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Theranostics 2013; 3(11):903-913. doi:10.7150/thno.5938 This issue Cite

Research Paper

Cardioprotective C-kit⁺ Bone Marrow Cells Attenuate Apoptosis after Acute Myocardial Infarction in Mice - In-vivo Assessment with Fluorescence Molecular Imaging

Angelique Ale^1*, Frank Siebenhaar^2*, Katja Kosanke³, Michaela Aichler⁴, Karin Radrich¹, Sina Heydrich², Matthias Schiemann^5,6, Isabella Bielicki³, Peter B. Noel³, Rickmer Braren³, Marcus Maurer², Axel K. Walch⁴, Ernst J. Rummeny³, Vasilis Ntziachristos¹, Moritz Wildgruber^{3,7 ✉}

1. Institute for Biological and Medical Imaging, Helmholtz Zentrum München and Technische Universität München, Germany
2. Department of Dermatology and Allergy, Charité - Universitätsmedizin Berlin, Germany
3. Department of Radiology, Klinikum Rechts der Isar, Technische Universität München, Germany
4. Research Unit Analytical Pathology, Institute of Pathology, Helmholtz Zentrum München, Germany
5. Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, Germany
6. Clinical Cooperation Groups ''Antigen-Specific Immunotherapy'' and “Immune Monitoring” Helmholtz Zentrum München, Germany
7. International Graduate School of Science and Engineering, Technische Universität München, Garching, Germany
* These authors contributed equally to this work.

✉ Corresponding author: Moritz Wildgruber MD, PhD, Department of Radiology, Klinikum Rechts der Isar, Technische Universität München, Ismaninger Strasse 22, D-81675 München, Germany. Phone: +49-89-4140-2621 Fax: +49-89-4140-4834 email: moritz.wildgruberde More

Abstract

Cardiomyocyte loss via apoptosis plays a crucial role in ventricular remodeling following myocardial infarction (MI). Cell-based therapy approaches using bone marrow derived c-kit⁺ pluripotent cells may attenuate apoptosis following ischemic injury. We therefore thought to examine the early course of apoptosis following myocardial infarction - in-vivo - and non-invasively determine the effect of c-kit⁺ bone marrow cells on post-MI remodeling. We studied apoptosis in wild-type Kit^+/+, c-kit mutant Kit^W/Kit^W-v and Kit^W/Kit^W-v mice after cell therapy with bone-marrow derived c-kit⁺ cells after ischemia-reperfusion injury. Mice were followed by hybrid Fluorescence Molecular Tomography/X-ray Computed Tomography (FMT-XCT) at 6h, 24h and 7 days after ischemia-reperfusion injury using an Annexin V-based fluorescent nanosensor targeting phosphatidylserine. Kit^W/Kit^W-v mice showed increased and prolonged apoptosis compared to control Kit^+/+ mice while c-kit cell therapy was able to attenuate the altered apoptosis rates. Increased apoptosis was accompanied by severe decline in heart function, determined by cardiac Magnetic Resonance Imaging, and cell therapy was able to rescue the animals from deleterious heart failure. Post-mortem cryoslicing and immunohistochemistry localized the fluorescence signal of the Annexin V sensor within the infarcted myocardium. Flow cytometry of digested infarct specimens identified apoptotic cardiomyocytes as the major source for the in-vivo Annexin V signal.

In-vivo molecular imaging using hybrid FMT-XCT reveals increased cardiomyocyte apoptosis in Kit^W/Kit^W-v mice and shows that c-kit⁺ cardioprotective cells are able to attenuate post-MI apoptosis and rescue mice from progressive heart failure.

Keywords: apoptosis, heart failure, infarction, imaging, reperfusion.

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