Résumé :
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Cell therapy has been long explored as a potential approach for DMD, although the positive results obtained in animal models have been followed by discouraging evidences in clinical trials. This emphasized the importance of investigating the in vivo behavior of transplanted human myogenic cells; however the ideal model, i.e. both immuno-tolerant and dystrophic, was still lacking.The immunodeficient murine models available so far (SCID, Nude, etc.) present several problems, such as low breeding efficiency, which results in difficulty in the maintenance of the colony, or incomplete immunodeficiency. Furthermore, the "classic" murine model for DMD (mdx) presents a variable percentage of dystrophin-positive ("revertant") fibers, which can hinder the evaluation of potential therapeutic approaches. For these reasons, we developed a new mutant strain of mice: the Rag2-/-Il2rb-/-Dmd-/- mouse model. This new mutant mouse lacks T, B and NK cells, plus it carries a mutant Dmd allele that prevents the production of any dystrophin isoform.This study focuses on the characterization of this new immunodeficient and dystrophic model, in comparison with the mdx mouse. We measured the body weight and muscle-weight at various time points. The dystrophic phenotype was also monitored by measuring the CK serum levels and by evaluating the percentage of regenerating fibers expressing the neonatal isoform of the myosin heavy chain.The results obtained show that the growth curves of our animals are comparable to those of the mdx model. The histopathological features were also akin, although slightly lower levels of fibrosis have been measured in the diaphragm of 40 weeks old Rag2-/-Il2rb-/-Dmd-/- mice. Importantly, no revertant fibers could be detected by immunohistochemistry in any of the muscles of this new model. The analysis of muscle regeneration yielded interesting results: Rag2-/-Il2rb-/-Dmd-/- animals present a better defined peak of regeneration, which lasts from 12 to 16 weeks of age in all muscles analyzed. Such 4 week-long regeneration bout will provide a larger and more reliable "therapeutic window" compared to mdx mice. Initial data on cell transplantation confirmed that grafting of human myogenic cells was possible in Rag2-/-Il2rb-/-Dmd-/- animals, and their participation to the host's muscle regeneration can be quantified; therefore this new model will represent a very valuable tool to assess in vivo the behaviour of human myogenic cells in a dystrophic context
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