Pluripotent stem cell-derived myogenic progenitors remodel their molecular signature upon in vivo engraftment
Pluripotent stem cell-derived myogenic progenitors remodel their molecular signature upon in vivo engraftment
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DOI：
10.1073/pnas.1808303116
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发表时间：
2019-03-05
影响因子：
11.1
通讯作者：
Perlingeiro, Rita C. R.
中科院分区：
文献类型：
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作者：
Incitti, Tania;Magli, Alessandro;Perlingeiro, Rita C. R.
用于治疗肌肉退行性疾病的最佳基于细胞的疗法不仅应该再生纤维，而且应该提供静止的卫星细胞池，确保长期维持和再生。Pax 3/Pax 7在分化的多能干细胞（PSC）中的条件表达允许产生具有增强的再生能力的肌原性祖细胞。为了确定其再生潜力的分子决定因素，我们对这些细胞和几个发育阶段的原代肌源性细胞进行了沿着转录组分析。在这里，我们表明，在体外产生的PSC衍生的肌源性祖细胞具有类似于胚胎/胎儿成肌细胞的分子特征。然而，与胎儿成肌细胞相比，移植后，它们显示出上级肌纤维植入和播种卫星细胞龛的能力，对多种再损伤作出反应，并有助于长期再生。在植入后，重新分离的Pax 3/Pax 7诱导的PSC衍生的肌源性祖细胞的转录组朝向出生后的分子特征变化，特别是在参与细胞外基质重塑的基因中。这些发现表明，Pax 3/Pax 7诱导的肌源性祖细胞在体内暴露于成人肌肉环境后重塑其分子特征并功能成熟。
Optimal cell-based therapies for the treatment of muscle degenerative disorders should not only regenerate fibers but provide a quiescent satellite cell pool ensuring long-term maintenance and regeneration. Conditional expression of Pax3/Pax7 in differentiating pluripotent stem cells (PSCs) allows the generation of myogenic progenitors endowed with enhanced regenerative capacity. To identify the molecular determinants underlying their regenerative potential, we performed transcriptome analyses of these cells along with primary myogenic cells from several developmental stages. Here we show that in vitro-generated PSC-derived myogenic progenitors possess a molecular signature similar to embryonic/fetal myoblasts. However, compared with fetal myoblasts, following transplantation they show superior myofiber engraftment and ability to seed the satellite cell niche, respond to multiple reinjuries, and contribute to long-term regeneration. Upon engraftment, the transcriptome of reisolated Pax3/Pax7-induced PSC-derived myogenic progenitors changes toward a postnatal molecular signature, particularly in genes involved in extracellular matrix remodeling. These findings demonstrate that Pax3/Pax7-induced myogenic progenitors remodel their molecular signature and functionally mature upon in vivo exposure to the adult muscle environment.