Institut Mondor de Recherche Biomédicale, INSERM U955-E10Créteil, France; Université Paris Est, Faculté de MedecineCréteil, France; Ecole Nationale Veterinaire d'AlfortMaison Alfort, France.
Institut Mondor de Recherche Biomédicale, INSERM U955-E10 Créteil, France.
Front Cell Dev Biol. 2016 Jun 21;4:58. doi: 10.3389/fcell.2016.00058. eCollection 2016.
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.
骨骼肌的生长和再生需要一群位于肌纤维附近的肌肉干细胞，即卫星细胞。这些细胞在小鼠的胚胎和早期出生后发育过程中，由 Pax3/7 种群的胚胎祖细胞特化而来。由于对其形成和维持的遗传控制知之甚少，我们进行了全基因组的时程表达谱分析，确定了一生中肌肉干细胞建立和获得肌肉干细胞特性所涉及的动态转录组变化。我们已经鉴定出多个与卫星细胞形成相关的基因和途径，包括一组特定诱导（EphA1、EphA2、EfnA1、EphB1、Zbtb4、Zbtb20）或抑制（EphA3、EphA4、EphA7、EfnA2、EfnA3、EfnA4、EfnA5、EphB2、EphB3、EphB4、EfnBs、Zfp354c、Zcchc5、Hmga2）的基因。Ephrin 受体和 Ephrin 配体已被证明参与许多组织（包括骨骼肌）中的细胞迁移和导向。在这里，我们表明 Ephrin 受体和 Ephrin 配体也参与调节成体肌生成程序。引人注目的是，卫星细胞中 EphB1 功能的损害导致在分离的肌纤维培养物中以自我更新为代价的分化增加。此外，我们还鉴定了新的转录因子，包括几种锌指蛋白。过表达 ZFP354C 和 ZCCHC5 会降低自我更新能力，而 ZBTB4 则会增加自我更新能力，ZBTB20 则会诱导肌生成进展。结构和转录调节剂 HMGA2 参与卫星细胞激活。总之，我们的研究表明，转录组谱分析与肌纤维培养分析相结合，为鉴定和验证与肌肉干细胞建立/维持相关的候选基因提供了一种有效的系统。此外，这项研究提供了大量的数据，为未来基于干细胞的肌肉治疗提供了信息。
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