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: α-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)-β–mediated fibrosis was addressed using anti–TGF-β 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 ≈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-β levels within the myocardium. Mechanistically, the in vitro differentiation of heart-infiltrating prominin-1⁺ cells into fibroblasts depended on TGF-β–mediated phosphorylation of Smad proteins. Accordingly, anti–TGF-β antibody treatment prevented myocardial fibrosis in immunized mice.

Conclusions: Taken together, heart-infiltrating prominin-1⁺ progenitors are the major source of subsequent TGF-β–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.