Piezo1 in neural stem cell mechano-regulation

Piezo1 在神经干细胞机械调节中的作用

• 批准号: 10441343
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10441343
• 关键词: Actomyosin; Age; Alzheimer' s Disease; Astrocytes; Back; Biochemical; Biocompatible Materials; Biological Assay; Biomedical Engineering; Biophysics; Brain; Cell Lineage; Cell membrane; Cells; 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; 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; mechanical signal; mechanotransduction; nerve stem cell; nervous system disorder; neural repair; neurodevelopment; neuroregulation; novel; relating to nervous system; 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.

机械信号是对发展，结构和功能的重要影响 中枢神经系统。神经/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提示特别敏感。期间 开发，机械信号驱动NSPC谱系规范，细胞迁移和轴突 指导。在干细胞移植疗法中，干细胞经历的机械提示都在体外 移植和移植后体内影响植入之前。尽管他们 表现出重要性，NSPCS检测，转导和生成机械的过程 力量仍然很少理解。我们的总体目标是发现新颖的分子机制 基本的NPSC机械调节，可以用于治疗策略 神经发育和神经退行性疾病。 我们最近报道说，机械激活的离子通道压电1产生Ca2+ NSPC中的闪烁，并表明其活性促进了分化为神经元而不是 神经胶质。我们的新初步数据还表明，小鼠的压电敲除导致总体 大脑异常。有趣的是，在没有外部应用的情况下，Piezo1也是活跃的 机械力和该活性是由细胞牵引力触发的 - 细胞内力 由细胞的Acto肌球蛋白细胞骨架生成，以探测 细胞外基质。在这里，我们检查了牵引力与压电1之间的功能动力学 在NSPC中。 AIM 1考试牵引力如何激活压电1； AIM 2询问Piezo1是否 活动反馈至调节肌球蛋白II活性； AIM 3考试机械的作用 发育过程中神经组织力学中的压电1和肌球蛋白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械洞察力 和体内。

项目成果

Membrane curvature governs the distribution of Piezo1 in live cells.

• DOI: 10.1038/s41467-022-35034-6
• 发表时间: 2022-12-03
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Yang, Shilong;Miao, Xinwen;Arnold, Steven;Li, Boxuan;Ly, Alan T.;Wang, Huan;Wang, Matthew;Guo, Xiangfu;Pathak, Medha M.;Zhao, Wenting;Cox, Charles D.;Shi, Zheng
• 通讯作者: Shi, Zheng