Stem Cell Therapy for Sensorineural Hearing Loss - How Do Glial Cells Interact With Auditory Stem Cells in the Peripheral Auditory System?

临床研究背景听力问题是一个极为重要的公共卫生问题。英国有近1000万人患有听力障碍，据预测，到2030年，这一数字将上升到1500万。“感音神经性听力损失”几乎占所有听力问题的90%，它是内耳，尤其是耳蜗受到不可逆损伤的结果，在耳蜗中，声音振动被转化为神经信号。尽管像人工耳蜗这样的电子设备已经成功地用于帮助所有年龄的患有严重感音神经性听力损失的患者，但这种设备的局限性正逐渐变得明显。再生医学为生物疗法提供了一些希望，这种疗法可能比目前用电子设备治疗感音神经性听力损失的效果更好。在最近的一项重大突破中，我们的实验室在感音神经性听力损失的动物模型中证明了干细胞修复和恢复受损听力神经功能的能力。这个项目将建立在我们之前的工作基础上，了解干细胞如何与受损的听力系统整合。“神经胶质细胞”是维持神经细胞健康的细胞。众所周知，神经损伤会导致“神经胶质细胞”的激活和增殖。在神经系统的某些部位，神经胶质细胞增殖的过程可以帮助修复受损的神经，但在其他部位，如大脑和脊髓，神经胶质细胞的增殖代表着疤痕，这限制了神经的进一步损伤，但也阻碍了修复。最近发现，听力神经的损伤也会导致神经胶质细胞的增殖，但尚不清楚这是否代表了一种支持修复的环境，还是代表了疤痕。这显然会对干细胞修复受损听力神经的能力产生影响。因此，了解听力系统胶质细胞和干细胞之间的关系是寻求将这种疗法转化为患者的关键因素。本项目的目的是了解干细胞与神经胶质细胞的交流方式，并说明神经胶质细胞对听力神经损伤的反应是否代表瘢痕形成，或者是否代表有利于干细胞修复听力神经的环境。然后，我们将展示移植的听觉干细胞如何与耳聋动物模型中的神经胶质细胞结合。研究计划本项目将分两个阶段进行。第一阶段将包括培养为听觉系统编程的干细胞，以检查它们是否有能力产生自己的胶质样细胞。干细胞随后将与耳蜗的神经胶质细胞一起培养，这将允许研究两种细胞类型之间的相互作用。第二阶段将包括确定干细胞是否能够在神经胶质细胞增殖的情况下修复受损的听力神经。这将包括对受损听力神经中的胶质细胞类型进行仔细分析，以及干细胞如何与它们相互作用。从前一阶段收集的信息将有助于描述这种关系。该项目将在谢菲尔德大学干细胞生物学中心进行，该中心是国际公认的干细胞研究卓越中心。该中心率先将干细胞用于内耳，并拥有开展这一项目所需的一切设施。

Clinical Background of ResearchHearing problems are an extremely significant public health issue. Almost 10 million people in Britain suffer with hearing impairment and forecasts suggest this will rise to 15 million by the year 2030. 'Sensorineural hearing loss' accounts for almost 90% of all hearing problems and occurs as a result of irreversible damage to the inner ear, especially the cochlea, where sound vibrations are converted into nerve signals. Although electrical devices such as Cochlear Implants have been used successfully to help patients of all ages suffering with severe sensorineural hearing loss, the limitations of such devices are gradually becoming apparent. Regenerative medicine provides some hope of biological therapies which may be able to treat sensorineural hearing loss with greater effect than current treatments with electrical devices. In a recent major breakthrough, our laboratory has demonstrated the ability of stem cells to repair and restore function of damaged hearing nerves in animal models of sensorineural hearing loss. This project will build on our previous work by understanding how stem cells integrate with a damaged hearing system. Importance of this Research'Glial Cells' are cells which maintain the health of nerve cells. It is well known that nerve damage results in the activation and multiplication of 'glial cells'. In some parts of the nervous system, this process of glial cell multiplication can help with the repair of damaged nerves, but in other parts, such as the brain and spinal cord, the multiplication of glial cells represents scarring which limits further damage to nerves, but also prevents repair. It has recently been discovered that damage to the hearing nerve also causes multiplication of glial cells, but it remains unclear if this represents an environment which would either support repair or whether it represents scarring. This would obviously have implications on the ability for stem cells to repair the damaged hearing nerve. Hence, understanding the relationship between the glial cells of the hearing system and stem cells is a key factor in the quest to translate this therapy to patients. Aims of this ResearchThe aims of this project are to understand the ways in which stem cells communicate with glial cells, and to illustrate whether the response of glial cells to damage of the hearing nerve represents scarring, or whether it represents a favourable environment for and stem cells to repair the hearing nerve. We will then demonstrate how transplanted auditory stem cells integrate with glial cells in animal models of deafness. Research PlanThe project will be conducted in two phases. The first phase will consist of culturing stem cells programmed for the auditory system to check if they are capable of producing their own glial-like cells. The stem cells will then be cultured alongside glial cells from the cochlea, which will allow the interaction between the two cell types to be studied. The second phase will consist of determining whether stem cells are able to repair the damaged hearing nerve despite the multiplication of glial cells. This will involve performing careful analysis of the glial cell types in the damaged hearing nerve and how stem cells interact with them. The information gathered from the previous phase will help in describing this relationship. Host InstitutionThis project will be undertaken at the Centre for Stem Cell Biology at the University of Sheffield which has international recognition as a centre of excellence for research into Stem Cells. The centre has pioneered the use of stem cells to the inner ear and has all the necessary facilities to carry out this project.