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

Research Paper

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

Angelique Ale1*, Frank Siebenhaar2*, Katja Kosanke3, Michaela Aichler4, Karin Radrich1, Sina Heydrich2, Matthias Schiemann5,6, Isabella Bielicki3, Peter B. Noel3, Rickmer Braren3, Marcus Maurer2, Axel K. Walch4, Ernst J. Rummeny3, Vasilis Ntziachristos1, Moritz Wildgruber3,7 ✉

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.

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 KitW/KitW-v and KitW/KitW-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. KitW/KitW-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 KitW/KitW-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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How to cite this article:
Ale A, Siebenhaar F, Kosanke K, Aichler M, Radrich K, Heydrich S, Schiemann M, Bielicki I, Noel PB, Braren R, Maurer M, Walch AK, Rummeny EJ, Ntziachristos V, Wildgruber M. Cardioprotective C-kit+ Bone Marrow Cells Attenuate Apoptosis after Acute Myocardial Infarction in Mice - In-vivo Assessment with Fluorescence Molecular Imaging. Theranostics 2013; 3(11):903-913. doi:10.7150/thno.5938. Available from http://www.thno.org/v03p0903.htm