Niche Regulation of Muscle Stem Cells

项目总结 这个利基是干细胞长期功能的关键调节器。我们的长期目标是理解 NICE在肌肉干细胞功能的调节中发挥作用。SC处于静止状态，并经历了一系列 当它们被激活和扩散时，就会发生转变。我们已经确定WNT4是一种组织驻留抑制因子， 通过Rho-FAK信号抑制静止卫星细胞(QSCs)的激活和迁移。这是第一次 单个旁分泌作用生态位因子的演示协调了 QSCS。因此，这项拟议研究的总体目标是了解WNT4-RHO-FAK信号轴是如何 抑制QSCs的激活和迁移及其对成年和老年小鼠SC功能的影响。第一 AIM将结合时间调节和细胞特异性遗传策略来调节肌肉纤维中WNT4的水平 确定WNT4(在肌肉纤维中)和Rho-FAK(在QSCs中)在QSCs激活和迁移中的作用 以及对伤害的反应。第二个目标将剖析阻止qsc激活的分子机制。 以及通过WNT4进行迁移。我们将研究WNT4-Rho信号在抑制mTORC1和mTORC1中的作用。 QSCs中的河马信号。了解利基市场在供应链职能中的作用将导致对 细胞治疗、肌肉退行性疾病和衰老。

PROJECT SUMMARY The niche is a critical regulator of long-term stem cell function. Our long-term goal is to understand the role the niche plays in regulation of muscle stem cell function. SCs reside in a quiescent state and undergo a series of transitions as they activate and proliferate. We have identified Wnt4 as a tissue resident inhibitory factor that represses activation and migration of quiescent satellite cells (QSCs) via Rho-FAK signaling. This is the first demonstration of a single paracrine acting niche factor coordinates the growth, migration and activation of QSCs. The overall goal of this proposed study is therefore to understand how Wnt4-Rho-FAK signaling axis represses activation and migration in QSCs and its implications for SC function in adult and aged mice. The first aim will combine temporal regulated and cell specific genetic strategies to modulate Wnt4 levels in muscle fibers to determine the role of Wnt4 (in muscle fibers) and Rho-FAK (in QSCs) on activation and migration in QSCs and the response to injury. The second aim will dissect the molecular mechanism that prevents QSC activation and migration via Wnt4. We will examine the role of Wnt4-Rho signaling in the repression of mTORC1 and Hippo signaling in QSCs. Understanding the role of the niche on SC function will lead to important insights for cell therapy, muscle degenerative diseases and aging.