Mesenchymal stem cells promote matrix metalloproteinase secretion by cardiac fibroblasts and reduce cardiac ventricular fibrosis after myocardial infarction.
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, alpha-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.
Mias
Céline
C
INSERM U858, 31-432 Toulouse, France.
Lairez
Olivier
O
Trouche
Elodie
E
Roncalli
Jérome
J
Calise
Denis
D
Seguelas
Marie-Hélène
MH
Ordener
Catherine
C
Piercecchi-Marti
Marie-Dominique
MD
Auge
Nathalie
N
Salvayre
Anne Negre
AN
Bourin
Philippe
P
Parini
Angelo
A
Cussac
Daniel
D
D000199:Actins / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D017364:Collagenases / Q000378:metabolism*; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004452:Echocardiography; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005355:Fibrosis / Q000517:prevention & control*; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology; D007150:Immunohistochemistry; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D016133:Polymerase Chain Reaction; D045663:Quantum Dots; D051381:Rats; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism
D000199:Actins; D017077:Culture Media, Conditioned; D019716:Tissue Inhibitor of Metalloproteinase-2; D003094:Collagen; D017364:Collagenases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1