Mesenchymal Stem Cells Modulate Inflammatory Responses in Murine Heart by Inhibition of the TNF System

Mesenchymal stem cells have been used to treat numerous different clinical conditions, although the mechanisms by which pathogenetic processes are affected are still poorly understood. We have recently demonstrated the homing of murine long-term renewing adult bone marrow-derived multipotent mesenchymal stem cells (BM-MASCs) to diseased tissues and postulated that BM-MASCs might modulate inflammatory reactions. We here show that administration of BM-MASCs modulates adverse cardiac remodeling inhibiting the TNF system in a transgenic mouse model of cardiac-specific expression of MCP-1-induced inflammatory dilative cardiomyopathy. Four-months old MCP-1 mice were analyzed before and after 4-week administration of MASCs, Etanercept (Amgen), Pentoxifylline (Sanofi-Aventis), or NaCl (sham). MRI, Histological (Masson's thricromic), immunofluorescent (CD45 and Collagen VI antibodies, and Lectin from Bandeiraera Simplicifolia), Western blot (sTNFR-I, TNF-β, Phosphorylated-nuclear factor k (NFkBp65), and Collagen VI), SILAC-base mass spectrometry, cytokine arrays, Mission shRNA system (NM_011609.2-1538s1c1, NM_011609.2-996s1c1, and NM_011609.2-1652s1c1), and survival analysis were performed. Our results show that administration of BM-MASCs to MCP-1 mice significantly reduced cardiac accumulation of infiltrating cells and fibrosis, improved capillary density and function, and extended lifespan. Comprehensive analysis of the secretome of MASCs unveiled the release of soluble tumor necrosis factor receptor I (sTNFR-I), which significantly suppressed activation of the NFκBp65 signaling pathway in MCP-1 hearts in vivo. Administration of TNFRI-knock-down BM-MASCs yielded no positive effects demonstrating the requirement of sTNFR-I for BM-MASCs-mediated improvement of inflammatory dilative cardiomyopathy. Substitution of BM-MASCs by recombinant soluble TNFR recapitulated several effects of BM-MASCs including lifespan expansion. We conclude that BM-MASCs suppress local inflammatory processes by release of numerous signaling molecules including sTNFR-I, which makes them useful tools for various clinical applications.