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Cardiovascular Research Advance Access [Accepted Manuscript] published online on July 11, 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 Kania, PhD1, Przemyslaw Blyszczuk, PhD1, Alan Valaperti, MSc1, Thomas Dieterle, MD2, Bernd Leimenstoll, MD3, Stephan Dirnhofer, MD4, Henryk Zulewski, MD5 and Urs Eriksson, MD1,6

1 Department of Biomedicine, Diabetes and Clinical Nutrition, University Hospital, Hebelstrasse 20, CH-4031 Basle, Switzerland
2 Clinical Cardiology, Department of Internal Medicine, Diabetes and Clinical Nutrition, University Hospital, Hebelstrasse 20, CH-4031 Basle, Switzerland
3 General Internal Medicine, Department of Internal Medicine, Diabetes and Clinical Nutrition, University Hospital, Hebelstrasse 20, CH-4031 Basle, Switzerland
4 Institute of Pathology, Diabetes and Clinical Nutrition, 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: Gabriela Kania, PhD Experimental Critical Care Department of Biomedicine University Hospital Hebelstrasse 20 CH-4031 Basle Switzerland phone: ++41-61-265-3524 fax: ++41-61-265-2350 E-mail: g.kania{at}unibas.ch

Aim: 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, analyzed 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 the 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.

Conclusions: 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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