Welcome to the research group of Elizabeth Oesterle, Ph.D. located at the Virginial Merrill Bloedel Hearing Research Center in the Department of Otolaryngology/Head and Neck Surgery at the University of Washington. 

We investigate supporting cell function and sensory hair cell regeneration. We study the cellular and molecular mechanisms guiding the production of hair cells and supporting cells in developing and mature inner ear sensory epithelia of mammals and birds with the hopes of ultimately applying this knowledge to develop therapies to trigger the production of new hair cells in damaged human ears.

Hair Cell Regeneration

Hair cells are specialized receptors necessary for detecting sound, head rotation, and gravity. They are located in the inner ear. Hair cells are killed by many agents including loud sounds, certain therapeutically useful drugs (e.g., aminoglycoside antibiotics and antimitotic drugs), infections, defective gene expression, and aging. Hair cell loss in humans is currently irreversible and leads to permanent deafness and debilitating balance dysfunctions. Birds, in contrast to humans (and rodents) robustly replace damaged and lost hair cells, a process called “hair cell regeneration”. Our research group is interested in identifying ways to induce hair cell regeneration in mature mammalian inner ears.

Growth factor regulation of inner-ear stem/progenitor cell proliferation: We are particularly interested in identifying the specific factors that regulate the proliferation and differentiation of inner-ear stem/progenitor cells. We developed a cell culture system for studying the factors that regulate the proliferation of hair cell progenitor cells in mature inner ears, and we used this culture system to identify 2 members of the epidermal growth factor (EGF) superfamily, EGF and transforming growth factor a (TGFa), that stimulate proliferation in the mature inner-ear sensory epithelium of rodents (Yamashita and Oesterle, 1995; Kuntz and Oesterle, 1998; Oesterle et al., 2003). Their effects are potentiated by insulin, a member of the insulin-like growth factor (IGF) family. Unfortunately, only small numbers of new cells are generated in the mature mammalian vestibular SE by the addition of these factors. However, these studies show that the initial stages of hair cell regeneration can be induced in adult mammalian inner-ear sensory epithelia. Currently, we are building on these important findings by examining ways to dramatically enhance the proliferative response of the mature mammalian inner-ear sensory epithelia. We are also studying the bird inner ear because this ear is able to robustly regenerate new hair cells to replace those lost to insult. An identification of the specific factors that regulate the proliferation and differentiation of stem cells in bird inner ear sensory epithelia may assist us in developing ways to better stimulate new hair cell production in mammals. In birds, we found that proliferation in the vestibular sensory epithelium is stimulated by insulin-like growth factor-I (IGF-I), and fibroblast growth factor-2 (FGF-2) inhibits both baseline proliferation (vestibular SE) and regenerative proliferation (cochlea and vestibular SE) (Oesterle et al., 1997, 2000).
		Mouse utricular macula grown in culture medium supplemented with the cell proliferation marker BrdU in the absence (A,B) or presence (C-E) of heregulin, a member of the EGF family of ligands. Utricles are labeled for BrdU (green), a hair cell specific marker (red), and a nuclear label (blue). Heregulin stimulates cell proliferation in neonatal (C-D), but not adult (E), mouse utricular sensory epithelia.
		TGFalpha or aminoglycoside-induced damage stimulates the production of new cells in adult mammalian vestibular sensory epithelium. Two nuclei are labeled by the cell proliferation marker tritiated thymidine.

Leukocyte involvement in triggering hair cell regeneration: Our research group also has been studying possible white blood cell involvement in triggering hair cell regeneration. Leukocytes are known to release mitogenic growth factors, and it has been suggested that leukocyte-produced growth factors or cytokines might be involved in triggering the regenerative replacement of inner ear hair cells. As a first step in exploring this idea, we have been identifying the specific leukocytes subtypes that are present in normal undamaged avian inner ear sensory epithelium. We have also been studying the responsiveness of the leukocytes to aminoglycoside-induced hair cell damage. Leukocytes are resident in normal undamaged auditory and vestibular sensory epithelia epithelium, and their numbers increase at lesions sites shortly after damage and prior to regenerative proliferation (e.g., Bhave et al., 1998). The most common leukocytes in inner ear SE are ramified in appearance and are cells of the myeloid lineage. Many of these cells are MHC class II positive (express major histocompatibility complex class II proteins), and a small percentage are mature tissue macrophages.

Bu-1 labeled leukocytes in posthatch chicken vestibular sensory epithelium

Methods

We use a variety of methodological approaches to address our experimental questions, including cell and organ culture techniques, gene expression analyses, gene transfer technologies, immunofluorescence and confocal microscopy.

Links

For more information on hair cell regeneration research at the Virginia Merrill Bloedel Hearing Research Center, visit the following sites:

Virginia Merrill Bloedel Hearing Research Center
Hearing Regeneration Initiative
Rotary International site
Center on Human Development and Disability
Society for Neuroscience
Research in Otolaryngology
University of Washington

    Elizabeth Oesterle, Ph.D.
email: oesterle@u.washington.edu
Phone:  206-616-2705
Fax: 206-221-5685