Stem cell transplantation holds great promise as a therapeutic strategy in human genetic disorders, including muscular dystrophies. This proposal aims at understanding and addressing three major hurdles of cell-based therapeutic approaches to Duchenne muscular dystrophy: stem cell isolation, propagation and engraftment. The proposal is based on the recent characterization of the novel ATP-binding cassette transporter ABCB5 P-glycoprotein by the applicant, which marks stem cell phenotype-expressing cell subsets in muscle and skin, and regulates as a determinant of membrane potential progenitor cell fusion and resultant differentiation. Preliminary studies indicate a myogenic potential of ABCB5 progenitors in vitro.
The specific aims of this study are 1. To define the myogenic potential of ABCBS-positiveprogenitors derived from muscle or skin vis-a-vis ABCBS-negative cell populations, and to dissect the role of ABCB5 in regulating myoprogenitor fusion into multinucleated myotubes using ABCB5-specific cell differentiation and fusion assays in vitro. 2. To identify the molecular regulatory networks associated with the ABCBS-positive progenitor phenotype and to determine whether such networks can be specifically modulated to induce in vitro myoprogenitor propagation. 3. To investigate the capacity of xeno- or allografted ABCBS-positive myoprogenitors isolated from human or murine muscle or skin to restore dystrophin expression in an immunodeficient mouse model of DMD (NOD/Rag1nullDMDmdx5cv) in vivo, and define the role of ABCB5 in donor cell fusion into recipient myofibers, and hence in donor cell engraftment and stem cell therapeutic efficacy. Thus, the proposal is highly relevant to efforts directed at developing novel therapeutic approaches to Duchenne muscular dystrophy and other inherited myopathies.
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