Neurowissenschaftliches Forschungszentrum, NeuroCure Cluster of Excellence, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Developmental Biology/Signal Transduction Group, 13125, Berlin, Germany.
Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Developmental Biology/Signal Transduction Group, 13125, Berlin, Germany.
Exp Cell Res. 2021 Dec 15;409(2):112933. doi: 10.1016/j.yexcr.2021.112933. Epub 2021 Nov 15.
The balance between proliferation and differentiation of muscle stem cells is tightly controlled, ensuring the maintenance of a cellular pool needed for muscle growth and repair. Muscle stem cells can proliferate, they can generate differentiating cells, or they self-renew to produce new stem cells. Notch signaling plays a crucial role in this process. Recent studies revealed that expression of the Notch effector HES1 oscillates in activated muscle stem cells. The oscillatory expression of HES1 periodically represses transcription from the genes encoding the myogenic transcription factor MYOD and the Notch ligand DLL1, thereby driving MYOD and DLL1 oscillations. This oscillatory network allows muscle progenitor cells and activated muscle stem cells to remain in a proliferative and 'undecided' state, in which they can either differentiate or self-renew. When HES1 is downregulated, MYOD oscillations become unstable and are replaced by sustained expression, which drives the cells into terminal differentiation. During development and regeneration, proliferating stem cells contact each other and the stability of the oscillatory expression depends on regular DLL1 inputs provided by neighboring cells. In such communities of cells that receive and provide Notch signals, the appropriate timing of DLL1 inputs is important, as sustained DLL1 cannot replace oscillatory DLL1. Thus, in cell communities, DLL1 oscillations ensure the appropriate balance between self-renewal and differentiation. In summary, oscillations in myogenic cells are an important example of dynamic gene expression determining cell fate.
肌肉干细胞的增殖和分化之间的平衡受到严格控制，以确保维持肌肉生长和修复所需的细胞池。肌肉干细胞可以增殖，可以产生分化细胞，也可以自我更新以产生新的干细胞。Notch 信号通路在这个过程中起着至关重要的作用。最近的研究表明，Notch 效应因子 HES1 在激活的肌肉干细胞中的表达呈振荡状态。HES1 的振荡表达周期性地抑制编码肌生成转录因子 MYOD 和 Notch 配体 DLL1 的基因的转录，从而驱动 MYOD 和 DLL1 的振荡。这个振荡网络使肌肉祖细胞和激活的肌肉干细胞保持在增殖和“未决定”状态，在这种状态下，它们可以分化或自我更新。当 HES1 下调时，MYOD 的振荡变得不稳定，并被持续表达所取代，这促使细胞进入终末分化。在发育和再生过程中，增殖的干细胞相互接触，振荡表达的稳定性取决于相邻细胞提供的规则 DLL1 输入。在接受和提供 Notch 信号的细胞群落中，DLL1 输入的适当时间很重要，因为持续的 DLL1 不能替代振荡的 DLL1。因此，在细胞群落中，DLL1 的振荡确保了自我更新和分化之间的适当平衡。总之，肌肉细胞的振荡是决定细胞命运的动态基因表达的一个重要例子。
