The quiescent muscle stem cell (QSC) pool is heterogeneous and generally characterized by the presence and levels of intrinsic myogenic transcription factors. Whether extrinsic factors maintain the diversity of states across the QSC pool remains unknown. The muscle fiber is a multinucleated syncytium that serves as a niche to QSCs, raising the possibility that the muscle fiber regulates the diversity of states across the QSC pool. Here we show that the muscle fiber maintains a continuum of quiescent states, through a gradient of Notch ligand, Dll4, produced by the fiber and captured by QSCs. The abundance of Dll4 captured by the QSC correlates with levels of the SC identity gene, Pax7. Niche-specific loss of Dll4 decreases QSC diversity and shifts the continuum, towards more proliferative and committed states. We reveal that fiber-derived Mindbomb1 (Mib1), an E3 ubiquitin ligase activates Dll4 and controls the spatial localization of Dll4. In response to injury, with a Dll4-replenished niche, the normal continuum and diversity of SC pool is restored, demonstrating bi-directionality within the SC continuum. Our data shows that a post-translational mechanism controls spatial heterogeneity of Notch ligands in a multinucleated niche cell to maintain a continuum of diverse states within the SC pool during tissue homeostasis.

中文翻译：

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多核小生境细胞内的三角洲样4的空间异质性保持肌肉干细胞多样性。

静态肌肉干细胞（QSC）库是异质的，并且通常以固有的成肌转录因子的存在和水平为特征。外部因素是否维持整个QSC库中状态的多样性仍然未知。肌肉纤维是多核合胞体，是QSC的利基，增加了肌肉纤维调节QSC池中状态多样性的可能性。在这里，我们显示出肌肉纤维通过由纤维产生并被QSC捕获的Notch配体Dll4的梯度保持了静态状态的连续性。QSC捕获的Dll4的丰度与SC同一性基因Pax7的水平相关。生态位特定的Dll4丢失会降低QSC多样性，并使连续体转移到更扩散和更富状态的状态。我们揭示了纤维衍生的Mindbomb1（Mib1），一种E3泛素连接酶激活Dll4，并控制Dll4的空间定位。响应伤害，使用Dll4补充的利基，恢复了SC池的正常连续体和多样性，这表明了SC连续体内的双向性。我们的数据表明，翻译后机制控制了多核小生境细胞中Notch配体的空间异质性，以在组织稳态期间维持SC库内各种状态的连续性。