Signal integration in muscle stem cells during tissue regeneration: Dissecting Notch signaling in quiescent and activated muscle stem cells

干细胞维持组织和修复组织损伤。它们在不需要时保持静止，但它们可以在需要时被激活再生。因此，通过对环境线索的反应，它们在静止和激活状态之间穿梭。剖析调节静止和激活之间的过渡的机制对于理解组织维护和修复至关重要，而且对于再生医学背景下的干细胞操作也至关重要。成年骨骼肌组织在受伤后具有非凡的再生能力。肌肉干细胞（MuSC）是修复的细胞来源，并驻留在称为小生境的特殊微环境中。我们的联盟先前表明，Notch信号传导对于两个不同且看似矛盾的过程至关重要，这两个过程取决于MuSC的状态，首先是维持MuSC的静止状态，这需要构建它们的生态位，其次是抑制激活的MuSC的分化，以确保它们能够增殖和自我更新。我们计划的实验将联合收割机小鼠遗传模型与高通量蛋白质组学相结合，以破译Notch信号调节MuSC静止和激活的机制。迄今为止，大多数关于MuSC静止和自我更新的分析都是基于转录组学作为蛋白质组的方便代理，并使用转录组学来推断谱系身份，活性生化途径和细胞功能。然而，蛋白质相互作用和可逆的翻译后修饰是调节整个细胞通路并使其适应变化条件的传感器。我们假设Notch的不同作用反映了与其他信号通路的串扰的结果，这决定了其相互作用的伙伴，它们的翻译后修饰和信号传播的动态。因此，在这个联盟中，我们将应用最先进的蛋白质组学方法与小鼠遗传学相结合，提供一个全面的研究信号整合和Notch信号在静止和激活的MuSC。

Stem cells maintain tissues and repair tissue injuries. They remain quiescent when they are not needed, but they can be activated for regeneration upon demand. Thus, by responding to environmental cues, they shuttle between quiescent and activated states. Dissecting the mechanisms that regulate the transition between quiescence and activation is critical for understanding tissue maintenance and repair, but also for the manipulation of stem cells in the context of regenerative medicine. The adult skeletal muscle tissue has an extraordinary capacity to regenerate after injury. Muscle stem cells (MuSCs) are the cellular source for repair and reside in a specialized microenvironment called the niche. Our Consortium showed previously that Notch signaling is critical for two distinct and seemingly contradictory processes that depend on the state of MuSCs, first the maintenance of the quiescent state of MuSCs, which requires the construction of their niche, and second the suppression of differentiation of activated MuSCs that ensures that they can proliferate and self-renew. Our planned experiments combine mouse genetic models with high-throughput proteomics to decipher the mechanisms by which Notch signaling regulates quiescence and activation of MuSCs. To date, the majority of analyses on MuSC quiescence and self-renewal are based on transcriptomics as a convenient proxy of the proteome, and use transcriptomics to infer lineage identity, active biochemical pathways and cellular functions. However, protein interactions and reversible posttranslational modifications are sensors that modulate entire cellular pathways and adopt them to changing conditions. We hypothesize that the diverse roles of Notch reflect the outcome of crosstalk with other signaling pathways, which determines its interacting partners, their posttranslational modifications and the dynamics of signaling propagation. Therefore, in this Consortium, we will apply cutting edge proteomic methodologies combined with mouse genetics to provide a comprehensive study on signal integration and Notch signaling in quiescent and activated MuSCs.