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Cell-lineage regulated myogenesis for dystrophin replacement: a novel therapeutic approach for treatment of muscular dystrophy.
Hum Mol Genet. 2008 Aug 15; 17(16):2507-17.HM

Abstract

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 (muDys/eGFP) fusion gene together with a tamoxifen-inducible form of the myogenic regulator MyoD [MyoD-ER(T)]. Fibroblasts isolated from mdx(4cv) mice, a mouse model for DMD, were efficiently transduced with lentiviral vectors expressing muDys/eGFP and MyoD-ER(T) and underwent myogenic conversion when exposed to tamoxifen. These cells could also be induced to differentiate into muDys/eGFP-expressing myocytes and myotubes. Transplantation of transduced mdx(4cv) fibroblasts into mdx(4cv) muscles enabled tamoxifen-dependent regeneration of myofibers that express muDys. 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.

Authors+Show Affiliations

Department of Neurology, University of Washington School of Medicine, Seattle, WA 98195-7720, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Evaluation Study
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18511457

Citation

Kimura, En, et al. "Cell-lineage Regulated Myogenesis for Dystrophin Replacement: a Novel Therapeutic Approach for Treatment of Muscular Dystrophy." Human Molecular Genetics, vol. 17, no. 16, 2008, pp. 2507-17.
Kimura E, Han JJ, Li S, et al. Cell-lineage regulated myogenesis for dystrophin replacement: a novel therapeutic approach for treatment of muscular dystrophy. Hum Mol Genet. 2008;17(16):2507-17.
Kimura, E., Han, J. J., Li, S., Fall, B., Ra, J., Haraguchi, M., Tapscott, S. J., & Chamberlain, J. S. (2008). Cell-lineage regulated myogenesis for dystrophin replacement: a novel therapeutic approach for treatment of muscular dystrophy. Human Molecular Genetics, 17(16), 2507-17. https://doi.org/10.1093/hmg/ddn151
Kimura E, et al. Cell-lineage Regulated Myogenesis for Dystrophin Replacement: a Novel Therapeutic Approach for Treatment of Muscular Dystrophy. Hum Mol Genet. 2008 Aug 15;17(16):2507-17. PubMed PMID: 18511457.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cell-lineage regulated myogenesis for dystrophin replacement: a novel therapeutic approach for treatment of muscular dystrophy. AU - Kimura,En, AU - Han,Jay J, AU - Li,Sheng, AU - Fall,Brent, AU - Ra,Jennifer, AU - Haraguchi,Miki, AU - Tapscott,Stephen J, AU - Chamberlain,Jeffrey S, Y1 - 2008/05/29/ PY - 2008/5/31/pubmed PY - 2008/9/16/medline PY - 2008/5/31/entrez SP - 2507 EP - 17 JF - Human molecular genetics JO - Hum. Mol. Genet. VL - 17 IS - 16 N2 - 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 (muDys/eGFP) fusion gene together with a tamoxifen-inducible form of the myogenic regulator MyoD [MyoD-ER(T)]. Fibroblasts isolated from mdx(4cv) mice, a mouse model for DMD, were efficiently transduced with lentiviral vectors expressing muDys/eGFP and MyoD-ER(T) and underwent myogenic conversion when exposed to tamoxifen. These cells could also be induced to differentiate into muDys/eGFP-expressing myocytes and myotubes. Transplantation of transduced mdx(4cv) fibroblasts into mdx(4cv) muscles enabled tamoxifen-dependent regeneration of myofibers that express muDys. 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. SN - 1460-2083 UR - https://www.unboundmedicine.com/medline/citation/18511457/Cell_lineage_regulated_myogenesis_for_dystrophin_replacement:_a_novel_therapeutic_approach_for_treatment_of_muscular_dystrophy_ L2 - https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddn151 DB - PRIME DP - Unbound Medicine ER -