Stochastic nanoroughness modulates neuron-astrocyte interactions and function via mechanosensing cation channels
Stochastic nanoroughness modulates neuron-astrocyte interactions and function via mechanosensing cation channels
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DOI：
10.1073/pnas.1412740111
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发表时间：
2014-11-11
影响因子：
11.1
通讯作者：
Shastri, V. Prasad
中科院分区：
文献类型：
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作者：
Blumenthal, Nils R.;Hermanson, Ola;Shastri, V. Prasad
已知细胞外可溶性信号在维持CNS中的神经元功能和稳态中起关键作用。然而，CNS也由细胞外基质大分子和神经胶质支持细胞组成，并且这些组分的物理属性在维持和调节神经元功能中的贡献还不清楚。由于这些组件具有明确的地形，我们理论的地形在神经元发育中的作用，我们表明，海马神经元的生存和功能以及端脑神经干细胞的分化是由纳米粗糙度调制。在对应于健康星形胶质细胞的粗糙度，海马神经元解离和存活独立于星形胶质细胞，并显示出上级功能特性（极性和钙流增加）。此外，端脑神经干细胞分化成神经元，即使在外源性信号，有利于星形胶质细胞分化。神经元与星形胶质细胞的解耦似乎是由星形胶质细胞顶端表面形貌对纳米粗糙度的反应而引起的。使用GsMTx 4通过机械传感阳离子通道阻断信号传导否定了神经元感知纳米粗糙度的能力，并促进了神经元与星形胶质细胞的解耦，从而为纳米形貌在神经元-星形胶质细胞相互作用中的作用提供了直接证据。我们外推地形的作用，以神经退行性疾病，并表明，在阿尔茨海默氏症患者的脑组织中的淀粉样斑块的积累区域伴随着组织粗糙度的有害变化。这些发现表明星形胶质细胞和ECM诱导的神经元病理学的地形变化的作用，并提供了新的见解，开发治疗靶点和神经生物材料的工程。
Extracellular soluble signals are known to play a critical role in maintaining neuronal function and homeostasis in the CNS. However, the CNS is also composed of extracellular matrix macromolecules and glia support cells, and the contribution of the physical attributes of these components in maintenance and regulation of neuronal function is not well understood. Because these components possess well-defined topography, we theorize a role for topography in neuronal development and we demonstrate that survival and function of hippocampal neurons and differentiation of telencephalic neural stem cells is modulated by nanoroughness. At roughnesses corresponding to that of healthy astrocytes, hippocampal neurons dissociated and survived independent from astrocytes and showed superior functional traits (increased polarity and calcium flux). Furthermore, telencephalic neural stem cells differentiated into neurons even under exogenous signals that favor astrocytic differentiation. The decoupling of neurons from astrocytes seemed to be triggered by changes to astrocyte apical-surface topography in response to nanoroughness. Blocking signaling through mechanosensing cation channels using GsMTx4 negated the ability of neurons to sense the nanoroughness and promoted decoupling of neurons from astrocytes, thus providing direct evidence for the role of nanotopography in neuron-astrocyte interactions. We extrapolate the role of topography to neurodegenerative conditions and show that regions of amyloid plaque buildup in brain tissue of Alzheimer's patients are accompanied by detrimental changes in tissue roughness. These findings suggest a role for astrocyte and ECM-induced topographical changes in neuronal pathologies and provide new insights for developing therapeutic targets and engineering of neural biomaterials.