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Mesoangioblast stem cells ameliorate muscle function in dystrophic dogs

A Corrigendum to this article was published on 12 March 2014

A Corrigendum to this article was published on 20 February 2013

This article has been updated

Abstract

Duchenne muscular dystrophy remains an untreatable genetic disease that severely limits motility and life expectancy in affected children. The only animal model specifically reproducing the alterations in the dystrophin gene and the full spectrum of human pathology is the golden retriever dog model. Affected animals present a single mutation in intron 6, resulting in complete absence of the dystrophin protein, and early and severe muscle degeneration with nearly complete loss of motility and walking ability. Death usually occurs at about 1 year of age as a result of failure of respiratory muscles. Here we report that intra-arterial delivery of wild-type canine mesoangioblasts (vessel-associated stem cells) results in an extensive recovery of dystrophin expression, normal muscle morphology and function (confirmed by measurement of contraction force on single fibres). The outcome is a remarkable clinical amelioration and preservation of active motility. These data qualify mesoangioblasts as candidates for future stem cell therapy for Duchenne patients.

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Figure 1: Characterization of dog mesoangioblasts.
Figure 2: Morphology of muscle in treated dogs.
Figure 3: Immunofluorescence analysis of tissue from treated dogs.
Figure 4: Quantitative analysis of dystrophin content in tissue from treated dogs.
Figure 5: Physiology.

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Change history

  • 20 February 2013

    Nature 444, 574–579 (2006), doi:10.1038/nature05282 In Fig. 4b of this Article, the gel for the loading control MyHC for the dog Vaccin was an unintentional duplication of the loading control for the dog Vampire (which is correct). The correct gel is shown below in Fig. 1. The error does not affect any of our results.

  • 12 March 2014

    Nature 444, 574–579 (2006), doi:10.1038/nature05282 and corrigendum Nature 494, 506 (2013); doi:10.1038/nature11976 In Fig. 4b of this Article, the gel for the loading control MyHC for the dog Varus was an unintentional duplication of the loading controls for the dog Vampire (which is correct). The correct gel is shown below in Fig.

References

  1. Emery, A. E. The muscular dystrophies. Lancet 359, 687–695 (2002)

    Article  CAS  Google Scholar 

  2. Cossu, G. & Sampaolesi, M. New therapies for muscular dystrophy: cautious optimism. Trends Mol. Med. 10, 516–520 (2004)

    Article  CAS  Google Scholar 

  3. Qu-Petersen, Z. et al. Identification of a novel population of muscle stem cells in mice: potential for muscle regeneration. J. Cell Biol. 157, 851–864 (2002)

    Article  CAS  Google Scholar 

  4. Sampaolesi, M. et al. Cell therapy of α-sarcoglycan null dystrophic mice through intra-arterial delivery of mesoangioblasts. Science 301, 487–492 (2003)

    Article  ADS  CAS  Google Scholar 

  5. Bachrach, E. et al. Systemic delivery of human microdystrophin to regenerating mouse dystrophic muscle by muscle progenitor cells. Proc. Natl Acad. Sci. USA 101, 3581–3586 (2004)

    Article  ADS  CAS  Google Scholar 

  6. Torrente, Y. et al. Human circulating AC133+ stem cells restore dystrophin expression and ameliorate function in dystrophic skeletal muscle. J. Clin. Invest. 114, 182–195 (2004)

    Article  CAS  Google Scholar 

  7. Rodriguez, A. M. et al. Transplantation of a multipotent cell population from human adipose tissue induces dystrophin expression in the immunocompetent mdx mouse. J. Exp. Med. 201, 1397–1405 (2005)

    Article  CAS  Google Scholar 

  8. Dezawa, M. et al. Bone marrow stromal cells generate muscle cells and repair muscle degeneration. Science 309, 314–317 (2005)

    Article  ADS  CAS  Google Scholar 

  9. Kornegay, J. N., Tuler, S. M., Miller, D. M. & Levesque, D. C. Muscular dystrophy in a litter of golden retriever dogs. Muscle Nerve 11, 1056–1064 (1988)

    Article  CAS  Google Scholar 

  10. Sharp, N. J. et al. An error in dystrophin mRNA processing in golden retriever muscular dystrophy, an animal homologue of Duchenne muscular dystrophy. Genomics 13, 115–121 (1992)

    Article  CAS  Google Scholar 

  11. Harper, S. Q. et al. Modular flexibility of dystrophin: implication for gene therapy of Duchenne muscular dystrophy. Nature Med. 8, 253–261 (2004)

    Article  Google Scholar 

  12. Minasi, M. G. et al. The meso-angioblast: a multipotent, self-renewing cell that originates from the dorsal aorta and differentiates into most mesodermal tissues. Development 129, 2773–2783 (2002)

    CAS  PubMed  Google Scholar 

  13. Galvez, B. G. et al. Complete rescue of dystrophic muscle by mesoangioblasts with enhanced migratory ability. J. Cell Biol. 174, 231–243 (2006)

    Article  CAS  Google Scholar 

  14. Kornegay, J. N., Cundiff, D. D., Bogan, D. J., Bogan, J. R. & Okamura, C. S. The cranial sartorius muscle undergoes true hypertrophy in dogs with golden retriever muscular dystrophy. Neuromuscul. Disord. 13, 493–500 (2003)

    Article  Google Scholar 

  15. Galli, D. et al. Mesoangioblasts, vessel-associated multipotent stem cells, repair the infarcted heart by multiple cellular mechanisms: a comparison with bone marrow progenitors, fibroblasts, and endothelial cells. Arterioscler. Thromb. Vasc. Biol. 25, 692–697 (2005)

    Article  CAS  Google Scholar 

  16. Childers, M. K. et al. Skinned single fibers from normal and dystrophin-deficient dogs incur comparable stretch-induced force deficits. Muscle Nerve 31, 768–771 (2005)

    Article  Google Scholar 

  17. Pavlath, G. K. Regulation of class I MHC expression in skeletal muscle: deleterious effect of aberrant expression on myogenesis. J. Neuroimmunol. 125, 42–50 (2002)

    Article  CAS  Google Scholar 

  18. Krampera, M. et al. Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide. Blood 101, 3722–3729 (2003)

    Article  CAS  Google Scholar 

  19. Reinhardt, R. L. et al. Visualizing the generation of memory CD4 T cells in the whole body. Nature 410, 101–105 (2001)

    Article  ADS  CAS  Google Scholar 

  20. Dell’Agnola, C. et al. Hematopoietic stem cell transplantation does not restore dystrophin expression in Duchenne muscular dystrophy dogs. Blood 104, 4311–4318 (2004)

    Article  Google Scholar 

  21. Karpati, G., Gilbert, R., Petrof, B. J. & Nalbantoglu, J. Gene therapy research for Duchenne and Becker muscular dystrophies. Curr. Opin. Neurol. 10, 430–435 (1997)

    Article  CAS  Google Scholar 

  22. Howell, J. M. et al. Use of the dog model for Duchenne muscular dystrophy in gene therapy trials. Neuromuscul. Disord. 7, 325–328 (1997)

    Article  CAS  Google Scholar 

  23. Cerletti, M. et al. Dystrophic phenotype of canine X-linked muscular dystrophy is mitigated by adenovirus-mediated utrophin gene transfer. Gene Ther. 10, 750–757 (2003)

    Article  CAS  Google Scholar 

  24. Emery, A. E. Clinical and molecular studies in Duchenne muscular dystrophy. Prog. Clin. Biol. Res. 306, 15–28 (1989)

    CAS  PubMed  Google Scholar 

  25. Ricordi, C. & Strom, T. M. Clinical islet transplantation: advances and clinical challenges. Nature Rev. Immunol. 4, 259–270 (2004)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank M. G. Roncarolo for helpful discussions; J. Chamberlain for the gift of the lentiviral vector expressing human microdystrophin; C. Drougard for technical assistance; X. Cauchois, I. Gruyer, S. Kouamé, E. Wembe and A. Brindejont and M. Carré at the Centre d'Elevage du Domaine des Souches for their care of the dogs; and N. Borenstein for the systemic delivery of cells. M.S. and G.C. thank P. Luban for a donation. This work was supported by grants from the Association Française contre les Myopathies, Telethon, the Muscular Dystrophy Association, the Parent Project Onlus, the European Community ‘Eurostemcell’, the Cariplo Foundation and the Italian Ministries of Health and Research. B.G.G. was supported by a 3+3 fellowship from the Centro Nacional de Investigationes Cardiovasculares, Spain. Author Contributions M.S. coordinated the work on cells with R.T. and M.G.C.D.; S.B. coordinated the work on dogs with N.G., J.L.T. and I.B.; R.B. and G.D.A. coordinated the physiology experiments with O.P., C.R. and P.M., who also developed, with S.M., the instrument to measure dog tetanic force; A.I. did the histology work; B.G.G. performed the homing experiments; L.P. and M.S. conducted the western blot analysis; M.G. did the immunology experiment; Y.T. and C.B. evaluated the clinical aspects of the work; G.C. coordinated the whole project.

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Correspondence to Roberto Bottinelli or Giulio Cossu.

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Supplementary information

Supplementary Notes

This file contains Supplementary Methods, Supplementary Figures and their legends. (PDF 24478 kb)

Supplementary Video 1

Untreated GRMD dog (MPG 5474 kb)

Supplementary Video 2

Valgus, GRMD dog treated with donor mesoangioblasts; inset movie, Valgus before the first treatment. (MPG 6378 kb)

Supplementary Video 3

Varus, GRMD dog treated with donor mesoangioblasts. (MPG 7875 kb)

Supplementary Video 4

Vampire, GRMD dog treated with autologous genetically modified mesoangioblasts. (MPG 2516 kb)

Supplementary Video 5

Azor, GRMD dog treated late with donor mesoangioblasts; inset movie, Azor before the first treatment. (MPG 7454 kb)

Supplementary Video 6

Azur, GRMD dog treated late with donor mesoangioblasts; inset movie, Azur before the first treatment. (MPG 4804 kb)

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Sampaolesi, M., Blot, S., D’Antona, G. et al. Mesoangioblast stem cells ameliorate muscle function in dystrophic dogs. Nature 444, 574–579 (2006). https://doi.org/10.1038/nature05282

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