Cellular & Molecular Hearing Research Laboratory
Department of Otolaryngology—Head and Neck Surgery
637 Evans Building
Boston University School of Medicine
72 East Concord Street, Boston, MA 02118
Principal Investigator: Douglas A. Cotanche
Visit the Cellular & Molecular Hearing Research Laboratory website for more information.
The major focus of this lab is to define the cellular and molecular signals that trigger hair cell regeneration in the avian and mammalian inner ear. Our goal is to one day use regeneration as a treatment for human hearing loss.
Hair Cell Regeneration in the Avian Cochlea
PI: Douglas A. Cotanche. This research project is directed at understanding hair cell regeneration in the avian cochlea. Hair cell regeneration was first identified in the chick cochlea by our lab in 1987. We have continued to explore the mechanisms that regulate regeneration and how it leads to a structural and functional recovery of the cochlea. Currently, we are investigating how the activation of apoptosis in gentamicin and sound-damaged hair cells regulates the death of the hair cells and also how it stimulates the proliferation and direct transdifferentiation of supporting cells to replace the lost hair cells. We are also exploring the genetic pathways that determine the fates of the progenitor cell progeny as they decide to become new hair cells or supporting cells during regeneration.
Gene Array Analysis of the Avian Sensory Epithelium
PI: Douglas Cotanche. Collaborator: Zheng-Yi Chen, Massachusetts Eye & Ear Infirmary. We have recently initiated a genechip microarray study examining the genes that are up or down regulated during specific time points in the regeneration response. We are using the Affymetrix chicken gene arrays to examine genes expressed in control, 48h (after hair cell death but before S phase begins), 72h (peak of S phase), and 120h (after S phase but during the peak in hair cell differentiation) after gentamicin injection. The sensory epithelium is isolated from the underlying basilar membrane by thermolysin treatment and divided into damaged (basal) and undamaged (apical) halves to increase the sensitivity of the assays. With this technique we have been able to pinpoint a few of the key molecules within the cellular pathways that control supporting cell proliferation and hair cell differentiation.
Stem Cell Transplantation into the Damaged Mammalian Inner Ear
PI: Douglas Cotanche. Collaborator: Dr. Mark Parker, Emerson College and Massachusetts Eye & Ear Infirmary. This project focuses on the utilization of stem cells to replace damaged hair cells in the mammalian organ of Corti. We are transplanting mouse and human neural stem cells into the cochleas of sound-damaged guinea pigs and have shown that these stem cells migrate throughout the spiral ganglion and into the organ of Corti where they begin to differentiate into tissue-specific cell types to replace those damaged by the sound exposure. We have also been exploring the genetic profiles of these neural stem cells and are developing methods for “priming” the neural stem cells by growing them in culture along with immortalized cochlear cells. We have been able to show that co-culturing the stem cells causes a change in the genes and proteins they express so that they take on the aspects of cochlear progenitor cells. This will enable us to target the stem cells so that they differentiate down specific pathways needed for cells to repair the damaged cochlear sensory epithelium. Eventually we hope to be able to use these stem cells as a therapeutic treatment for sensorineural hearing loss in humans.
Tissue Engineering of Cultured Avian Cochlear Sensory Epithelia
PI: Doug Cotanche. Collaborator: Dr. Cathie Klapperich, Department of Biomedical Engineering, BU. These experiments are focused on developing appropriate biomatrices for culturing the chick cochlear sensory epithelia. We have greatly increased the quality of the hair cell survival and the longevity of the culture system by combining the defined biomatrices with a newly developed two-chambered culture system that allows the upper surfaces of the hair cells to be bathed in an endolymph-like solution, while the basolateral surfaces are immersed in a perilymph-like solution. This represents a significant advance in our ability to work with long-term cultures of the mature cochlear sensory epithelium. Moreover, further experiments with inhibitors of cell motility have shown that the cytoskeleton of the supporting cells plays a direct and active role in physically ejecting the dying hair cells from the cochlear sensory epithelium.