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Nitric oxide synthase 2 is required for conversion of pro-fibrogenic inflammatory CD133+ progenitors into F4/80+ macrophages in experimental autoimmune myocarditis


Blyszczuk, Przemyslaw; Berthonneche, Corrine; Behnke, Silvia; Glönkler, Marcel; Moch, Holger; Pedrazzini, Thierry; Lüscher, Thomas F; Eriksson, Urs; Kania, Gabriela (2013). Nitric oxide synthase 2 is required for conversion of pro-fibrogenic inflammatory CD133+ progenitors into F4/80+ macrophages in experimental autoimmune myocarditis. Cardiovascular Research, 97(2):219-229.

Abstract

AIMS: Experimental Autoimmune Myocarditis (EAM) model mirrors important mechanisms of inflammatory dilated cardiomyopathy (iDCM). In EAM, inflammatory CD133(+) progenitors are a major cellular source of cardiac myofibroblasts in post-inflammatory myocardium. We hypothesized that exogenous delivery of Macrophage-Colony Stimulating Factor (M-CSF) can stimulate macrophage lineage differentiation of inflammatory progenitors and therefore prevent their naturally occurring myofibroblast fate in EAM.Methods and ResultsEAM was induced in wild-type (BALB/c) and Nitric oxide synthase 2 deficient (Nos2(-/-)) mice and CD133(+) progenitors were isolated from inflamed hearts. In vitro, M-CSF converted inflammatory CD133(+) progenitors into nitric oxide-producing F4/80(+) macrophages and prevented TGF-β-mediated myofibroblast differentiation. Importantly, only a subset of heart-infiltrating CD133(+) progenitors expresses macrophage-specific antigen F4/80 in EAM. These CD133(+)/F4/80(hi) cells show impaired myofibrogenic potential compared to CD133(+)/F4/80(-) cells. M-CSF treatment of wild-type mice with EAM at the peak of disease markedly increased CD133(+)/F4/80(hi) cells in the myocardium, and CD133(+) progenitors isolated from M-CSF-treated mice failed to differentiate into myofibroblasts. In contrast, M-CSF was not effective in converting CD133(+) progenitors from inflamed hearts of Nos2(-/-) mice into macrophages, and M-CSF treatment did not result in increased CD133(+)/F4/80(hi) cell population in hearts of Nos2(-/-) mice. Accordingly, M-CSF prevented post-inflammatory fibrosis and left ventricular dysfunction in wild-type but not in Nos2(-/-) mice. CONCLUSIONS: Active and NOS2-dependent induction of macrophage lineage differentiation abrogates the myofibrogenic potential of heart-infiltrating CD133(+) progenitors. Modulating the in vivo differentiation fate of specific progenitors might become a novel approach for the treatment of inflammatory heart diseases.

Abstract

AIMS: Experimental Autoimmune Myocarditis (EAM) model mirrors important mechanisms of inflammatory dilated cardiomyopathy (iDCM). In EAM, inflammatory CD133(+) progenitors are a major cellular source of cardiac myofibroblasts in post-inflammatory myocardium. We hypothesized that exogenous delivery of Macrophage-Colony Stimulating Factor (M-CSF) can stimulate macrophage lineage differentiation of inflammatory progenitors and therefore prevent their naturally occurring myofibroblast fate in EAM.Methods and ResultsEAM was induced in wild-type (BALB/c) and Nitric oxide synthase 2 deficient (Nos2(-/-)) mice and CD133(+) progenitors were isolated from inflamed hearts. In vitro, M-CSF converted inflammatory CD133(+) progenitors into nitric oxide-producing F4/80(+) macrophages and prevented TGF-β-mediated myofibroblast differentiation. Importantly, only a subset of heart-infiltrating CD133(+) progenitors expresses macrophage-specific antigen F4/80 in EAM. These CD133(+)/F4/80(hi) cells show impaired myofibrogenic potential compared to CD133(+)/F4/80(-) cells. M-CSF treatment of wild-type mice with EAM at the peak of disease markedly increased CD133(+)/F4/80(hi) cells in the myocardium, and CD133(+) progenitors isolated from M-CSF-treated mice failed to differentiate into myofibroblasts. In contrast, M-CSF was not effective in converting CD133(+) progenitors from inflamed hearts of Nos2(-/-) mice into macrophages, and M-CSF treatment did not result in increased CD133(+)/F4/80(hi) cell population in hearts of Nos2(-/-) mice. Accordingly, M-CSF prevented post-inflammatory fibrosis and left ventricular dysfunction in wild-type but not in Nos2(-/-) mice. CONCLUSIONS: Active and NOS2-dependent induction of macrophage lineage differentiation abrogates the myofibrogenic potential of heart-infiltrating CD133(+) progenitors. Modulating the in vivo differentiation fate of specific progenitors might become a novel approach for the treatment of inflammatory heart diseases.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Pathology and Molecular Pathology
04 Faculty of Medicine > Center for Integrative Human Physiology
04 Faculty of Medicine > University Hospital Zurich > Clinic for Cardiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2013
Deposited On:05 Nov 2012 17:16
Last Modified:05 Apr 2016 16:03
Publisher:Oxford University Press
ISSN:0008-6363
Additional Information:This is a pre-copy-editing, author-produced PDF of an article accepted for publication in Cardiovascular Research following peer review. The definitive publisher-authenticated version is available online at:http://cardiovascres.oxfordjournals.org/content/early/2012/10/21/cvr.cvs317
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1093/cvr/cvs317
PubMed ID:23090609

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