Oscillations of MyoD and Hes1 proteins regulate the maintenance of activated muscle stem cells
Oscillations of MyoD and Hes1 proteins regulate the maintenance of activated muscle stem cells
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DOI：
10.1101/gad.322818.118
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发表时间：
2019-05-01
影响因子：
10.5
通讯作者：
Birchmeier, Carmen
中科院分区：
文献类型：
--
作者：
Lahmann, Ines;Broehl, Dominique;Birchmeier, Carmen
肌肉干细胞的增殖和分化之间的平衡受到严格控制，确保维持肌肉生长和修复所需的细胞库。我们在这里证明，转录调节因子Hes1控制在发育和再生肌肉中激活的肌肉干细胞的增殖和分化之间的平衡。我们观察到Hes1在激活的干细胞中以振荡方式表达，在那里它驱动MyoD的振荡表达。在各种条件下，来自产后和成人肌肉的激活肌肉干细胞中MyoD表达会发生振荡：当干细胞分散在培养物中时，当它们保持与单个肌肉纤维相关时，或者当它们驻留在肌肉活检中时。在分化细胞中观察到不稳定的MyoD振荡和长时间的持续MyoD表达。消融干细胞中的Hes1振荡器干扰稳定的MyoD振荡，并导致持续MyoD表达的时间延长，导致分化倾向增加。这干扰了激活的肌肉干细胞的维持，并损害了肌肉的生长和修复。我们得出结论，振荡MyoD表达允许细胞保持在未分化和增殖状态，并且是激活的干细胞池扩增所需的。
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. We demonstrate here that the transcriptional regulator Hes1 controls the balance between proliferation and differentiation of activated muscle stem cells in both developing and regenerating muscle. We observed that Hes1 is expressed in an oscillatory manner in activated stem cells where it drives the oscillatory expression of MyoD. MyoD expression oscillates in activated muscle stem cells from postnatal and adult muscle under various conditions: when the stem cells are dispersed in culture, when they remain associated with single muscle fibers, or when they reside in muscle biopsies. Unstable MyoD oscillations and long periods of sustained MyoD expression are observed in differentiating cells. Ablation of the Hes1 oscillator in stem cells interfered with stable MyoD oscillations and led to prolonged periods of sustained MyoD expression, resulting in increased differentiation propensity. This interfered with the maintenance of activated muscle stem cells, and impaired muscle growth and repair. We conclude that oscillatory MyoD expression allows the cells to remain in an undifferentiated and proliferative state and is required for amplification of the activated stem cell pool.