Les mécanismes liant la dynamique mitochondriale à l'état de quiescence et à l'activation des cellules souches musculaires

线粒体动力与静止与肌肉激活的机械主义

• 批准号: 577222-2022
• 负责人: Hulea, LauraL
• 金额: $ 3.28万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Alliance Grants
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=760646
• 关键词: Les; canismes; liant; la; dynamique

Adult stem cells are necessary for normal tissue physiology and under conditions of stress, such as injury or advanced aging. Regulation of their state of dormancy (or quiescence) is important towards how adult stem cells are maintained, activated, as well as their regeneration potential. Yet, how this regulation takes places and the underlying cellular mechanisms are not fully understood.Our preliminary work has uncovered that physiological and transient changes in the shape of mitochondria, one of the major cellular organelles, regulate the quiescent state of adult muscle stem cells (MuSC). We observed that mitochondria in stem cells rapidly fragment in response to an environmental activation stimulus. This pushes the cells toward an exit from deep quiescence and is dependent on a major cellular complex called mTOR. Moreover, we have found that, following exit from dormancy, adult MuSC undergo modifications in histone protein complexes (epigenetic changes), which lead to changes in the way genes are expressed in the cells. This in turn could lead to physiological changes at the cellular and tissue level.In this proposal, we aim to investigate in depth(1) the role of mTOR complexes and the cellular processes they control in the exit from deep quiescence of adult MuSC.(2) what epigenetic changes occur following mitochondria fragmentation and the exit from dormancy of adult MuSC, and what is the causal role between these changes and the subsequence stem cell activation.To tackle these questions, we have formed a collaborative team of three laboratories, each with unique and complementary expertise: Dr Laura Hulea (mTOR complexes and the cellular processes they control), Dr Mireille Khacho (stem cells biology and mitochondria dynamics) and Dr Frédérick Mallette (epigenetic regulation and aging). Each laboratory has the know-how and the specific tools, both in tissue culture and using mice, to address the aforementioned interrogations.

成体干细胞对于正常组织生理学和应激条件（例如损伤或晚期衰老）是必需的。调节其休眠（或静止）状态对于成体干细胞的维持、激活及其再生潜力非常重要。然而，这种调节是如何发生的以及潜在的细胞机制尚不完全清楚。我们的初步工作发现，线粒体（主要细胞器之一）形状的生理和短暂变化调节成体肌肉干细胞（MuSC）的静止状态。我们观察到干细胞中的线粒体响应环境激活刺激而迅速断裂。这推动细胞退出深度静止状态，并且依赖于一种称为 mTOR 的主要细胞复合物。此外，我们发现，在退出休眠后，成体 MuSC 会经历组蛋白复合物的修饰（表观遗传变化），从而导致基因在细胞中表达方式的变化。这反过来可能导致细胞和组织水平的生理变化。在本提案中，我们的目标是深入研究（1）mTOR复合物及其控制的细胞过程在成体MuSC退出深度静止过程中的作用。（2）线粒体破碎和成体MuSC退出休眠后发生哪些表观遗传变化，以及这些变化与随后的干细胞激活之间的因果作用是什么。 为了解决这些问题，我们组建了一个由三个实验室组成的合作团队，每个实验室都拥有独特且互补的专业知识：Laura Hulea 博士（mTOR 复合物及其控制的细胞过程）、Mireille Khacho 博士（干细胞生物学和线粒体动力学）和 Frédérick Mallette 博士（表观遗传调控和衰老）。每个实验室都拥有组织培养和使用小鼠方面的专业知识和特定工具来解决上述问题。