Regulation of Mammalian Cochlear Regeneration by BMP4

近一半50岁以上的成年人患有感觉神经性耳聋。主要是感觉神经性耳聋 是由耳蜗中机械感觉细胞的累积损失引起的，即感觉毛细胞，它 在胚胎发育过程中分化，不会被取代。相比之下，成年的非哺乳动物脊椎动物可以 再生丢失的感觉毛细胞，但允许这些动物再生的信号尚不清楚。 我们希望研究可能调节哺乳动物出生后感觉毛细胞分化的信号。 使用一种新的体外系统进行耳蜗术。在这个系统中，小鼠胚胎耳蜗上皮细胞可以存活， 增殖，并分化为感觉毛细胞。我们在这里展示了初步数据，净化的新生儿 在本实验中，支持细胞具有重新进入细胞周期并表达感觉毛细胞标志物的能力。 通过反复试验，我们已经确定BMP4是一种潜在的细胞周期进入的负调控因子 支持细胞。这一数据之所以重要，有几个原因：首先，BMP4在两者的耳蜗中都有表达 鸟类和老鼠，尽管在不同的种群中；第二，BMP4在再生的鸟类中下调 耳蜗，但可能不存在于哺乳动物体内。因此，我们的模型提供了一个简单且可检验的假设来解释为什么 鸟类可能会再生，但哺乳动物不会。我们建议通过实验来确定这一机制 哪些BMP4可能抑制增殖，BMP4是否也在感觉毛细胞分化中发挥作用， 以及干扰BMP4信号通路是否可能促进哺乳动物的再生 体外培养的耳蜗组织。 随着年龄的增长，人们会失去听力，因为他们内耳中的振动感应细胞会死亡。 鸟类会自然地再生它们的振动感应细胞，我们认为这个过程是由一个分子调节的 名为BMP4。我们想通过改变小鼠内耳器官培养中BMP4的活性来测试这一想法。

Sensorineural deafness affects nearly half of adults over the age of 50. Primarily, sensorineural deafness is caused by the accumulated loss of mechanosensory cells in the cochlea, the sensory hair cells, which differentiate during embryogenesis and are not replaced. Adult non-mammalian vertebrates, in contrast, can regenerate lost sensory hair cells, but the signals that permit regeneration in these animals are unknown. We wish to investigate signals that may regulate sensory hair cell differentiation in the post-natal mammalian cochlea using a novel in vitro system. In this system mouse embryonic cochlear epithelial cells can survive, proliferate, and differentiate into sensory hair cells. We show here as preliminary data that purified neonatal supporting cells have the ability to re-enter the cell cycle and express sensory hair cell markers in this assay. Through trial and error, we have identified BMP4 as a potential negative regulator of cell cycle entry by supporting cells. This data is important for several reasons: first, BMP4 is expressed in the cochleae of both birds and mice, although in different populations; second, BMP4 is down-regulated in the regenerating avian cochlea, but probably not in mammals. Thus, our model provides a simple and testable hypothesis for why birds might regenerate, but mammals do not. We propose experiments to determine the mechanism by which BMP4 might inhibit proliferation, whether BMP4 also plays a role in sensory hair cell differentiation, and whether interfering with the BMP4 signaling pathway might promote regeneration in the mammalian cochlea in vitro. People lose their hearing as they get older because the vibration-sensing cells in their inner ears die. Birds naturally regenerate their vibration-sensing cells, and we think this process is regulated by a molecule called BMP4. We want to test this idea by changing BMP4 activity in cultures of mouse inner ear organs.