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.

机械信号对发育、结构和功能有重要影响 中枢神经系统。神经干/祖细胞（NSPCs），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谱系特化，细胞迁移和轴突 指导在干细胞移植治疗中，无论是在体外还是在体外， 移植前和移植后体内影响植入。尽管他们 显然重要的是，NSPCs检测，识别和产生机械的过程 人们对这些力量仍然知之甚少。我们的总体目标是揭示新的分子机制 潜在的NPSC机械调节，可用于治疗策略， 神经发育和神经变性疾病。 我们最近报道了机械激活的离子通道Piezo 1产生Ca 2 + 闪烁，并表明其活性促进分化为神经元，而不是 神经胶质。我们新的初步数据还表明，小鼠中的Piezo 1敲除导致总的 大脑的异常有趣的是，Piezo 1即使在没有外部应用的情况下也是活跃的。 机械力，并且该活动由细胞牵引力-细胞内力触发 产生的细胞的肌动球蛋白细胞骨架，以探测机械性能的 细胞外基质在这里，我们研究牵引力和压电之间的功能动力学1 在NSPC中。目标1检查牵引力如何激活Piezo 1;目标2询问Piezo 1是否 活性反馈调节肌球蛋白II的活性;目的3检查机械的作用， Piezo 1和肌球蛋白II在发育过程中神经组织力学中的信号传导。这些 这些研究将为Piezo 1在体外调节NSPC行为中的作用提供一个机制性的见解 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