Gene Expression Profiling of Muscle Stem Cells Identifies Novel Regulators of Postnatal Myogenesis.
Gene Expression Profiling of Muscle Stem Cells Identifies Novel Regulators of Postnatal Myogenesis.
复制标题
DOI：
10.3389/fcell.2016.00058
复制
发表时间：
2016
影响因子：
5.5
通讯作者：
Relaix F
中科院分区：
文献类型：
--
作者：
Alonso-Martin S;Rochat A;Mademtzoglou D;Morais J;de Reyniès A;Auradé F;Chang TH;Zammit PS;Relaix F
骨骼肌的生长和再生需要一群肌肉干细胞，即卫星细胞，与肌纤维紧密接触。这些细胞在小鼠的胎儿和出生后早期发育过程中从胚胎祖细胞的Pax 3/7群体中指定。由于对它们的形成和维持的遗传控制知之甚少，我们进行了全基因组按时间顺序的表达谱，鉴定了在整个生命过程中建立肌肉干细胞和获得肌肉干细胞特性所涉及的动态转录组变化。我们已经鉴定了与卫星细胞形成相关的多个基因和途径，包括在成体干细胞中特异性诱导（EphA 1、EphA 2、EfnA 1、EphB 1、Zbtb 4、Zbtb 20）或抑制（EphA 3、EphA 4、EphA 7、EfnA 2、EfnA 3、EfnA 4、EfnA 5、EphB 2、EphB 3、EphB 4、EfnBs、Zfp 354 c、Zcchc 5、Hmga 2）的基因组。肝配蛋白受体和肝配蛋白配体已经涉及在包括骨骼肌的许多组织中的细胞迁移和引导。在这里，我们表明，肝配蛋白受体和肝配蛋白配体也参与调节成人生肌程序。引人注目的是，卫星细胞中EPHB 1功能的损伤导致分离的肌纤维培养物以自我更新为代价的分化增加。此外，我们发现了新的转录因子，包括几个锌指蛋白。ZFP 354 C和ZCCHC 5在过表达时降低自我更新能力，而ZBTB 4增加自我更新能力，ZBTB 20诱导肌源性进展。结构和转录调节因子HMGA 2参与卫星细胞的激活。总之，我们的研究表明，转录组分析加上肌纤维培养分析，提供了一个有效的系统，以确定和验证候选基因参与建立/维持肌肉干细胞。此外，tour de force转录组学分析提供了丰富的数据，为未来基于干细胞的肌肉治疗提供信息。
Skeletal muscle growth and regeneration require a population of muscle stem cells, the satellite cells, located in close contact to the myofiber. These cells are specified during fetal and early postnatal development in mice from a Pax3/7 population of embryonic progenitor cells. As little is known about the genetic control of their formation and maintenance, we performed a genome-wide chronological expression profile identifying the dynamic transcriptomic changes involved in establishment of muscle stem cells through life, and acquisition of muscle stem cell properties. We have identified multiple genes and pathways associated with satellite cell formation, including set of genes specifically induced (EphA1, EphA2, EfnA1, EphB1, Zbtb4, Zbtb20) or inhibited (EphA3, EphA4, EphA7, EfnA2, EfnA3, EfnA4, EfnA5, EphB2, EphB3, EphB4, EfnBs, Zfp354c, Zcchc5, Hmga2) in adult stem cells. Ephrin receptors and ephrins ligands have been implicated in cell migration and guidance in many tissues including skeletal muscle. Here we show that Ephrin receptors and ephrins ligands are also involved in regulating the adult myogenic program. Strikingly, impairment of EPHB1 function in satellite cells leads to increased differentiation at the expense of self-renewal in isolated myofiber cultures. In addition, we identified new transcription factors, including several zinc finger proteins. ZFP354C and ZCCHC5 decreased self-renewal capacity when overexpressed, whereas ZBTB4 increased it, and ZBTB20 induced myogenic progression. The architectural and transcriptional regulator HMGA2 was involved in satellite cell activation. Together, our study shows that transcriptome profiling coupled with myofiber culture analysis, provides an efficient system to identify and validate candidate genes implicated in establishment/maintenance of muscle stem cells. Furthermore, tour de force transcriptomic profiling provides a wealth of data to inform for future stem cell-based muscle therapies.