Department of Medicine, Lillehei Heart Institute, University of Minnesota, 312 Church Street SE, Minneapolis, Minnesota 55455, USA.
Nat Commun. 2013;4:1549. doi: 10.1038/ncomms2550.
Duchenne muscular dystrophy is a progressive and incurable neuromuscular disease caused by genetic and biochemical defects of the dystrophin-glycoprotein complex. Here we show the regenerative potential of myogenic progenitors derived from corrected dystrophic induced pluripotent stem cells generated from fibroblasts of mice lacking both dystrophin and utrophin. We correct the phenotype of dystrophic induced pluripotent stem cells using a Sleeping Beauty transposon system carrying the micro-utrophin gene, differentiate these cells into skeletal muscle progenitors and transplant them back into dystrophic mice. Engrafted muscles displayed large numbers of micro-utrophin-positive myofibers, with biochemically restored dystrophin-glycoprotein complex and improved contractile strength. The transplanted cells seed the satellite cell compartment, responded properly to injury and exhibit neuromuscular synapses. We also detect muscle engraftment after systemic delivery of these corrected progenitors. These results represent an important advance towards the future treatment of muscular dystrophies using genetically corrected autologous induced pluripotent stem cells.
杜氏肌营养不良症是一种由肌营养不良蛋白聚糖复合物的遗传和生化缺陷引起的进行性和不可治愈的神经肌肉疾病。在这里，我们展示了从缺乏肌营养不良蛋白和 utrophin 的小鼠成纤维细胞生成的经校正的肌营养不良诱导多能干细胞衍生的肌原性祖细胞的再生潜力。我们使用携带微 utrophin 基因的 Sleeping Beauty 转座子系统校正肌营养不良诱导多能干细胞的表型，将这些细胞分化为骨骼肌祖细胞并将其移植回肌营养不良小鼠体内。移植的肌肉显示出大量微 utrophin 阳性肌纤维，其肌营养不良蛋白聚糖复合物具有生物化学恢复，收缩力得到改善。移植的细胞定位于卫星细胞区室，对损伤有适当反应，并表现出神经肌肉突触。我们还在这些经校正的祖细胞全身给药后检测到肌肉移植物。这些结果代表了使用经基因校正的自体诱导多能干细胞治疗肌肉营养不良症的重要进展。
