The goal of this project is to characterize stem cells in the mammalian inner ear. The mammalian inner ear is unable to replace sensory hair cells lost due to damage or the long-term effects of age. Despite the considerable interest in the possibility of hair cell regeneration in mammals, virtually nothing is known concerning the identity and properties of the progenitors of sensory hair cells in the mammalian inner ear, nor whether any cells in the inner ear have the properties of stem cells. We have developed a novel cell culture system in which dissociated cells from the embryonic mouse inner ear can divide and generate hair cells, supporting cells and neurons over several weeks in culture. We will use this system to achieve the following Specific Aims. ? First, we will address whether single progenitor cells in the ear are multipotent and can give rise to hair cells, supporting cells and neurons, or whether they are more restricted and give rise to only a subset of these cell types. We will also test whether the developmental potential of these progenitor cells changes with time. Second, we will test whether the progenitor cells in our cultures have the extensive self-renewal capacity characteristic of true stem cells. Last, we will attempt to understand the mechanism by which Bone Morphogenetic Protein 4 (BMP-4) is able to influence multipotent progenitor cell fates in the inner ear. Our preliminary evidence suggests this growth factor causes a fivefold increase in hair cell production in cultures of inner ear epithelium. We will use both the addition of exogenous growth factors and cell-autonomous activation or repression of the BMP-4 signaling pathway to determine whether BMP-4 acts directly or indirectly, and instructively or selectively on sensory hair cell progenitors to promote hair cell differentiation. ? ?
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