Stretch-activated ion channel Piezo1 directs lineage choice in human neural stem cells
Stretch-activated ion channel Piezo1 directs lineage choice in human neural stem cells
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DOI：
10.1073/pnas.1409802111
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发表时间：
2014-11-11
影响因子：
11.1
通讯作者：
Tombola, Francesco
中科院分区：
文献类型：
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作者：
Pathak, Medha M.;Nourse, Jamison L.;Tombola, Francesco
神经干细胞是多能细胞，具有分化为神经元、星形胶质细胞和少突胶质细胞的能力。谱系特征对细胞环境的机械特性非常敏感。然而，将基质机械信号转导到与谱系规范相关的细胞内信号通路的分子通路仍不清楚。我们发现，机械门控离子通道Piezo1由人脑来源的神经干细胞/祖细胞表达，并负责机械诱导的离子电流。由牵引力触发的PIEZO1活性以底物硬度依赖的方式引起钙离子内流，这是一种已知的分化调节因子。药物抑制剂GsMTx-4或siRNA介导的Piezo1基因敲除抑制了通道活性，抑制了神经发生和增强了星形发生。PIEZO1基因敲除也减少了机械反应转录辅活化子Yes相关蛋白的核定位。我们认为，机械门控离子通道Piezo1是神经干细胞机械敏感性谱系选择的重要决定因素，并可能在其他多能干细胞中发挥类似的作用。
Neural stem cells are multipotent cells with the ability to differentiate into neurons, astrocytes, and oligodendrocytes. Lineage specification is strongly sensitive to the mechanical properties of the cellular environment. However, molecular pathways transducing matrix mechanical cues to intracellular signaling pathways linked to lineage specification remain unclear. We found that the mechanically gated ion channel Piezo1 is expressed by brain-derived human neural stem/progenitor cells and is responsible for a mechanically induced ionic current. Piezo1 activity triggered by traction forces elicited influx of Ca2+, a known modulator of differentiation, in a substrate-stiffness-dependent manner. Inhibition of channel activity by the pharmacological inhibitor GsMTx-4 or by siRNA-mediated Piezo1 knockdown suppressed neurogenesis and enhanced astrogenesis. Piezo1 knockdown also reduced the nuclear localization of the mechanoreactive transcriptional coactivator Yes-associated protein. We propose that the mechanically gated ion channel Piezo1 is an important determinant of mechanosensitive lineage choice in neural stem cells and may play similar roles in other multipotent stem cells.