Lipid Nanoparticle–Curcumin Cryostructurates for Wound Healing Applications

“…The best structural conditions were provided by native collagen cryostructurates obtained by freeze‐drying of 1% w/v collagen gel in acetic acid, characterized by high matrix porosity and thick fiber bundles . Under these conditions, cells proliferated, migrated, and adhered to the collagen fibers through extended filopodia …”