October 8, 2004
Title:Vestibular Hair Cell Regeneration in Mammals
Department of Surgery
UCLA School of Medicine
Abstract: The discovery that inner ear hair cells, once thought to be terminal and irreplaceable, do have the capacity to regenerate represents an époque-defining moment in auditory and vestibular science. Hair cell regeneration has been convincingly demonstrated in lower animals, including birds, but in mammals many attempts to verify this possibility only provided controversial results. The inner ears of mammals and particularly the vestibular sensory organs are much more complex with two major classes of hair cells, type I and type II, and three different types of afferent neurons, calyceal, dimorphic and bouton. The combined neurosensory units (hair cell/neuron pairings) have different distributions at different regions of the end organs, and a sophisticated homeostasis system that produces the inner ear fluids and their unique ionic compositions.
In the vestibular system the method used to damage hair cells to investigate their possible regeneration depends on the use of ototoxic drugs such as aminoglycosides. However, the use of these drugs is empirical, and half a century after their discovery, the mechanisms of ototoxicity and the relation between drug dose and effect have eluded quantitative description.
It is our hypothesis that, since inner ear hair cells derive
from common primordial progenitors, the failure to demonstrate
regenerative behavior in mammals is due to deficient knowledge
of the effects of these drugs for the design of appropriate experimental
protocols.
This presentation will address the following topics from experiments
conducted in chinchillas, a widely used animal model for anatomical
and physiological vestibular research.
1. Normal distribution of hair cells and neurons in the crista
of the horizontal semicircular canals.
2. Logistic analysis of the dose-effect relationship between the
four different doses of the aminoglycoside gentamicin (10, 20,
50, and 100 micrograms) and the destruction of type I and type
II hair cells as a function of time and location in the crista,
with the maximal effect occurring at 2 weeks.
3. Quantitative description of the effects of the drug on type
I and type II hair cells in different areas of the crista.
4. Measurement of vestibular ocular reflexes (VOR) function before
and after treatment.
5. Comparison of morphological and physiological effects of treatments.
The results demonstrate that different doses of gentamicin affect differently type I and type II hair cells and their role in VOR function. The anatomical and physiological recovery begins to take place six weeks after treatment and depends on the type of hair cells originally destroyed.
In addition to contributing to the understanding of hair cell
regeneration, the data are consistent with a symmetrical topographical
gradient of hair cell and neuronal representation in every direction
from the center of the crista, a tonotopic equivalent map in the
vestibular organ underlying the different physiological roles.