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

Kania, Gabriela and Blyszczuk, Przemyslaw and Stein, Sokrates and Valaperti, Alan and Germano, Davide and Dirnhofer, Stephan and Hunziker, Lukas and Matter, Christian M. and Eriksson, Urs. (2009) Heart-infiltrating prominin-1+/CD133+ progenitor cells represent the cellular source of transforming growth factor beta-mediated cardiac fibrosis in experimental autoimmune myocarditis. Circulation research : journal of the American Heart Association, Vol. 105. pp. 462-470.

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Official URL: http://edoc.unibas.ch/dok/A6005030

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Abstract

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.
Faculties and Departments:03 Faculty of Medicine > Bereich Medizinische Fächer (Klinik) > Allgemeine innere Medizin USB
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Medizinische Fächer (Klinik) > Allgemeine innere Medizin USB
03 Faculty of Medicine > Bereich Querschnittsfächer (Klinik) > Pathologie USB > Histopathologie (Dirnhofer)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Querschnittsfächer (Klinik) > Pathologie USB > Histopathologie (Dirnhofer)
UniBasel Contributors:Dirnhofer, Stephan and Eriksson, Urs
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Lippincott Williams & Wilkins
ISSN:0009-7330
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:01 Feb 2013 08:46
Deposited On:01 Feb 2013 08:42

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