Lillehei Heart Institute, Department of Medicine, University of Minnesota, Minneapolis, MN 55455.
Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455.
Proc Natl Acad Sci U S A. 2019 Mar 5;116(10):4346-4351. doi: 10.1073/pnas.1808303116. Epub 2019 Feb 13.
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.
用于治疗肌肉退行性疾病的最佳基于细胞的疗法不仅应再生纤维，还应提供静止的卫星细胞池，以确保长期维持和再生。在分化的多能干细胞（PSCs）中条件表达 Pax3/Pax7 可产生具有增强再生能力的成肌祖细胞。为了确定其再生潜力的分子决定因素，我们对这些细胞以及来自几个发育阶段的原代肌细胞进行了转录组分析。在这里，我们表明体外生成的 PSC 衍生的成肌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，它们在移植后表现出更好的肌纤维植入和种子卫星细胞龛的能力，能够响应多次再损伤，并有助于长期再生。在植入后，重新分离的 Pax3/Pax7 诱导的 PSC 衍生的成肌祖细胞的转录组向出生后分子特征转变，特别是在涉及细胞外基质重塑的基因中。这些发现表明，Pax3/Pax7 诱导的成肌祖细胞在体内暴露于成年肌肉环境时重塑其分子特征并在功能上成熟。
