Niche Regulation of Muscle Stem Cells

项目摘要 小生境是长期干细胞功能的关键调节因子。我们的长期目标是了解 niche在调节肌肉干细胞功能中起作用。SC处于静止状态，并经历一系列的 在它们激活和增殖的过程中发生转变。我们已经将Wnt 4鉴定为组织驻留抑制因子， 通过Rho-FAK信号传导抑制静止卫星细胞（QSC）的活化和迁移。这是第一 一个单一的旁分泌作用的生态位因子协调的增长，迁移和激活的证明， QSC。因此，本研究的总体目标是了解Wnt 4-Rho-FAK信号转导轴如何在细胞内表达。 抑制QSC的活化和迁移及其对成年和老年小鼠SC功能的影响。第一 本研究旨在结合联合收割机时间调控和细胞特异性遗传策略来调节肌纤维中的Wnt 4水平 确定Wnt 4（在肌纤维中）和Rho-FAK（在QSC中）对QSC中活化和迁移的作用 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 通过Wnt 4迁移。我们将研究Wnt 4-Rho信号转导在mTORC 1抑制中的作用， QSC中的Hippo信号传导。了解供应链功能的利基的作用将导致重要的见解， 细胞疗法、肌肉退化性疾病和衰老。

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.