A major obstacle in the application of cell-based therapies for the treatment of neuromuscular disorders is obtaining the appropriate number of stem/progenitor cells to produce effective engraftment. The use of embryonic stem (ES) or induced pluripotent stem (iPS) cells could overcome this hurdle. However, to date, derivation of engraftable skeletal muscle precursors that can restore muscle function from human pluripotent cells has not been achieved. Here we applied conditional expression of PAX7 in human ES/iPS cells to successfully derive large quantities of myogenic precursors, which, upon transplantation into dystrophic muscle, are able to engraft efficiently, producing abundant human-derived DYSTROPHIN-positive myofibers that exhibit superior strength. Importantly, transplanted cells also seed the muscle satellite cell compartment, and engraftment is present over 11 months posttransplant. This study provides the proof of principle for the derivation of functional skeletal myogenic progenitors from human ES/iPS cells and highlights their potential for future therapeutic application in muscular dystrophies.
Bibliographical noteFunding Information:
This project was supported by NIH grants RC1 AR058118, R01 AR055299, RC2 AR058919, R01 AR055685, R21 AG034370, and P01 GM081627. We also thank the generous support from the Dr. Bob and Jean Smith Foundation. The monoclonal antibody to MHC was obtained from the Developmental Studies Hybridoma Bank, developed under the auspices of the NICHD and maintained by the University of Iowa. We thank Cynthia Dekay for assistance in graphic design and members of iPierian's R&D team for technical support. R.D. designed and conducted the in vitro and in vivo experiments with iPAX7 ES and iPS cells, performed final analysis of the data, and contributed to writing the paper. S.I., J.T.D., and M.G. designed and conducted experiments regarding the generation and characterization of iPS cells. R.W.A. and M.K. developed the NSG-mdx 4Cv mice and M.K. contributed to writing the paper. R.C.R.P. supervised the overall project, designed experiments, analyzed the data, and wrote the paper.