Heart-Infiltrating Prominin-1+/CD133+Progenitor Cells Represent the Cellular Source of Transforming Growth Factor β–Mediated Cardiac Fibrosis in Experimental Autoimmune Myocarditis
- 28 August 2009
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Circulation Research
- Vol. 105 (5), 462-470
- https://doi.org/10.1161/circresaha.109.196287
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: 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.Keywords
This publication has 34 references indexed in Scilit:
- Identification of Cardiac Troponin I Sequence Motifs Leading to Heart Failure by Induction of Myocardial Inflammation and FibrosisCirculation, 2008
- The immune system and cardiac repairPharmacological Research, 2008
- TGF‐β signaling: A tale of two responsesJournal of Cellular Biochemistry, 2007
- Potential risks of bone marrow cell transplantation into infarcted heartsPublished by American Society of Hematology ,2007
- The role of TGF-β signaling in myocardial infarction and cardiac remodelingCardiovascular Research, 2007
- Cardiac side population cells have a potential to migrate and differentiate into cardiomyocytes in vitro and in vivoThe Journal of cell biology, 2007
- Bone marrow-derived fibroblast precursors mediate ischemic cardiomyopathy in miceProceedings of the National Academy of Sciences of the United States of America, 2006
- T-bet negatively regulates autoimmune myocarditis by suppressing local production of interleukin 17The Journal of Experimental Medicine, 2006
- Resident Nestin + Neural-Like Cells and Fibers Are Detected in Normal and Damaged Rat MyocardiumHypertension, 2005
- Intracardiac fibroblasts, but not bone marrow derived cells, are the origin of myofibroblasts in myocardial infarct repairCardiovascular Pathology, 2005