In the absence of noise or other ototoxins, age-related hearing loss is largely the result of the degenerationof specific non-sensory cells in the cochlea resulting in metabolic presbyacusis. Unlike sensory hair cellsthat are unable to regenerate, non-sensory cells, such as fibrocytes in the spiral ligament and glia-like cellsin the auditory nerve, are able to repopulate themselves after injury, although their regenerative ability seemsto decline with age. The mechanism whereby these non-sensory cells are able to repair themselves remainsunknown. Recent investigations have shown that bone marrow (BM) stem cells have the potential todifferentiate into multiple non-hematopoietic cell lineages with the caveat that aged BM stem cells are lesseffective at homing, engraftment and differentiation. Our studies have documented that some non-sensorycochlear cells in the adult mouse are continually derived from hematopoietic stem cells (HSCs). Moreover,we have shown that engraftment of the HSC-derived cells in the cochlear lateral wall and auditory nerve issignificantly increased after fibrocytes and spiral ganglion neurons are chemically injured. Here, we proposeto determine whether human inner ear cells are derived from HSCs using human-murine xenograft models(humanized mice). Our central hypotheses are that certain cell types in the human inner ear are continuallyderived from HSCs, and that HSC aging and cochlear injury significantly affect stem cell engraftment anddifferentiation.
Three specific aims are proposed.
Aim 3. 1 determines the potential of human stem cellsisolated from cord blood to engraft and differentiate into specific cochlear cell types.
Aim 3. 2 determines theextent to which BM stem cells from younger and older human subjects, especially those with metabolicpresbyacusis, differ in their abilities to engraft and differentiate in the inner ear.
Aim 3. 3 tests the effects ofcochlear injury on the engraftment and differentiation of BM stem cells from younger and older humansubjects. The aged stem cells will be isolated from the BM of older human subjects with normal hearing andwith metabolic presbyacusis as determined by auditory performance measures in the Human Subjects Core.This translational project will help further the understanding of how BM cells contribute to cellularhomeostasis in the human inner ear. Such knowledge will provide the intellectual foundation needed todesign treatments for age-related hearing loss, especially metabolic presbyacusis.
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