Abstract
Cell transplantation holds promise as a potential treatment for cardiac dysfunction. Our group has isolated populations of murine skeletal muscle-derived stem cells (MDSCs) that exhibit stem cell-like properties. Here, we investigated the fate of MDSCs after transplantation into the hearts of dystrophin-deficient mdx mice, which model Duchenne muscular dystrophy (DMD). Transplanted MDSCs generated large grafts consisting primarily of numerous dystrophin-positive myocytes and, to a lesser degree, dystrophin-negative nonmyocytes that expressed an endothelial phenotype. Most of the dystrophin-positive myocytes expressed a skeletal muscle phenotype and did not express a cardiac phenotype. However, some donor myocytes, located at the graft–host myocardium border, were observed to express cardiac-specific markers. More than half of these donor cells that exhibited a cardiac phenotype still maintained a skeletal muscle phenotype, demonstrating a hybrid state. Sex-mismatched donors and hosts revealed that many donor-derived cells that acquired a cardiac phenotype did so through fusion with host cardiomyocytes. Connexin43 gap junctions were not expressed by donor-derived myocytes in the graft. Scar tissue formation in the border region may inhibit the fusion and gap junction connections between donor and host cells. This study demonstrates that MDSC transplantation warrants further investigation as a potential therapy for cardiac dysfunction in DMD.
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Acknowledgements
This work was supported in part by grants to Dr Johnny Huard from the Muscular Dystrophy Association (USA), the NIH (1U54AR050733-01; R01-HL069368-02), the Pittsburgh Tissue Engineering Initiative (PTEI), the William F and Jean W Donaldson Chair and the Orris C Hirtzel and Beatrice Dewey Hirtzel Memorial Foundation at Children's Hospital of Pittsburgh, and the Henry J Mankin Endowed Chair at the University of Pittsburgh. This work was also supported by a predoctoral fellowship from the American Heart Association (0315349U, TR Payne). We thank Dr Yong Li, Nikhil Kekre, Michael Thompson, William H Foster, Marcelle Pellerin, Jing Zhou and Dr Zhuqing Qu for their technical assistance, Ryan Sauder for his excellent editorial assistance with the manuscript, Dr Ronald J Jankowski for his participation in helpful discussions, and Dr Bruno PĂ©ault for his critical comments on the manuscript. We would also like to thank Dr Terry Partridge for his gracious gift of the dystrophin antibody, Dr Roscoe Stanyon for his gracious gift of mouse chromosomal probes and primary PCR DNA products and for answering many questions pertaining to FISH, and Dr Paul Robbins for the nLacZ retrovirus.
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Payne, T., Oshima, H., Sakai, T. et al. Regeneration of dystrophin-expressing myocytes in the mdx heart by skeletal muscle stem cells. Gene Ther 12, 1264–1274 (2005). https://doi.org/10.1038/sj.gt.3302521
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DOI: https://doi.org/10.1038/sj.gt.3302521
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