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Cell Journal، جلد ۱۶، شماره Suppl ۱، صفحات ۲۳-۲۳
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عنوان انگلیسی Is-24: Making Muscle In Vitro from Embryonic Stem Cells
چکیده انگلیسی مقاله Key cell types including skeletal muscle have proven difficult to differentiate in vitro from pluripotent cells. Differentiation of mature contractile muscle fibers in vitro from mouse or human pluripotent cells has so far not been reported. During embryonic development, skeletal muscles arise from somites, which derive from the presomitic mesoderm (PSM). Based on our understanding of PSM development, we established conditions allowing efficient differentiation of monolayer cultures of mouse embryonic stem (ES) cells into PSM-like cells without introduction of exogenous genetic material or cell sorting. To optimize the differentiation of ES cells toward the muscle lineage, we used a series of reporter ES cell lines, expressing fluorescent proteins under the control of genes specific for key stages of myogenic development. These reporter lines were used to sequentially optimize the differentiation conditions in order to reach maximal differentiation for each population. Our optimized conditions were inferred based on the development of the PSM in vivo and from a microarray series of early developmental stages of this tissue. We next established simple conditions to recapitulate primary and secondary/foetal myogenesis in vitro from these PSMlike cells. Our strategy allowed for the production of contractile fibers from pluripotent cells in vitro with an efficiency comparing well with current cardiomyocytes differentiation protocols. The muscle fibers produced are striated and multinucleated and exhibit post-natal characteristics. They also provide a niche allowing the development of Pax7-positive satellite-like cells. We used these conditions to differentiate ES cells derived from dystrophin-deficient mdx mice. We show that these fibers exhibit a strikingly abnormal organization of the myofibrils accompanied by a dramatic increase in the number of branches. While such a branched phenotype has been reported in vivo in mdx animals or in Duchenne patients, it has been attributed to fusion defects consequent to the cycles of regeneration occurring in dystrophic muscles. Our results rather argue that the defect is intrinsic to the fibers thus challenging current views on the origin of the pathology of Duchenne Muscular Dystrophy. Thus our work opens the possibility to study pathological mutations in mouse models for muscular dystrophies in vitro.
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نشانی اینترنتی http://celljournal.org/journal/article/abstract/318
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