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Cardioprotective C-kit? bone marrow cells attenuate apoptosis after acute myocardial infarction in mice - in-vivo assessment with fluorescence molecular imaging.

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.

SUBMITTER: Ale A

PROVIDER: S-EPMC3841340 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Cardioprotective C-kit⁺ bone marrow cells attenuate apoptosis after acute myocardial infarction in mice - in-vivo assessment with fluorescence molecular imaging.

Ale Angelique A Siebenhaar Frank F Kosanke Katja K Aichler Michaela M Radrich Karin K Heydrich Sina S Schiemann Matthias M Bielicki Isabella I Noel Peter B PB Braren Rickmer R Maurer Marcus M Walch Axel K AK Rummeny Ernst J EJ Ntziachristos Vasilis V Wildgruber Moritz M

Theranostics 20131102 11

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 mu ...[more]

PMID: 24312159

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Project description:Ischemic heart diseases such as myocardial infarction (MI) are the largest contributors to cardiovascular disease worldwide. The resulting cardiac cell death impairs function of the heart and can lead to heart failure and death. Reperfusion of the ischemic tissue is necessary but causes damage to the surrounding tissue by reperfusion injury. Cortical bone stem cells (CBSCs) have been shown to increase pump function and decrease scar size in a large animal swine model of MI. To investigate the potential mechanism for these changes, we hypothesized that CBSCs were altering cardiac cell death after reperfusion. To test this, we performed TUNEL staining for apoptosis and antibody-based immunohistochemistry on tissue from Göttingen miniswine that underwent 90 min of lateral anterior descending coronary artery ischemia followed by 3 or 7 days of reperfusion to assess changes in cardiomyocyte and noncardiomyocyte cell death. Our findings indicate that although myocyte apoptosis is present 3 days after ischemia and is lower in CBSC-treated animals, myocyte apoptosis accounts for <2% of all apoptosis in the reperfused heart. In addition, nonmyocyte apoptosis trends toward decreased in CBSC-treated hearts, and although CBSCs increase macrophage and T-cell populations in the infarct region, the occurrence of apoptosis in CD45+ cells in the myocardium is not different between groups. From these data, we conclude that CBSCs may be influencing cardiomyocyte and noncardiomyocyte cell death and immune cell recruitment dynamics in the heart after MI, and these changes may account for some of the beneficial effects conferred by CBSC treatment.NEW & NOTEWORTHY The following research explores aspects of cell death and inflammation that have not been previously studied in a large animal model. In addition, apoptosis and cell death have not been studied in the context of cell therapy and myocardial infarction. In this article, we describe interactions between cell therapy and inflammation and the potential implications for cardiac wound healing.

Dataset Information

Cardioprotective C-kit? bone marrow cells attenuate apoptosis after acute myocardial infarction in mice - in-vivo assessment with fluorescence molecular imaging.

Publications

Cardioprotective C-kit⁺ bone marrow cells attenuate apoptosis after acute myocardial infarction in mice - in-vivo assessment with fluorescence molecular imaging.

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