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February 22, 2017

Drug Combo Can Regenerate Hair Cells, May Restore Hearing Loss

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    This is a picture of large clonal colonies of cochlear progenitor cells formed from single cells and converted into high-purity colonies of hair cells (cyan) with intricate hair bundles (red). [Will McLean, Ph.D.]

    Each of us has just 15,000 cochlear hair cells, which is a problem because our hearing wanes a little bit every time one of these cells is lost or damaged. Ordinarily, we cannot regenerate these cells, so when we lose large numbers of them due to noise exposure, toxic drugs, or aging, we’re out of luck. But hair cells have been regenerated in the laboratory, raising hopes that treatments could be developed to restore full hearing to those who have suffered hearing loss due to hair cell reductions.

    For any new treatment to be effective, it must not only regenerate hair cells, it must also produce them in abundance. Until recently, attempts to regenerate hair cells have failed to produce the luxuriant growth that would be needed to combat hearing loss. A fresh attempt, however, is looking more promising.

    In a study published online February 21 in Cell Reports ("Clonal Expansion of Lgr5-Positive Cells from Mammalian Cochlea and High-Purity Generation of Sensory Hair Cells"), a research team from Massachusetts Eye and Ear, Brigham and Women's Hospital (BWH), and Massachusetts Institute of Technology (MIT) has shown that hair cell precursors, LGR5+ cells, can be augmented to a much higher volume and then converted into hair cells. From a single mouse, the team generated more than 11,500 hair cells (compared to less than 200 hair cells generated without efforts to augment).

    The augmentation step is the crucial innovation. "We have shown that we can expand Lgr5-expressing cells to differentiate into hair cells in high yield, which opens the door for drug discovery for hearing," said Albert Edge, Ph.D., director of the Tillotson Cell Biology Unit at Massachusetts Eye and Ear and a professor of otolaryngology at Harvard Medical School. "We hope that by stimulating these cells to divide and differentiate that we will improve on our previous results in restoring hearing."

    Dr. Edge is a co-corresponding author, along with MIT’s Robert Langer, Ph.D., and BWH’s Jeffrey Karp, Ph.D., of the Cell Reports paper describing how the scientific team used a small-molecule approach to expand cochlear supporting cells expressing and maintaining Lgr5, an epithelial stem cell marker. The expansion occurred in response to stimulation of Wnt signaling by a glycogen synthase kinase 3 beta (GSK3β) inhibitor and transcriptional activation by a histone deacetylase inhibitor.

    Essentially, the researchers extracted the Lgr5+ cells from the inner ears of mice, placed them in a dish, and used a combination of drugs and growth factors to make them multiply. They then treated the cells with a second drug cocktail to convert the expanded Lgr5+ cells into large populations of hair cells.

    “The Lgr5-expressing cells differentiate into hair cells in high yield,” the article’s authors wrote. “The newly generated hair cells have bundles and molecular machinery for transduction, synapse formation, and specialized hair cell activity.”

    The scientists demonstrated that hair cells can be generated from cells of the adult mouse and primate cochlea. Also, in a second experiment, the scientists showed that Lgr5+ cells and hair cells can be expanded in situ in the cochlea.

    In the second experiment, the researchers did not need to add the second set of drugs because once the progenitor cells were formed, they were naturally exposed to signals that stimulated them to become mature hair cells.

    Because this treatment involves a simple drug exposure, the researchers believe it could be easy to administer it to human patients. They envision that the drugs could be injected into the middle ear, from which they would diffuse across a membrane into the inner ear. This type of injection is commonly performed to treat ear infections.

    "We only need to promote the proliferation of these supporting cells, and then the natural signaling cascade that exists in the body will drive a portion of those cells to become hair cells," noted Dr. Karp.

    The researchers were encouraged by earlier work conducted at Massachusetts Eye and Ear. This work indicated that the inner ear contained stem cells that could be turned into hair cells in a dish. These cells contained a protein called Lgr5, which is also found in adult intestinal stem cells, where they actively regenerate to replace the entire lining of human intestines every eight days. Their regenerative properties motivated the researchers to explore their potential use in hair cell regeneration in the ear.

    The results of the new study identify drugs that will be useful for a combination of first expanding Lgr5+ cells in the inner ear and then converting them to hair cells, opening the door for better therapies to be developed to restore hearing to those with acquired forms of deafness.

    "With this knowledge, we can make better shots on goal, which is critical for repairing damaged ears," said Dr. Edge. "We have identified the cells of interest and have identified the pathways and drugs to target to improve on previous results. These clues may lead us closer to finding drugs that could treat hearing loss in adults."

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