Published online before print July 23, 2009, doi: 10.1161/CIRCRESAHA.109.196287
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© 2009 American Heart Association, Inc.
Cellular Biology |
Heart-Infiltrating Prominin-1+/CD133+ Progenitor Cells Represent the Cellular Source of Transforming Growth Factor β–Mediated Cardiac Fibrosis in Experimental Autoimmune Myocarditis
From the Division of Cardioimmunology (G.K., P.B., D.G., U.E.), Institute of Physiology, University of Zurich; Experimental Critical Care (G.K., P.B., A.V., D.G., U.E.), Department of Biomedicine, University Hospital, Basel; Cardiovascular Research and Zurich Center for Integrative Human Physiology (S.S., C.M.M.), University of Zurich; Institute of Pathology (S.D.), University Hospital, Basel; Department of Internal Medicine (L.H.), University Hospital, Basel; and Cardiology (C.M.M., U.E.), Cardiovascular Center, University Hospital, Zurich, Switzerland.
Correspondence to Gabriela Kania, PhD, Division of Cardioimmunology, Institute of Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland. E-mail gabriela.kania{at}access.uzh.ch
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: 
-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.
Key Words: prominin-1+ progenitor cells • myocarditis • cardiac fibrosis • TGF-β
Related Article:
Circ. Res. 2009 105: 403-405.
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  P. Blyszczuk, G. Kania, T. Dieterle, R. R. Marty, A. Valaperti, C. Berthonneche, T. Pedrazzini, C. T. Berger, S. Dirnhofer, C. M. Matter, et al. Myeloid Differentiation Factor-88/Interleukin-1 Signaling Controls Cardiac Fibrosis and Heart Failure Progression in Inflammatory Dilated Cardiomyopathy Circ. Res., October 23, 2009; 105(9): 912 - 920. [Abstract] [Full Text] [PDF]
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M. W. Cunningham Turning Point in Myocarditis Circ. Res., August 28, 2009; 105(5): 403 - 405. [Full Text] [PDF]
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