Defining the role of mesenchymal stromal cells on the regulation of matrix metalloproteinases in skeletal muscle cells

Year: 2014

Authors: Sassoli C., Nosi D., Tani A., Chellini F., Mazzanti B., Quercioli F., Zecchi-Orlandini S., Formigli L.

Autors Affiliation: Dept. of Experimental and Clinical Medicine-Section of Anatomy and Histology, University of Florence, Largo Brambilla, 3, 50134, Florence, Italy; Dept. of Experimental and Clinical Medicine-Section of Haematology, University of Florence, Largo Brambilla, 3, 50134, Florence, Italy; CNR-National Institute of Optics (INO), Largo Enrico Fermi 6, 50125 Arcetri-Florence, Italy

Abstract: Recent studies indicate that mesenchymal stromal cell (MSC) transplantation improves healing of injured and diseased skeletal muscle, although the mechanisms of benefit are poorly understood. In the present study, we investigated whether MSCs and/or their trophic factors were able to regulate matrix metalloproteinase (MMP) expression and activity in different cells of the muscle tissue. MSCs in co-culture with C2C12 cells or their conditioned medium (MSC-CM) up-regulated MMP-2 and MMP-9 expression and function in the myoblastic cells; these effects were concomitant with the down-regulation of the tissue inhibitor of metalloproteinases (TIMP)-1 and -2 and with increased cell motility. In the single muscle fiber experiments, MSC-CM administration increased MMP-2/9 expression in Pax-7+ satellite cells and stimulated their mobilization, differentiation and fusion. The anti-fibrotic properties of MSC-CM involved also the regulation of MMPs by skeletal fibroblasts and the inhibition of their differentiation into myofibroblasts. The treatment with SB-3CT, a potent MMP inhibitor, prevented in these cells, the decrease of a-smooth actin and type-I collagen expression induced by MSC-CM, suggesting that MSC-CM could attenuate the fibrogenic response through mechanisms mediated by MMPs. Our results indicate that growth factors and cytokines released by these cells may modulate the fibrotic response and improve the endogenous mechanisms of muscle repair/regeneration.


Volume: 323 (2)      Pages from: 297  to: 313

More Information: This study was supported by research founding from MIUR (Ministero dell’Istruzione dell’Università e della Ricerca)- Italy to C.S, D.N., L.F. and S.Z-O. and by a research grant from the Ente Cassa di Risparmio di Firenze (Florence, Italy) to L.F.
KeyWords: Alpha smooth muscle actin; collagen type 1; gelatinase A; gelatinase B; matrix metalloproteinase; tissue inhibitor of metalloproteinase 1; tissue inhibitor of metalloproteinase 2, adult; animal cell; animal tissue; article; cell differentiation; cell fusion; cell motility; cell stimulation; coculture; controlled study; culture medium; down regulation; enzyme activity; enzyme induction; enzyme regulation; fibroblast; fibrogenesis; male; mesenchymal stroma cell; mouse; muscle cell; muscle tissue; myoblast; myofibroblast; nonhuman; primary cell culture; priority journal; protein expression; skeletal muscle; skeletal muscle satellite cell; young adult, Matrix metalloproteinases (MMPs); Mesenchymal stromal cells (MSCs); Myoblast differentiation; Satellite cells; Skeletal fibroblasts, Actins; Animals; Cell Differentiation; Cell Movement; Cells, Cultured; Collagen Type I; Culture Media, Conditioned; Cytokines; Fibroblasts; Heterocyclic Compounds, 1-Ring; Humans; Intercellular Signaling Peptides and Proteins; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Mesenchymal Stromal Cells; Mice; Muscle Fibers, Skeletal; NIH 3T3 Cells; Sulfones; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinase-2
DOI: 10.1016/j.yexcr.2014.03.003

Citations: 32
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