Heart-infiltrating prominin-1+/CD133+ progenitor cells represent the cellular source of transforming growth factor beta-mediated cardiac fibrosis in experimental autoimmune myocarditis

Gabriela Kania, Przemyslaw Blyszczuk, Sokrates Stein, Alan Valaperti, Davide Germano, Stephan Dirnhofer, Lukas Hunziker, Christian M Matter, Urs Eriksson
Circulation Research 2009 August 28, 105 (5): 462-70

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.

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