Thesis

Directing skeletal muscle progenitor cell fate from human pluripotent stem cells

Duchenne Muscular Dystrophy (DMD) is a devastating and fatal muscle wasting disease with no known cure, caused by mutations in the dystrophin gene. Stem cell based regenerative treatments hold promise to potentially restore healthy muscle to DMD patients. However, the differentiation of pluripotent stem cells must be learned to be precisely controlled for any such treatment to be usable, as uncontrolled differentiation can lead to tumor formation. Skeletal muscle progenitor cells (SMPCs) are a muscle-specific stem cell type which generate only muscle cells, and so would be an ideal cell type to test for use in treatment. Development of an efficient protocol for differentiating human pluripotent stem cells (hPSCs) to a skeletal muscle progenitor cell (SMPC) would open up the possibility of a cell based treatment for Duchenne Muscular Dystrophy (DMD) and other muscle wasting diseases. Any such treatment would have to be used in combination with one of many gene based therapies currently being studied to repair the mutations in the dytrophin gene responsible for causing DMD. In this study we test two different experimental methods for their ability to differentiate hPSCs to SMPCs: directed differentiation with developmentally relevant growth factors, and direct reprogramming via overexpression of master regulator transcription factors via a novel nanotechnology system. While not yet successful in deriving the SMPC cell type from hPSCs, this study describes significant progress towards that goal.

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