The Challenge of Hair Cell Regeneration
By Andrew K. Groves, PhD, and Neil Segil, PhD
The Problem
Loss of the sensory hair cells of the inner ear is the leading cause of deafness in humans. The mammalian cochlea cannot regenerate its complement of sensory hair cells and thus, at present, the only treatment for deafness due to sensory hair cell loss is the use of prosthetics such as hearing aids and cochlear implants.
Loss of the sensory hair cells of the inner ear is the leading cause of deafness in humans. The mammalian cochlea cannot regenerate its complement of sensory hair cells and thus, at present, the only treatment for deafness due to sensory hair cell loss is the use of prosthetics such as hearing aids and cochlear implants.
Andrew K. Groves, PhD, (l) is the chief scientist in the Section on Molecular development and Neil Segil, PhD, (r) is the chief scientist in the section on Cell Growth and differentiation.
More than a decade ago, it was discovered that, unlike humans and other mammals, hair cell regeneration does occur in birds and other "lower vertebrates." Since that time, many attempts to bring about regeneration in mammals have been tried without success. Recently, with the aid of a grant from the National Organization for Hearing Research, laboratories of the House Ear Institute have undertaken a new project to examine the underlying biology of hair cell generation. We hope that by understanding where hair cells come from in the embryo and how their progenitors are controlled at the molecular level, we will better understand the reasons for the lack of regeneration in humans and, ultimately, discover ways of curing hair cell loss.
The Goal
Two broad strategies can be proposed to bring about hair cell regeneration in mammals and, by extension, humans. The first is to demonstrate the presence of hair cell precursors in the adult Organ of Corti,and to attempt to stimulate them to re-enter the cell cycle to generate differentiated hair cells.
A second complementary strategy does not rely on the persistence of hair cell precursors in the adult Organ of Corti, but instead seeks to transplant hair cell precursors into the adult cochlea to affect hair cell replacement. Our first goal is to identify the cells in the embryo that give rise to the sensory hair cells of the inner ear.
These are the same strategies being taken by scientists whose goal is to cure other neurological disorders such as ParkinsonÕs disease and spinal cord injuries. For instance, recent progress in stem cell biology has allowed the identification of neuronal precursors that may someday be used for regenerating nerves or transplantation to form new nerves. Unfortunately, we do not yet know the nature of the sensory hair cell precursor, so our current work is aimed at identifying the cells in the embryo that give rise to the sensory hair cells of the inner ear.
Two broad strategies can be proposed to bring about hair cell regeneration in mammals and, by extension, humans. The first is to demonstrate the presence of hair cell precursors in the adult Organ of Corti,and to attempt to stimulate them to re-enter the cell cycle to generate differentiated hair cells.
A second complementary strategy does not rely on the persistence of hair cell precursors in the adult Organ of Corti, but instead seeks to transplant hair cell precursors into the adult cochlea to affect hair cell replacement. Our first goal is to identify the cells in the embryo that give rise to the sensory hair cells of the inner ear.
These are the same strategies being taken by scientists whose goal is to cure other neurological disorders such as ParkinsonÕs disease and spinal cord injuries. For instance, recent progress in stem cell biology has allowed the identification of neuronal precursors that may someday be used for regenerating nerves or transplantation to form new nerves. Unfortunately, we do not yet know the nature of the sensory hair cell precursor, so our current work is aimed at identifying the cells in the embryo that give rise to the sensory hair cells of the inner ear.
The Approach
Identifying cells in developing embryos is a daunting task. The key to success is identifying genes that are expressed in the cell types that you want to study, in this case the cells in the embryo that give rise to the hair cells.
Our experiments have been made somewhat easier because of a new mouse that has been engineered in the laboratory of our collaborator Dr. Jane Johnson at the Univ. of Texas, Southwestern. This mouse expresses a protein that glows green when fluorescent light is shined on it. Because of the way this mouse has been engineered, this Green Fluorescent Protein (GFP) is only expressed in newly born hair cells of the inner ear (see figure). So if we want to track the origin of these cells, we need only watch for exactly when these cells start turning green and then look at which cells they are coming from.
Of course, our ultimate goal is to purify the progenitors before they turn into hair cells. By purifying the progenitors we can study what makesthem stop dividing permanently and perhaps how to make them divide again. It will also allow us to identify additional markers for hair cell progenitors that we can use to search for progenitors that may be present in the adult inner ear.
Although it is believed that most of these embryonic progenitors disappear shortly after embryonic development, it is possible that some progenitors of hair cells persist in the adult inner ear, and that they are simply deficient in some way and so are unable to contribute to regeneration. The discovery of such cells would provide an important target for therapeutic attempts at inducing hair cell regeneration. This possibility is one of the motivating factors behind our quest for hair cell progenitors in the embryo.
Identifying cells in developing embryos is a daunting task. The key to success is identifying genes that are expressed in the cell types that you want to study, in this case the cells in the embryo that give rise to the hair cells.
Our experiments have been made somewhat easier because of a new mouse that has been engineered in the laboratory of our collaborator Dr. Jane Johnson at the Univ. of Texas, Southwestern. This mouse expresses a protein that glows green when fluorescent light is shined on it. Because of the way this mouse has been engineered, this Green Fluorescent Protein (GFP) is only expressed in newly born hair cells of the inner ear (see figure). So if we want to track the origin of these cells, we need only watch for exactly when these cells start turning green and then look at which cells they are coming from.
Of course, our ultimate goal is to purify the progenitors before they turn into hair cells. By purifying the progenitors we can study what makesthem stop dividing permanently and perhaps how to make them divide again. It will also allow us to identify additional markers for hair cell progenitors that we can use to search for progenitors that may be present in the adult inner ear.
Although it is believed that most of these embryonic progenitors disappear shortly after embryonic development, it is possible that some progenitors of hair cells persist in the adult inner ear, and that they are simply deficient in some way and so are unable to contribute to regeneration. The discovery of such cells would provide an important target for therapeutic attempts at inducing hair cell regeneration. This possibility is one of the motivating factors behind our quest for hair cell progenitors in the embryo.
The Hope
Current knowledge is insufficient to design clinical trials aimed at hair cell regeneration in humans. By first identifying the cells in the embryonic inner ear that give rise to hair cells and then studying their properties, we hope to provide the intellectual underpinning needed to design treatments that will eventually lead to regeneration and the restoration of hearing.
The first panel of the figure depicts (from left to right) a scanning electron micrograph of the surface of a normal adult human organ of Corti. The three rows of stereocilia which protrude from the underlying hair cells are seen are on the left and the single row of stereocillia corresponding to the inner hair cells are on the right. The second panel shows a comparable damaged organ of Corti from an adult. Note the many missing stereocilia. The third panel is a surface preparation of the organ of Corti from an embryonic mouse viewed under fluorescent light. This mouse contains the engineered GFP protein discussed in our article.
"Reprinted with permission from The Hearing Review and Medical World Communications, March 2001 (Vol. 8, no3), p 23. All rights reserved."
Section on Cell Cycle,
Growth and Differentiation
Laboratory of Developmental Biology
Gonda Dept. of Cell and Molecular Biology
Growth and Differentiation
Laboratory of Developmental Biology
Gonda Dept. of Cell and Molecular Biology
