Mesenchymal Stem Cells Promote Matrix Metalloproteinase Secretion by Cardiac Fibroblasts and Reduce Cardiac Ventricular Fibrosis After Myocardial Infarction

Abstract

Recent studies showed that mesenchymal stem cells (MSCs) transplantation significantly decreased cardiac fibrosis; however, the mechanisms involved in these effects are still poorly understood. In this work, we investigated whether the antifibrotic properties of MSCs involve the regulation of matrix metalloproteinases (MMPs) and matrix metalloproteinase endogenous inhibitor (TIMP) production by cardiac fibroblasts. In vitro experiments showed that conditioned medium from MSCs decreased viability, a-smooth muscle actin expression, and collagen secretion of cardiac fibroblasts. These effects were concomitant with the stimulation of MMP-2/MMP-9 activities and membrane type 1 MMP expression. Experiments performed with fibroblasts from MMP2-knockout mice demonstrated that MMP-2 plays a preponderant role in preventing collagen accumulation upon incubation with conditioned medium from MSCs. We found that MSC-conditioned medium also decreased the expression of TIMP2 in cardiac fibroblasts. In vivo studies showed that intracardiac injection of MSCs in a rat model of postischemic heart failure induced a significant decrease in ventricular fibrosis. This effect was associated with the improvement of morphological and functional cardiac parameters. In conclusion, we showed that MSCs modulate the phenotype of cardiac fibroblasts and their ability to degrade extracellular matrix. These properties of MSCs open new perspectives for understanding the mechanisms of action of MSCs and anticipate their potential therapeutic or side effects. STEM

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

“…It is necessary to prevent fibrosis, promoting ECM molecules breakdown and this aspect is further reinforced by the evidence that mesenchimal stem cells stimulate secretion of MMP-2 and delay fibrosis (Giricz et al, 2006;Mias et al, 2009). However, recently reported evidence indicates that MMP-2 activity could trigger the pathological tenascin-C deposition upon fibronectin degradation, suggesting that a MMP-2 inhibition therapeutical strategy should improve the MI outcome .…”

Stem cell transplantation as a therapy for cardiac fibrosis

“…As mentioned above, MI leads to a marked cardiomyocyte loss, which is replaced by fibrotic tissue that develops a permanent scar with a clear deterioration in heart function. In an attempt to replace the lost cardiomyocytes following ischaemia, to decrease fibrous tissue formation, and to improve cardiac performance, cellular therapy has been pursued as an alternative to classic pharmacological management [9]. Examples of the effects of different stem-cell transplantations on cardiac fibrosis are shown in Table 1.…”

“…A growing body of evidence supports the concept that MSCs decrease myocardial fibrosis and thereby attenuate cardiac remodelling [19]. Chronic cardio-renal disease Anti-fibrotic paracrine factor(s) that inhibited the activity of the TGF-β receptor complex [26] MSCs MI Down-regulates the ECM expression via decreasing fibroblast viability [9] MI Down-regulates the ECM expression via attenuating mRNA expression of TGF-β [28] Dilated cardiomyopathy and global heart failure Decreases the expression of MMP-2 and MMP-9; paracrine signalling through the anti-fibrotic, HGF [23,29] Global heart failure Down-regulates the ECM expression via decreasing fibroblast proliferation through the up-regulation of anti-proliferation-related genes such as adrenomedullin [31] MI Decreases protein production and gene expression of inflammatory cytokines such as TNF-α, IL-1β, and IL-6, as well as gene and protein expression of MMP-1 and TIMP-1 [35] Acute myocarditis Attenuated the increase in CD68 + inflammatory cells and myocardial MCP-1 expression [36] Global heart failure Decreased MMP-9 and TIMP-1 expression and collagen deposition through NF-κB-mediated mechanism [37] Cardiomyopathic hamsters Suppressed expression of collagens, MMPs, and TIMPs most probably through engagement of the skeletal muscle JAK-STAT3 axis [38,39] VSMCs Cardiomyopathic hamsters Preserved myocardial matrix homeostasis by enhancing the ratios TIMP-3/MMP-9 and TIMP-2/MMP-2…”

“…The reparative response following MI encompasses three overlapping phases: the inflammatory phase; the proliferative (granulation) phase; and the maturation phase [6][7][8]. During the initial inflammatory phase, activated macrophages and inflammatory cells produce a variety of cytokines and growth factors (fibrogenic mediators) such as transforming growth factor (TGF)-β, platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), tumour necrosis factor (TNF)-α, connective tissue growth factor (CTGF), and monocyte chemoattractant protein (MCP)-1 to stimulate the proliferation and phenotypic differentiation of fibroblasts into myofibroblasts [1,6,9]. In fibrotic hearts, the myofibroblasts are generated through proliferation and activation of resident cardiac fibroblasts, from endothelial cells via a cellular transition process known as the endothelial-mesenchymal transition, or through recruitment of bone marrow (BM)-derived progenitor cells [3].…”

Vieillissement

“…Il pourrait ainsi participer à un état inflammatoire généralisé qui accélèrerait les phénomènes de vieillissement et favoriserait le développement de maladies chroniques [45]. Les cellules stromales du coeur, en particulier les cellules souches/progénitrices et les fibroblastes, ont une activité sécrétrice intense qui participe très activement au maintien de l'homéostasie cardiaque, mais aussi au développement de l'insuffisance cardiaque [48][49][50]. Ces cellules seraient donc de très bons candidats pour l'analyse du rôle du sécrétome dans le vieillissement et la physiopathologie cardiaque.…”