Cell-lineage regulated myogenesis for dystrophin replacement: A novel therapeutic approach for treatment of muscular dystrophy

En Kimura, Jay J. Han, Sheng Li, Brent Fall, Jennifer Ra, Miki Haraguchi, Stephen J. Tapscott, Jeffrey S. Chamberlain

Research output: Contribution to journalArticlepeer-review

53 Scopus citations


Duchenne muscular dystrophy (DMD) is characterized in skeletal muscle by cycles of myofiber necrosis and regeneration leading to loss of muscle fibers and replacement with fibrotic connective and adipose tissue. The ongoing activation and recruitment of muscle satellite cells for myofiber regeneration results in loss of regenerative capacity in part due to proliferative senescence. We explored a method whereby new myoblasts could be generated in dystrophic muscles by transplantation of primary fibroblasts engineered to express a micro-dystrophin/enhanced green fluorescent protein (μDys/eGFP) fusion gene together with a tamoxifen-inducible form of the myogenic regulator MyoD [MyoD-ER(T)]. Fibroblasts isolated from mdx4cv mice, a mouse model for DMD, were efficiently transduced with lentiviral vectors expressing μDys/ eGFP and MyoD-ER(T) and underwent myogenic conversion when exposed to tamoxifen. These cells could also be induced to differentiate into μDys/eGFP-expressing myocytes and myotubes. Transplantation of transduced mdx4cv fibroblasts into mdx4cv muscles enabled tamoxifen-dependent regeneration of myofibers that express μDys. This lineage control method therefore allows replenishment of myogenic stem cells using autologous fibroblasts carrying an exogenous dystrophin gene. This strategy carries several potential advantages over conventional myoblast transplantation methods including: (i) the relative simplicity of culturing fibroblasts compared with myoblasts, (ii) a readily available cell source and ease of expansion and (iii) the ability to induce MyoD gene expression in vivo via administration of a medication. Our study provides a proof of concept for a novel gene/stem cell therapy technique and opens another potential therapeutic approach for degenerative muscle disorders.

Original languageEnglish (US)
Pages (from-to)2507-2517
Number of pages11
JournalHuman Molecular Genetics
Issue number16
StatePublished - Aug 2008
Externally publishedYes

ASJC Scopus subject areas

  • Genetics


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