Piezo1 in neural stem cell mechano-regulation

Piezo1 在神经干细胞力学调节中的作用

• 批准号: 10207802
• 负责人: Medha M Pathak
• 金额: $ 33.82万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10207802
• 关键词: Actomyosin; Age; Alzheimer' s Disease; Astrocytes; Back; Biochemical; Biocompatible Materials; Biological Assay; Biomedical Engineering; Biophysics; Brain; Cell Lineage; Cell membrane; Cells; Cues; Cytoskeleton; Data; Development; Disease; Embryo; Engraftment; Environment; Extracellular Matrix; Feeds; Generations; Genetic; Goals; Image; In Vitro; Injury; Ion Channel; Knock-out; Knockout Mice; Measurement; Measures; Mechanics; Microscopy; Molecular; Motor; Mus; Myosin ATPase; Myosin Type II; Neuraxis; Neurodegenerative Disorders; Neuroglia; Neurons; Nonmuscle Myosin Type IIB; Oligodendroglia; Organ; Parkinson Disease; Pharmacology; Phenocopy; Physiological; Piezo 1 ion channel; Preparation; Process; Regulation; Reporting; Role; Shapes; Signal Transduction; Spinal cord injury; Stem cell transplant; Structure; System; Therapeutic; Tissues; Traction; Transplantation; Work; axon guidance; base; behavior in vitro; brain abnormalities; cell motility; cell type; experience; genetic approach; genetic manipulation; high resolution imaging; imaging approach; in vivo; insight; mechanical force; mechanical properties; mechanotransduction; nerve stem cell; nervous system disorder; neurodevelopment; neuroregulation; novel; relating to nervous system; repaired; single molecule; stem; stem cells; transplantation therapy

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.

机械信号对发育、结构和功能有重要影响 中枢神经系统的。神经干/祖细胞（NSPC），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。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线索 移植前和移植后体内影响着床。尽管他们的 NSPC 检测、转换和产生机械力的过程显然很重要 力量仍然知之甚少。我们的总体目标是发现新的分子机制 潜在的 NPSC 机械调节可用于治疗策略 神经发育和神经退行性疾病。 我们最近报道机械激活离子通道 Piezo1 产生 Ca2+ NSPC 中闪烁，表明其活性促进分化为神经元而不是 神经胶质细胞。我们的新初步数据还表明，小鼠中 Piezo1 敲除会导致总体 大脑异常。有趣的是，即使没有外部施加电压，Piezo1 仍然活跃 机械力，这种活动是由细胞牵引力（细胞内力）触发的 由细胞的肌动球蛋白细胞骨架产生，用于探测肌球蛋白的机械特性 细胞外基质。在这里，我们检查牵引力和 Piezo1 之间的功能动力学 在 NSPC 中。目标 1 检查牵引力如何激活 Piezo1；目标 2 询问 Piezo1 是否 活性反馈调节肌球蛋白 II 活性；目标 3 检查机械的作用 发育过程中神经组织力学中 Piezo1 和 Myosin II 之间的信号传导。这些 研究将为 Piezo1 在体外调节 NSPC 行为中的作用提供机制见解 和体内。