Piezo1 in neural stem cell mechano-regulation

机械信号对人体的发育、结构和功能有着重要的影响 中枢神经系统。神经干细胞/祖细胞(NSPC)，它产生神经元， 星形胶质细胞和少突胶质细胞对机械信号特别敏感。在.期间 发育、机械信号驱动NSPC谱系规范、细胞迁移和轴突 指导。在干细胞移植治疗中，干细胞在体外经历的机械信号 移植前和移植后体内均影响植入。尽管他们 明显的重要性，即NSPC检测、转换和产生机械的过程 对部队的了解仍然很少。我们的总体目标是发现新的分子机制 潜在的NPSC机制调节，可用于治疗策略 神经发育和神经退行性疾病。 我们最近报道了机械激活的离子通道Piezo1产生钙 在NSPC中闪烁，并表明其活性促进向神经元分化，而不是 神经胶质细胞。我们新的初步数据还表明，在小鼠中敲除Piezo1基因会导致 大脑的异常。有趣的是，Piezo1即使在没有外用的情况下也是活跃的 机械力，这种活动是由细胞牵引力--细胞内力--触发的 由细胞的acto-myosin细胞骨架产生，以探测 细胞外基质。在这里，我们研究牵引力和Piezo1之间的功能动力学 在国家石油公司。目标1研究牵引力如何激活Piezo1；目标2询问Piezo1是否 活动反馈以调节肌球蛋白II的活动；目标3检查机械的作用 发育过程中Piezo1和肌球蛋白II在神经组织力学中的信号转导。这些 研究将提供对Piezo1的S在体外调节NSPC行为中的作用的机制的洞察 在活体内。

Mechanical signals are an important influence on the development, structure, and function of the central nervous system. Neural stem/progenitor cells (NSPCs), which generate neurons, astrocytes, and oligodendrocytes, are particularly sensitive to mechanical cues. During development, mechanical signals drive NSPC lineage specification, cell migration, and axon guidance. In stem cell transplant therapy, mechanical cues experienced by stem cells both in vitro before transplantation and in vivo after transplantation influence engraftment. Despite their manifest importance, the processes by which NSPCs detect, transduce, and generate mechanical forces remain poorly understood. Our overall objective is to uncover novel molecular mechanisms underlying NPSC mechano-regulation that could be harnessed for therapeutic strategies against neurodevelopmental and neurodegenerative diseases. We recently reported that the mechanically-activated ion channel Piezo1 generates Ca2+ flickers in NSPCs, and showed that its activity promotes differentiation into neurons rather than glia. Our new preliminary data also shows that Piezo1 knockout in mice results in gross abnormalities of the brain. Intriguingly, Piezo1 is active even in the absence of externally-applied mechanical force and this activity is triggered by cellular traction forces – intracellular forces generated by the cell’s acto-myosin cytoskeleton to probe mechanical properties of the extracellular matrix. Here we examine the functional dynamics between traction forces and Piezo1 in NSPCs. Aim 1 examines how traction forces activate Piezo1; Aim 2 asks whether Piezo1 activity feeds back to modulate Myosin II activity; and Aim 3 examines the role of the mechanical signaling between Piezo1 and Myosin II in neural tissue mechanics during development. These studies will provide a mechanistic insight into Piezo1’s role in regulating NSPC behavior in vitro and in vivo.