title: Prosurvival Factors Improve Functional Engraftment of Myogenically Converted Dermal Cells into Dystrophic Skeletal Muscle.
abstract: In Duchenne muscular dystrophy (DMD) and other muscle wasting disorders, cell therapies are a promising route for promoting muscle regeneration by supplying a functional copy of the missing dystrophin gene and contributing new muscle fibers. The clinical application of cell-based therapies is resource intensive, and it will therefore be necessary to address key limitations that reduce cell engraftment into muscle tissue. A pressing issue is poor donor cell survival following transplantation, which in preclinical studies limits the ability to effectively test the impact of cell-based therapy on whole muscle function. We, therefore, sought to improve engraftment and the functional impact of in vivo myogenically converted dermal fibroblasts (dFbs) using a prosurvival cocktail (PSC) that includes heat shock followed by treatment with insulin-like growth factor-1, a caspase inhibitor, a Bcl-XL peptide, a KATPchannel opener, basic fibroblast growth factor, Matrigel, and cyclosporine A. Advantages of dFbs include compatibility with the autologous setting, ease of isolation, and greater proliferative potential than DMD satellite cells. dFbs expressed tamoxifen-inducible MyoD and carried a mini-dystrophin gene driven by a muscle-specific promoter. After transplantation into muscles of mdx mice, a 70% reduction in donor cells was observed by day 5, and a 94% reduction by day 28. However, treatment with PSC gave a nearly three-fold increase in donor cells in early engraftment, and greatly increased the number of donor-contributed muscle fibers and total engrafted area in transplanted muscles. Furthermore, dystrophic muscles that received dFbs with PSC displayed reduced injury with eccentric contractions and an increase in maximum isometric force. Thus, enhancing survival of myogenic cells increases engraftment and improves structure and function of dystrophic muscle.
authors: 1 Department of Neurology, University of Washington , Seattle, Washington.|2 Molecular and Cellular Biology Program, University of Washington , Seattle, Washington.
authors: Lindsey A
authors: LA
authors: Muir
authors: 3 Center for Cardiovascular Biology, University of Washington , Seattle, Washington.|4 Institute for Stem Cell and Regenerative Medicine, University of Washington , Seattle, Washington.|5 Department of Pathology, University of Washington , Seattle, Washington.|6 Department of Bioengineering, University of Washington , Seattle, Washington.|7 Department of Medicine/Cardiology, University of Washington , Seattle, Washington.
authors: Charles E
authors: CE
authors: Murry
authors: 1 Department of Neurology, University of Washington , Seattle, Washington.|8 Department of Biochemistry, University of Washington , Seattle, Washington.|9 Department of Medicine/Medical Genetics, University of Washington , Seattle, Washington.
authors: Jeffrey S
authors: JS
authors: Chamberlain