title: Defining the role of mesenchymal stromal cells on the regulation of matrix metalloproteinases in skeletal muscle cells.
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 α-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.
authors.affiliation: Dept. of Experimental and Clinical Medicine-Section of Anatomy and Histology, University of Florence, Largo Brambilla, 3, 50134, Florence, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Sassoli
authors.affiliation: Dept. of Experimental and Clinical Medicine-Section of Anatomy and Histology, University of Florence, Largo Brambilla, 3, 50134, Florence, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Nosi
authors.affiliation: Dept. of Experimental and Clinical Medicine-Section of Anatomy and Histology, University of Florence, Largo Brambilla, 3, 50134, Florence, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Tani
authors.affiliation: Dept. of Experimental and Clinical Medicine-Section of Anatomy and Histology, University of Florence, Largo Brambilla, 3, 50134, Florence, Italy.
authors.forename: Flaminia
authors.initials: F
authors.lastname: Chellini
authors.affiliation: Dept. of Experimental and Clinical Medicine-Section of Haematology, University of Florence, Largo Brambilla, 3, 50134, Florence, Italy.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Mazzanti
authors.affiliation: CNR-National Institute of Optics (INO), Largo Enrico Fermi 6, 50125 Arcetri-Florence, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Quercioli
authors.affiliation: Dept. of Experimental and Clinical Medicine-Section of Anatomy and Histology, University of Florence, Largo Brambilla, 3, 50134, Florence, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Zecchi-Orlandini
authors.affiliation: Dept. of Experimental and Clinical Medicine-Section of Anatomy and Histology, University of Florence, Largo Brambilla, 3, 50134, Florence, Italy. Electronic address: formigli@unifi.it.
authors.forename: Lucia
authors.initials: L
authors.lastname: Formigli
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D002465:Cell Movement; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006573:Heterocyclic Compounds, 1-Ring / Q000494:pharmacology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism*; D041681:NIH 3T3 Cells; D013450:Sulfones / Q000494:pharmacology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000378:metabolism
chemical_list: D000199:Actins; D024042:Collagen Type I; D017077:Culture Media, Conditioned; D016207:Cytokines; D006573:Heterocyclic Compounds, 1-Ring; D036341:Intercellular Signaling Peptides and Proteins; D061965:Matrix Metalloproteinase Inhibitors; C429533:SB 3CT compound; D013450:Sulfones; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9
keywords: Matrix metalloproteinases (MMPs); Mesenchymal stromal cells (MSCs); Myoblast differentiation; Satellite cells; Skeletal fibroblasts