Stretch-activated ion channels in human neural stem cell mechanotransduction

 描述（由申请人提供）：机械力有力地调节干细胞命运。 尽管这些力量在干细胞分化中的重要性日益显现，但机械线索指导细胞命运的分子机制仍然未知。 我们认为，牵张激活离子通道（SAC）将质膜上感受到的机械信息传递给下游控制细胞命运的信号分子。 在这个修订后的申请中，我们将根据我们小组的新的初步数据来测试这一假设，这些数据表明最近鉴定的SAC Piezo 1是人类神经干/祖细胞中机械转导电流的基础，并影响神经元-胶质细胞谱系的选择。 在目标1中，我们将直接测试 Piezo 1将机械信号与下游转录因子活性和机械敏感谱系特化联系起来的假设。 在目标2中，我们将确定Piezo 1活性是否参与体内谱系特化。 这两个目标将共同确立Piezo 1作为机械调节人类神经干/祖细胞命运的ke信号分子。 总之，这项提案汇集了我们在离子通道生物物理学，力学，生物材料和干细胞生物学方面的专业知识，以揭示一个新的分子参与者，对基础干细胞生物学和再生医学的未来发展都有影响。

 DESCRIPTION (provided by applicant): Mechanical forces powerfully modulate stem cell fate. Despite the emerging importance of these forces in stem cell differentiation, the molecular mechanisms by which mechanical cues direct cell fate remain unknown. We propose that the stretch-activated ion channels (SACs) transduce mechanical information sensed at the plasma membrane to downstream signaling molecules that control cell fate. In this revised application we will test this hypothesis in light of new preliminary data from our group demonstrating that the recently-identified SAC Piezo1 underlies mechanotransduction currents in human neural stem/progenitor cells and influences neuronal-glial lineage choice. In Aim 1 we will directly test the hypothesis that Piezo1 links mechanical signals to downstream transcription factor activity and mechanosensitive lineage specification. In Aim 2 we will determine whether Piezo1 activity is involved in lineage specification in vivo. Together, the two Aims will establish Piezo1 as a ke signaling molecule in mechanoregulation of human neural stem/progenitor cell fate. In summary, this proposal brings together our expertise in ion channel biophysics, mechanics, biomaterials and stem cell biology to uncover a new molecular player with implications for both, basic stem cell biology and future developments in regenerative medicine.