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Lupu M., Kuhr C. S., Tapscott S., Storb R. Hematopoietic stem cells do not reconstitute satellite cells nor myofibers in hematopoietic canine chimeras with X-linked muscular dystrophy - Invited paper - Oral presentation. In Modiano J. F. (ed.), Genes, Dogs and Cancer: Fourth Annual Canine Cancer Conference, Sept. 14-17, Chicago, IL, USA. International Veterinary Information Service, Ithaca NY (www. ivis. org), Last updated: 17-Sep-2006; P4043. 0906, 2006.

Abstract: Canine X-linked muscular dystrophy (c-xmd) is the homologue of human Duchenne muscular dystrophy (DMD), a degenerative disorder that affects 1 in 3,500 boys born worldwide. The disease is caused by mutations in the gene encoding dystrophin, an essential component of the striated muscle cytoskeletal protein complex, leading to progressive skeletal and cardiac muscle damage and early death.

Studies in mice have suggested that hematopoietic stem cells participated in skeletal muscle fiber regeneration, following intravenous and/or intramuscular delivery. We had shown that hematopoietic cell transplantation (HCT) from unaffected donors into dog leukocyte antigen-identical DMD littermates did not result in regeneration of muscle cells or muscle precursor cells. Here we sought to investigate whether unmodified bone marrow cells from HCT donors, injected intramuscularly into DMD recipients, which were hematopoietic chimeras, could transdifferentiate into dystrophin expressing myocytes or satellite cells. More than 15 weeks after intramuscular marrow injection, immunofluorescence and reverse-transcriptase-PCR analyses showed that donor cells did not contribute to dystrophin protein and dystrophin mRNA expression, respectively. Furthermore, segregation analyses of microsatellite polymorphisms using DNA extracted from cloned satellite cells indicated that there were no detectable donor contributions to the recipientsí satellite cell populations.

Given the close similarity between c-xmd and human DMD, these results provided evidence that therapeutic strategies that relied on hematopoietic stem cell transdifferentiation to regenerate skeletal muscle would likely fail in human DMD patients. However, hematopoietic stem cell based therapies might be used in the future to deliver cloned genes for the treatment of genetic diseases and cancer.

Keywords: Duchenne muscular dystrophy, hematopoietic cell transplantation, bone marrow, hematopoietic stem cell plasticity, cell therapy, muscle regeneration, preclinical canine model, translational research

Posted by Marilena Plesu (Lupu)

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