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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Increased survival of muscle stem cells lacking the MyoD gene after transplantation into regenerating skeletal muscle
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Increased survival of muscle stem cells lacking the MyoD gene after transplantation into regenerating skeletal muscle

机译：缺少MyoD基因的肌肉干细胞移植入骨骼肌再生后存活率提高

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摘要

MyoD is a myogenic master transcription factor that plays an essential role in muscle satellite cell (muscle stem cell) differentiation. To further investigate the function of MyoD in satellite cells, we examined the transplantation of satellite cell-derived myo-blasts lacking the MyoD gene into regenerating skeletal muscle. After injection into injured muscle, MyoD~(-/-) myoblasts engrafted with significantly higher efficiency compared with wild-type myoblasts. In addition, MyoD~(-/-) myoblast-derived satellite cells were detected underneath the basal lamina of muscle fibers, indicating the self-renewal property of MyoD~(-/-) myoblasts. To gain insights into MyoD gene deficiency in muscle stem cells, we investigated the pathways regulated by MyoD by GeneChip microarray analysis of gene expression in wild-type and MyoD~(-/-) myoblasts. MyoD deficiency led to down-regulation of many muscle-specific genes and up-regulation of some stem cell markers. Importantly, in MyoD~(-/-) myoblasts, many antiapoptotic genes were up-regulated, whereas genes known to execute apoptosis were down-regulated. Consistent with these gene expression profiles, MyoD~(-/-) myoblasts were revealed to possess remarkable resistance to apoptosis and increased survival compared with wild-type myoblasts. Forced expression of MyoD or the proapoptotic protein Puma increased cell death in MyoD~(-/-) myoblasts. Therefore, MyoD~(-/-) myoblasts may preserve stem cell characteristics, including their resistance to apoptosis, expression of stem cell markers, and efficient engraftment and contribution to satellite cells after transplantation. Furthermore, our data offer evidence for improved therapeutic stem cell transplantation for muscular dystrophy, in which suppression of MyoD in myogenic progenitors would be beneficial to therapy by providing a selective advantage for the expansion of stem cells.
机译：MyoD是一种成肌主转录因子，在肌肉卫星细胞（肌肉干细胞）的分化中起着至关重要的作用。为了进一步研究MyoD在卫星细胞中的功能，我们检查了缺少MyoD基因的卫星细胞来源的成肌细胞向骨骼肌的再生过程。注入受伤的肌肉后，与野生型成肌细胞相比，植入MyoD〜（-/-）成肌细胞的效率明显更高。另外，在肌纤维基底层的下方检测到了MyoD〜（-/-）成肌细胞来源的卫星细胞，表明MyoD〜（-/-）成肌细胞的自我更新特性。为了深入了解肌肉干细胞中MyoD基因的缺乏，我们通过GeneChip微阵列分析基因在野生型和MyoD〜（-/-）成肌细胞中的表达，研究了MyoD调控的途径。 MyoD缺乏导致许多肌肉特异性基因的下调和某些干细胞标志物的上调。重要的是，在MyoD〜（-/-）成肌细胞中，许多抗凋亡基因被上调，而已知执行凋亡的基因被下调。与这些基因表达谱一致，与野生型成肌细胞相比，MyoD〜（-/-）成肌细胞被发现对凋亡具有显着的抵抗力，并提高了存活率。 MyoD或促凋亡蛋白Puma的强迫表达增加了MyoD〜（-/-）成肌细胞的细胞死亡。因此，MyoD〜（-/-）成肌细胞可以保留干细胞特性，包括它们对凋亡的抗性，干细胞标志物的表达以及移植后有效植入和对卫星细胞的贡献。此外，我们的数据提供了改善的治疗性肌营养不良的干细胞移植的证据，其中肌源性祖细胞中MyoD的抑制将通过为干细胞的扩增提供选择性优势而对治疗有益。

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