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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-28979

Kania, G; Blyszczuk, P; Stein, S; Valaperti, A; Germano, D; Dirnhofer, S; Hunziker, L; Matter, C M; Eriksson, U (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, 105(5):462-470.

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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.

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27 citations in Web of Science®
29 citations in Scopus®
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology

04 Faculty of Medicine > Center for Integrative Human Physiology
04 Faculty of Medicine > University Hospital Zurich > Clinic for Cardiology
DDC:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2009
Deposited On:17 Mar 2010 09:14
Last Modified:27 Nov 2013 22:29
Publisher:Lippincott Williams & Wilkins
ISSN:0009-7330 (P) 1524-4571 (E)
Additional Information:This is a non-final version of an article published in final form in Circ Res. 2009 Aug 28;105(5):462-70. Epub 2009 Jul 23
Publisher DOI:10.1161/CIRCRESAHA.109.196287
PubMed ID:19628793

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