Cardiomyopathy is a serious heart disease that often leads to congestive heart failure, a condition in whichthe heart muscle can no longer effectively pump blood. Patients that suffer from various muscle diseases,including Duchenne muscular dystrophy (DMD), develop progressive cardiomyopathy. Cellularcardiomyoplasty (CCM), a procedure that involves the transplantation of exogenous cells into damagedmyocardium, has been proposed as a possible therapy to regenerate diseased myocardium and delivertherapeutic genes. Although a wide variety of cell types has been used for CCM, various limitations(including ethical, biological, or technical challenges) have impeded their suitability for use in humanpatients. We recently have used the modified preplate technique to isolate a novel population of musclederivedstem cells (MDSCs) that display improved transplantation capacity in skeletal muscle whencompared to satellite cells. The MDSCs' ability to proliferate in vivo for an extended period of time--combined with their strong capacity for serf-renewal, multipotent differentiation, and immune-t_rivilegedbehavior--reveals, at least in part, a basis for the benefits associated with their use in cell transplantation inskeletal muscle. The proposed project will investigate the use of MDSCs as a novel cell source for cardiaccell transplantation in a cardiomyopathic murine model of muscular dystrophy. We already have observedthat MDSCs delivered by intra-cardiac injection display good cell survival and can deliver dystrophin withinthe dystrophic myocardium. In this project we will investigate whether MDSCs implanted in the hearts ofdystrophic mdx mice display an improved transplantation capacity when compared to conventional satellitecell implantation (Aim #1). We then will explore the relative contribution of the MDSCs' capacity for tong-termproliferation and self-renewal (Aim #2) to the increased regenerative capacity of these cells aftertransplantation in heart muscle. Finally, we will determine the degree to which development of approaches toprevent fibrosis (Aim #3) and improve angiogenesis (Aim #4) would further enhance the regenerativecapacity of muscle-derived cells in the heart. This project will increase our understanding of the basic biologyof myogenic cell populations that display stem cell characteristics. This information may, in tum, unveil newtechniques to improve heart regeneration and repair via the transplantation of muscle-derived stem cells.
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