Mesenchymal stem cells inhibit both endogenous and exogenous MMPs via secreted TIMPs.
Mesenchymal stem cells (MSCs) have been shown to be perivascular, occupying a prime location for regulating vessel stability. Here, we focused on the MSC-contribution of key regulators of the perivascular niche, the matrix metalloproteinases (MMPs) and their inhibitors, the TIMPs. Despite secretion of active forms of MMPs by MSCs, MMP enzyme activity was not detected in MSC-conditioned medium (MSC-CM) due to TIMP-mediated inhibition. By means of bifunctional-crosslinking to probe endogenous MMP:TIMP interactions, we showed MMP-2-inhibition by TIMP-2. MSCs also inhibited high levels of exogenous MMP-2 and MMP-9 through TIMP-2 and TIMP-1, respectively. Furthermore, MSC-CM protected vascular matrix molecules and endothelial cell structures from MMP-induced disruption. MSCs remained matrix-protective when exposed to pro-inflammatory cytokines and hypoxia, countering these stresses with increased TIMP-1 expression and augmented MMP-inhibition. Thus, MSCs are revealed as robust sources of TIMP-mediated MMP-inhibition, capable of protecting the perivascular niche from high levels of MMPs even under pathological conditions.
Lozito
Thomas P
TP
Department of Health and Human Services, Cartilage Biology and Orthopaedics Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Tuan
Rocky S
RS
D002478:Cells, Cultured; D003470:Culture Media / Q000737:chemistry; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D006801:Humans; D000860:Hypoxia; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D008875:Middle Aged; D020033:Protein Isoforms / Q000378:metabolism*; D055153:Stem Cell Niche; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism*
D003470:Culture Media; D061965:Matrix Metalloproteinase Inhibitors; D020033:Protein Isoforms; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D020782:Matrix Metalloproteinases