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Comparative Analysis of Genetically Engineered Immunodeficient Mouse Strains as Recipients for Human Myoblast Transplantation

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Abstract:

The development of an optimized animal model for the in vivo analysis of human muscle cells remains an important goal in the search of therapy for muscular dystrophy. Here we examined the efficiency of human myoblast xenografts in three distinct immunodeficient mouse models. We found that different conditioning regimes used to provoke host muscle regeneration (i.e., cardiotoxin versus cryodamage) had a marked impact on xenograft success. Tibialis anterior muscle of Rag2, Rag/c, and Rag/ c/C5 mice was treated by cardiotoxin or cryodamage, submitted to enzymatic digestion, and analyzed by cytofluorometry to quantitate inflammatory cells. Human myoblasts were injected into pretreated muscles from immunodeficient recipients and the cell engraftment evaluated by immunocytochemistry, 4–8 weeks after transplantation. Donor cell differentiation and dispersion within the host muscles was also investigated. Host regeneration in cardiotoxin-treated mice was accompanied by a higher inflammatory cell infiltration when compared to that induced by cryodamage. Accordingly, when compared to the cardiotoxin group, more human myogenic cells were found after cryodamage. When the distinct immunodeficient mice were compared, we found that the alymphoid strain lacking the complement component C5 (Rag/c/C5 mice) was the most efficient host for human muscle xenografts, when compared with C5+Rag/c mice or Rag mice. Our results demonstrate that cryolesion-conditioned muscles of Rag/c/C5 mice provide the best environment for long-term in vivo human myoblast differentiation, opening the way for a novel approach to study the pathophysiology of human muscle disorders.

Keywords: Immunodeficient mice; MyHC; Skeletal muscle; Transplantation

Document Type: Research Article

DOI: http://dx.doi.org/10.3727/000000005783982837

Affiliations: 1: CNRS UMR 7000, Cytosquelette et Développement, Hôpital Pitié-Salpêtrière, Paris, France 2: Unité des Cytokines et Développement Lymphoïde, Départeament d'Immunologie, Institute Pasteur, Paris, France

Publication date: July 1, 2005

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  • Cell Transplantation publishes original, peer-reviewed research and review articles on the subject of cell transplantation and its application to human diseases. To ensure high-quality contributions from all areas of transplantation, separate section editors and editorial boards have been established. Articles deal with a wide range of topics including physiological, medical, preclinical, tissue engineering, and device-oriented aspects of transplantation of nervous system, endocrine, growth factor-secreting, bone marrow, epithelial, endothelial, and genetically engineered cells, among others. Basic clinical studies and immunological research papers are also featured. To provide complete coverage of this revolutionary field, Cell Transplantation will report on relevant technological advances, and ethical and regulatory considerations of cell transplants. Cell Transplantation is now an Open Access journal starting with volume 18 in 2009, and therefore there will be an inexpensive publication charge, which is dependent on the number of pages, in addition to the charge for color figures. This will allow work to be disseminated to a wider audience and also entitle the corresponding author to a free PDF, as well as prepublication of an unedited version of the manuscript.

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