Generation of hES/iPS cell-derived sensory neurons: a new approach to study mechanosensation

hES/iPS 细胞来源的感觉神经元的生成：研究机械感觉的新方法

• 批准号: 363239741
• 负责人: Dr. Katrin Schrenk-Siemens
• 金额: --
• 依托单位: Pharmakologisches Institut
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/363239741?language=en
• 关键词: Generation; hES; iPS; cell; derived

The ability to perceive and discriminate mechanical stimuli is of fundamental importance to our wellbeing. We encounter a large variety of tactile stimuli during the course of a day. These stimuli can broadly be categorized as pleasant -such as mechanical stimuli that allow us to discriminate different textures and surfaces - or painful such as a pinprick, which can serve as warning signal to change our behavior in order to avoid tissue damage.Although over the last decades we have learned a great deal about the different subtypes of sensory neurons responsible for the detection of different forms of mechanical stimulation (mechanoreceptors respond to innocuous mechanical stimuli while nociceptors are specialized to detect noxious mechanical input), the molecular mechanisms responsible for transducing the different types of mechanical stimuli are just beginning to be uncovered.Piezo2, a large transmembrane protein expressed by a variety of different sensory neuron subtypes, was identified as one main transducer of innocuous mechanical stimuli in mammalian mechanoreceptors. But it is still unclear, if this protein is also involved in transducing noxious mechanical stimuli to elicit painful sensations. Likewise, nothing is known yet about the mechanism by which Piezo2 is transducing mechanical stimuli and how it is modulated and fine-tuned to serve as a molecular mechanoreceptor. Similarto other known sensory receptors, we propose that a number of accessory proteins are required to assist Piezo2 in fulfilling its highly specialized function.We therefore propose to investigate the role of Piezo2 in sensory neurobiology in more detail, using human embryonic stem cell (hESC)-derived nociceptors and mechanoreceptors as a model system. Our aim is first to understand the role of Piezo2 in transducing noxious mechanical stimuli in nociceptors that mediate the perception of pain. We next want to analyze the Piezo2 proteom in order to identify regulatory proteins required for Piezo2 function. We are confident that our human cell-based modelsystem is an excellent tool to find answers to these questions, which will not only help us to better understand the basic mechanisms underlying this highly specialized sensory transduction machinery, but are also essential prerequisites to develop interventions when pain perception becomes maladaptive.

感知和区分机械刺激的能力对我们的健康至关重要。我们在一天中会遇到各种各样的触觉刺激。这些刺激可以大致分为愉快的-如机械刺激，使我们能够区分不同的纹理和表面-或痛苦的，如针刺，虽然在过去的几十年里，我们已经了解了很多关于负责检测不同形式的机械刺激的感觉神经元的不同亚型，Piezo 2是一种跨膜蛋白，由多种感觉神经元亚型表达，是哺乳动物机械感受器中传递机械刺激的主要分子。但目前还不清楚，如果这种蛋白质也参与转导有害的机械刺激，引起疼痛的感觉。同样，Piezo 2转导机械刺激的机制以及它如何被调节和微调以充当分子机械感受器，目前还不清楚。与其他已知的感觉感受器相似，我们认为Piezo 2在完成其高度特异性的功能时需要一些辅助蛋白，因此我们拟以人胚胎干细胞（hESC）源性伤害感受器和机械感受器为模型系统，更详细地研究Piezo 2在感觉神经生物学中的作用。我们的目的是首先了解Piezo 2在介导疼痛感知的伤害感受器中转导伤害性机械刺激的作用。我们接下来要分析Piezo 2蛋白质组，以确定Piezo 2功能所需的调节蛋白。我们相信，我们的基于人类细胞的模型系统是找到这些问题答案的绝佳工具，这不仅有助于我们更好地理解这种高度专业化的感觉转导机制的基本机制，而且也是在疼痛感知变得适应不良时开发干预措施的必要先决条件。

项目成果

HESC-derived sensory neurons reveal an unexpected role for PIEZO2 in nociceptor mechanotransduction

HESC 衍生的感觉神经元揭示了 PIEZO2 在伤害感受器机械转导中的意外作用

• DOI: 10.1101/741660
• 期刊: bioRxiv
• 作者: Katrin Schrenk-Siemens;Jörg Pohle;Charlotte Rostock;Muad Abd El Hay;Ruby M. Lam;Marcin Szczot;Shiying Lu;Alexander T. Chesler;Jan Siemens
• 通讯作者: Jan Siemens