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

点击翻译按钮获取中文摘要

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.