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Cardiovascular Research Advance Access first published online on July 11, 2008
This version [Corrected Proof] published online on July 29, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn190
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Prominin-1+/CD133+ bone marrow-derived heart-resident cells suppress experimental autoimmune myocarditis

Gabriela Kania1,*, Przemyslaw Blyszczuk1, Alan Valaperti1, Thomas Dieterle2, Bernd Leimenstoll3, Stephan Dirnhofer4, Henryk Zulewski5 and Urs Eriksson1,6

1 Experimental Critical Care, Department of Biomedicine, University Hospital, Hebelstrasse 20, CH-4031 Basle, Switzerland
2 Clinical Cardiology, Department of Internal Medicine, University Hospital, Hebelstrasse 20, CH-4031 Basle, Switzerland
3 General Internal Medicine, Department of Internal Medicine, University Hospital, Hebelstrasse 20, CH-4031 Basle, Switzerland
4 Institute of Pathology, University Hospital, Hebelstrasse 20, CH-4031 Basle, Switzerland
5 Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital, Hebelstrasse 20, CH-4031 Basle, Switzerland
6 Department of Cardiology, University Hospital, Rämistrasse 100, CH-8091 Zurich, Switzerland

* Corresponding author. Tel: +41 61 265 3524; fax: +41 61 265 2350. E-mail address: g.kania{at}unibas.ch

Aims: Experimental autoimmune myocarditis (EAM) is a CD4+ T cell-mediated mouse model of inflammatory heart disease. Tissue-resident bone marrow-derived cells adopt different cellular phenotypes depending on the local milieu. We expanded a specific population of bone marrow-derived prominin-1-expressing progenitor cells (PPC) from healthy heart tissue, analysed their plasticity, and evaluated their capacity to protect mice from EAM and heart failure.

Methods and results: PPC were expanded from healthy mouse hearts. Analysis of CD45.1/CD45.2 chimera mice confirmed bone marrow origin of PPC. Depending on in vitro culture conditions, PPC differentiated into macrophages, dendritic cells, or cardiomyocyte-like cells. In vivo, PPC acquired a cardiac phenotype after direct injection into healthy hearts. Intravenous injection of PPC into myosin alpha heavy chain/complete Freund's adjuvant (MyHC-{alpha}/CFA)-immunized BALB/c mice resulted in heart-specific homing and differentiation into the macrophage phenotype. Histology revealed reduced severity scores for PPC-treated mice compared with control animals [treated with phosphate-buffered saline (PBS) or crude bone marrow at day 21 after MyHC-{alpha}/CFA immunization]. Echocardiography showed preserved fractional shortening and velocity of circumferential shortening in PPC but not PBS-treated MyHC-{alpha}/CFA-immunized mice. In vitro and in vivo data suggested that interferon-{gamma} signalling on PPC was critical for nitric oxide-mediated suppression of heart-specific CD4+ T cells. Accordingly, PPC from interferon-{gamma} receptor-deficient mice failed to protect MyHC-{alpha}/CFA-immunized mice from EAM.

Conclusion: Prominin-1-expressing, heart-resident, bone marrow-derived cells combine high plasticity, T cell-suppressing capacity, and anti-inflammatory in vivo effects.

KEYWORDS Prominin-1+ bone marrow-derived cells; Heart failure; Myocarditis; Autoimmunity; Inflammatory dilated cardiomyopathy

Time for primary review: 34 days


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