Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK.
Department of Functional Genomics, Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK; Computational Biology Facility, Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK.
Stem Cell Reports. 2018 Mar 13;10(3):970-983. doi: 10.1016/j.stemcr.2018.01.007. Epub 2018 Feb 8.
Satellite cells are adult muscle stem cells residing in a specialized niche that regulates their homeostasis. How niche-generated signals integrate to regulate gene expression in satellite cell-derived myoblasts is poorly understood. We undertook an unbiased approach to study the effect of the satellite cell niche on satellite cell-derived myoblast transcriptional regulation and identified the tumor suppressor p53 as a key player in the regulation of myoblast quiescence. After activation and proliferation, a subpopulation of myoblasts cultured in the presence of the niche upregulates p53 and fails to differentiate. When satellite cell self-renewal is modeled ex vivo in a reserve cell assay, myoblasts treated with Nutlin-3, which increases p53 levels in the cell, fail to differentiate and instead become quiescent. Since both these Nutlin-3 effects are rescued by small interfering RNA-mediated p53 knockdown, we conclude that a tight control of p53 levels in myoblasts regulates the balance between differentiation and return to quiescence.
卫星细胞是存在于特定龛位的成体肌肉干细胞，该龛位调节着卫星细胞的体内平衡。龛位产生的信号如何整合以调节卫星细胞衍生的成肌细胞中的基因表达，目前还知之甚少。我们采用了一种无偏的方法来研究卫星细胞龛对卫星细胞衍生的成肌细胞转录调控的影响，并确定肿瘤抑制因子 p53 是调节成肌细胞静止的关键因子。在存在龛位的情况下培养的成肌细胞经过激活和增殖后，一小部分细胞会上调 p53 并无法分化。当在储备细胞测定中体外模拟卫星细胞自我更新时，用 Nutlin-3 处理的成肌细胞，Nutlin-3 可增加细胞内的 p53 水平，无法分化，反而变得静止。由于这两种 Nutlin-3 作用都可以通过小干扰 RNA 介导的 p53 敲低来挽救，因此我们得出结论，成肌细胞中 p53 水平的严格控制调节着分化和回归静止之间的平衡。
