RATIONALE: Myocardial fibrosis is a hallmark of inflammation-triggered end-stage heart disease, a common cause of heart failure in young patients. OBJECTIVE: We used CD4(+) T-cell-mediated experimental autoimmune myocarditis model to determine the parameters regulating cardiac fibrosis in inflammatory heart disease. METHODS AND RESULTS: alpha-Myosin heavy chain peptide/complete Freund's adjuvant immunization was used to induce experimental autoimmune myocarditis in BALB/c mice. Chimeric mice, reconstituted with enhanced green fluorescence protein (EGFP)(+) bone marrow, were used to track the fate of inflammatory cells. Prominin-1(+) cells were isolated from the inflamed hearts, cultured in vitro and injected intracardially at different stages of experimental autoimmune myocarditis. Transforming growth factor (TGF)-beta-mediated fibrosis was addressed using anti-TGF-beta antibody treatment. Myocarditis peaked 21 days after immunization and numbers of cardiac fibroblasts progressively increased on follow-up. In chimeric mice, >60% of cardiac fibroblasts were EGFP(+) 46 days after immunization. At day 21, cardiac infiltrates contained approximately 30% of prominin-1(+) progenitors. In vitro and in vivo experiments confirmed that prominin-1(+) but not prominin-1(-) cells isolated from acutely inflamed hearts represented the cellular source of cardiac fibroblasts at late stages of disease, characterized by increased TGF-beta levels within the myocardium. Mechanistically, the in vitro differentiation of heart-infiltrating prominin-1(+) cells into fibroblasts depended on TGF-beta-mediated phosphorylation of Smad proteins. Accordingly, anti-TGF-beta antibody treatment prevented myocardial fibrosis in immunized mice. CONCLUSIONS: Taken together, heart-infiltrating prominin-1(+) progenitors are the major source of subsequent TGF-beta-triggered cardiac fibrosis in experimental autoimmune myocarditis. Recognizing the critical, cytokine-dependent role of bone marrow-derived progenitors in cardiac remodeling might result in novel treatment concepts against inflammatory heart failure.
RATIONALE: Myocardial fibrosis is a hallmark of inflammation-triggered end-stage heart disease, a common cause of heart failure in young patients. OBJECTIVE: We used CD4(+) T-cell-mediated experimental autoimmune myocarditis model to determine the parameters regulating cardiac fibrosis in inflammatory heart disease. METHODS AND RESULTS:alpha-Myosin heavy chain peptide/complete Freund's adjuvant immunization was used to induce experimental autoimmune myocarditis in BALB/c mice. Chimeric mice, reconstituted with enhanced green fluorescence protein (EGFP)(+) bone marrow, were used to track the fate of inflammatory cells. Prominin-1(+) cells were isolated from the inflamed hearts, cultured in vitro and injected intracardially at different stages of experimental autoimmune myocarditis. Transforming growth factor (TGF)-beta-mediated fibrosis was addressed using anti-TGF-beta antibody treatment. Myocarditis peaked 21 days after immunization and numbers of cardiac fibroblasts progressively increased on follow-up. In chimeric mice, >60% of cardiac fibroblasts were EGFP(+) 46 days after immunization. At day 21, cardiac infiltrates contained approximately 30% of prominin-1(+) progenitors. In vitro and in vivo experiments confirmed that prominin-1(+) but not prominin-1(-) cells isolated from acutely inflamed hearts represented the cellular source of cardiac fibroblasts at late stages of disease, characterized by increased TGF-beta levels within the myocardium. Mechanistically, the in vitro differentiation of heart-infiltrating prominin-1(+) cells into fibroblasts depended on TGF-beta-mediated phosphorylation of Smad proteins. Accordingly, anti-TGF-beta antibody treatment prevented myocardial fibrosis in immunized mice. CONCLUSIONS: Taken together, heart-infiltrating prominin-1(+) progenitors are the major source of subsequent TGF-beta-triggered cardiac fibrosis in experimental autoimmune myocarditis. Recognizing the critical, cytokine-dependent role of bone marrow-derived progenitors in cardiac remodeling might result in novel treatment concepts against inflammatory heart failure.
Authors: Florian Leuschner; Gabriel Courties; Partha Dutta; Luke J Mortensen; Rostic Gorbatov; Brena Sena; Tatiana I Novobrantseva; Anna Borodovsky; Kevin Fitzgerald; Victor Koteliansky; Yoshiko Iwamoto; Marina Bohlender; Soeren Meyer; Felix Lasitschka; Benjamin Meder; Hugo A Katus; Charles Lin; Peter Libby; Filip K Swirski; Daniel G Anderson; Ralph Weissleder; Matthias Nahrendorf Journal: Eur Heart J Date: 2014-06-20 Impact factor: 29.983
Authors: Suresh K Verma; Venkata N S Garikipati; Prasanna Krishnamurthy; Sarah M Schumacher; Laurel A Grisanti; Maria Cimini; Zhongjian Cheng; Mohsin Khan; Yujia Yue; Cindy Benedict; May M Truongcao; Joseph E Rabinowitz; David A Goukassian; Douglas Tilley; Walter J Koch; Raj Kishore Journal: Circulation Date: 2017-06-30 Impact factor: 29.690
Authors: Joshua G Travers; Fadia A Kamal; Jeffrey Robbins; Katherine E Yutzey; Burns C Blaxall Journal: Circ Res Date: 2016-03-18 Impact factor: 17.367
Authors: Jennifer M Myers; Leslie T Cooper; David C Kem; Stavros Stavrakis; Stanley D Kosanke; Ethan M Shevach; DeLisa Fairweather; Julie A Stoner; Carol J Cox; Madeleine W Cunningham Journal: JCI Insight Date: 2016-06-16