Résumé :
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The possibility to use stem-cells in the future as a therapy for progressive muscular dystrophies has been of great interest. However, many questions still need to be addressed. What is the best way of delivery: local or systemic? What are the best cells to be injected? When to transplant? One injection is enough or multiple injections are necessary? Is immunosupression required? What directs homing? In order to address these questions we have injected human mesenchymal stem-cells(hMSCS) in two animal models: SJL mice and GRMD dogs. All xenotransplantations were done without immunosupression. Our first studies, injecting systemically hMSCs from both umbilical cord tissue (UCT) and adipose tissue (AT), into the SJL mice, showed that cells from both sources were able to reach the muscle. However only cells from AT expressed human muscle proteins and promoted significant clinical improvement in injected animals. Systemic injections of human AT and UC MSCs into the cephalic vein of GRMD dogs, showed results comparable to the observed in SJL mice. Biopsies taken from biceps femuralis revealed that only hMSC from AT were able to express human muscle proteins. A strong dystrophin band was seen through WB 2 months after the last injection and less after 6 months but not after 12 months which suggests that multiple injections are required. When injected locally, no cells were found at the injected muscle. In order to assess if the dystrophic process interfere in the process of homing we have repeated the same experiment with AT-hMSCs in normal mice. No cells were found after two months which suggests that factors released during muscle degeneration direct homing. The presence and amount of dystrophin in recipient muscles has been used as a marker to analyze the success of different therapeutic pproaches; however it is very difficult to assess any clinical impact taking into account the enormous variability seen in GRMD dogs. How much dystrophin is required to rescue the phenotype is an opened question since a mild phenotype may occur, at least in GRMD dogs, without any muscle dystrophin. Therefore, other parameters should be analyzed in order to evaluate the impact of cell therapy in the dog model. SUPPORTED by FAPESP, INCT, CNPQ , FINEP, ABDIM and GM trust.
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