The overall goal of this project is to determine the role of bone marrow (BM) stem/progenitor cells in regulating fibrocyte homeostasis in the mammalian inner ear. It is well established that specific subpopulations of inner ear fibrocytes are actively involved in the generation of electrochemical gradients essential to normal auditory function. Injury to or loss of these cells resulting from ototoxins, noise-trauma, genetic defects and aging is associated with a range of hearing and balance disorders. These highly specialized fibrocytes undergo continuous replacement throughout life and their turnover rate has been shown to increase with injury and decrease with age. However, it is not known whether this self renewal is mediated by a resident population of adult stem/progenitor cells or through some other mechanism. New data provided here document that cells derived from BM have the capacity to engraft and differentiate towards ion transport fibrocyte phenotypes in the mouse inner ear. These data also suggest that BM may provide a continuous source of stem/progenitor cells for fibrocyte turnover in the inner ear but this remains unproven.
Three Specific Aims are designed to address these important issues.
Aim 1 will evaluate the relative ability of two highly purified populations of BM stem/progenitor cells to engraft and differentiate into fibrocytes in the normal inner ear.
Aim 2 will investigate the potential of BM stem/progenitor cells to replace fibrocytes or other inner ear cell types damaged by chemical injury, genetic mutations or aging.
Aim 3 seeks to develop and optimize procedures for the direct introduction of BM stem/progenitor cells into the inner ear. The experimental design incorporates mouse BM transplantation and parabiosis models employing donor cells that express high levels of EGFP, allowing their tracking with immunological and histochemical procedures. Given the increasing evidence that defects or injuries to inner ear fibrocytes are associated with a wide range of hearing and balance disorders, it is important to obtain further knowledge about the derivation of these cells and the mechanisms mediating their turnover and replacement in both the normal, traumatized and aging inner ear. Such knowledge will be essential in the design of therapeutic strategies for the treatment of inner ear disorders associated with injury or destruction of specialized populations of inner ear fibrocytes. ? ? ?
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