Because current treatments have had limited success in reducing morbidity and mortality associated with heart failure, the transplantation of cells into the heart has emerged as a potential therapy to repair damaged myocardium and reverse end-stage heart failure. While an array of lineage-committed cell types has been evaluated for experimental cardiac cell transplantation, recent studies have focused on adult stem cells due to their capacity for self-renewal and potential for multilineage differentiation. Here we investigated the application of postnatal murine skeletal musclederived stem cells (MDSCs) for cardiac cell therapy. We initially tested the ability of MDSCs to regenerate cardiac muscle after intramyocardial injection into the hearts of dystrophin-deficient mdx mice, a model of cardiomyopathy and muscular dystrophy. After transplantation, we observed that MDSCs generated large persistent grafts consisting primarily of numerous skeletal muscle myocytes and, to a substantially lesser degree, donor-derived cardiomyocytes, which were primarily located at the grafthost myocardium border. Further experiments revealed that more than half of these donor-derived cardiomyocytes resulted from the fusion of transplanted MDSCs with host cardiomyocytes. Next, we investigated the therapeutic potential of MDSC transplantation for cardiac repair using a mouse model for acute myocardial infarction. We report that in comparison with committed skeletal myoblast and control saline-injected hearts, MDSCs implanted into infarcted hearts elicited significant improvements in cardiac performance. This beneficial effect was partially attributed to the ability of MDSCs to induce neovascularization of ischemic myocardium. In the final study, we investigated the mechanism by which transplanted MDSCs contribute to revascularization of ischemic myocardium. To address this issue, we employed a gain- and loss-of-function approach using MDSCs genetically engineered to express the potent angiogenic factor vascular endothelial growth factor (VEGF) or the anti-angiogenic factor soluble Flt1, a VEGF-specific antagonist. When we transplanted MDSCs expressing soluble Flt1, we observed significantly less neoangiogenesis and a significant decrease in cardiac function when compared to the transplantation of control MDSCs and VEGF-engineered MDSCs. These results suggest that the transplantation of MDSCs elicits improvements in cardiac performance by inducing neovascularization of ischemic myocardium through the secretion of VEGF. In conclusion, these results suggest that MDSCs represent a promising cell type for cardiac repair and further translational research is warranted.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-11162005-151038 |
| Date | 01 February 2006 |
| Creators | Payne, Thomas Richard |
| Contributors | Sanjeev Shroff, Bruno Peault, Johnny Huard, Bradley Keller, William Wagner |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-11162005-151038/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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