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的组织生理和在应激条件下是必需的，例如损伤或高级衰老。对它们休眠(或静止)状态的调节对于成体干细胞如何维持、激活以及它们的再生潜力是重要的。然而，这种调控是如何发生的，其潜在的细胞机制还不完全清楚。我们的初步工作发现，作为主要细胞细胞器之一的线粒体形状的生理性和暂时性的变化，调节着成体肌肉干细胞(MUSC)的静止状态。我们观察到干细胞中的线粒体对环境激活刺激的反应迅速碎裂。这将细胞推向深度静止的出口，并依赖于一种名为mTOR的主要细胞复合体。此外，我们发现，在脱离休眠后，成年的MUSC在组蛋白蛋白复合体中经历了修饰(表观遗传变化)，这导致了基因在细胞中表达方式的变化。这进而可能导致细胞和组织水平的生理变化。在这个建议中，我们的目标是深入研究(1)mTOR复合体及其控制的细胞过程在成年MUSC退出深度静止状态时的作用。(2)成年MUSC线粒体断裂和休眠后发生什么表观遗传变化，以及这些变化与随后的干细胞激活之间的因果关系。为了解决这些问题，我们组建了一个由三个实验室组成的协作团队，每个实验室都有独特的和互补的专业知识：Laura Hulea博士(mTOR复合体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)。每个实验室都有专门技术和特定工具，无论是在组织培养方面还是在使用小鼠方面，都可以解决上述审讯问题。