Noninvasive monitoring and tracking of muscle stem cells

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DESCRIPTION (provided by applicant): The overall objective of this proposal is to develop high resolution imaging methods to noninvasively evaluate cell based therapies in skeletal- and cardiac myopathies. Current methods for the analysis of cell based therapies are largely restricted to invasive measurements in animal models. In this proposal, emphasis is placed on the development of noninvasive magnetic resonance (MR) assays to monitor in vivo stem cell migration, viability, and engraftment following cell delivery to cardiac and skeletal muscle. An immediate application of this technology is the monitoring of cell therapies to mitigate the devastating effects of muscular dystrophy. In order to achieve in vivo single cell sensitivity, stem cells will be magnetically labeled supraparamagnetic iron oxide (SPIO) complexes. SPIO labeled cells will be monitored in dystrophic animal model (mdx) following intramuscular injection (Aim 1). In Aim 2, 31p-spectroscopic and imaging methods will be developed to track the differentiation and integration of muscle derived stem cells (MDSC) in dystrophic skeletal muscle. MDSCs will be engineered to conditionally express a unique muscle specific MR marker gene (arginine kinase). In Aim 3, the ability of MR to detect cell homing through the circulatory system into remote, local sites of muscle damage and regeneration will be determined. In order to maximize cell migration, we will utilize targeted endogenous (induced by acute injury) and exogenous (viral delivery of SDF-1) expression of stem cell chemotactic factors. Finally, in Aim 4 we will determine the ability of MR to monitor cell transplantation therapy in the dystrophic mouse heart. We anticipate that these noninvasive methods will provide essential feedback for pre-clinical studies targeting cell-based therapy in muscular dystrophy, as well as in other diseases involving skeletal- or cardiac myopathies.