Closed-Chest Cell Injections into Mouse Myocardium Targeted by Ultrasound

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DESCRIPTION (provided by applicant): Intramyocardial cell implantation and injection of therapeutic genes have been proposed as therapies for ischemic heart disease. However, the recent literature contains numerous contradictory results. Different research groups inject identical cell populations into mouse hearts and report disparate findings, ranging from improvement of cardiac function to lack of improvement and absence of differentiated stem cells. This proposal is designed to evaluate the hypothesis that these contradictions stem, in part, from varying success of injection into the myocardial wall rather than the left ventricular cavity, and that non-invasive imaging with high resolution echocardiography can accurately target injections into normal and infarcted mouse hearts, providing a clinically relevant system with which to study potential cell implantation and gene therapies. First, a mixture of echocardiography contrast agent and fluorescent microspheres will be injected to correlate the observed needle position during echo-guided injections with the actual injection site as evidenced by histological examination. After the system has been optimized, high resolution echocardiography will be used to guide transthoracic implantations of labeled cells into the hearts of surgically infarcted mice, targeting the infarct border zone and demonstrating proof of concept. The system will be used to study the ability of labeled bone marrow derived cells to migrate through cardiac muscle to damaged tissue by targeted injections of labeled cells mixed with fluorescent microspheres of different sizes and colors. It will also be used to compare the effects of intramyocardial cell implantation during the infarction procedure to implantation several days after infarction, a more clinically relevant model that is very difficult to achieve without echo-guidance; as well as at multiple times. This will lead to further studies of targeted injection into the infarct border zone of both bone marrow-derived cells and myoblasts expressing growth factors. RELEVANCE: The implantation of so-called adult stem cells and the injection of genes encoding growth factors are potential treatments for poor cardiac function that typically plagues heart attack survivors. Many experiments can be carried out in mice; however, their hearts are so small that it is difficult to inject into them in a clinically relevant way. This research will use high-resolution ultrasound to guide such injections into the mouse heart, without surgery, and will make the mouse a much better model for such experiments.