- Studying how hair cells in the inner ear regenerate has been a challenge for researchers who have long relied on complex mouse models and a limited set of relevant tools
- Investigators at Mass Eye and Ear combined genetic tools with inner ear organoid technology to uncover a new molecular player in hair cell regeneration called hypermethylated in cancer 1 (HIC1)
- HIC1 hinders the regeneration of hair cells in mammals and could move scientists one step closer to developing new treatments for hearing loss
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Over 400 million people worldwide live with sensorineural hearing loss. This type of hearing loss occurs most often when sensory hair cells, the cells responsible for hearing, deteriorate as a result of aging, infections, medications or exposure to loud noises. There are no built-in replacements for the damaged hair cells – once permanently lost, irreversible hearing loss ensues.
Dunia Abdul-Aziz, MD, and Albert Edge, PhD, researchers at Mass Eye and Ear, used a combination of genetic tools with inner ear organoid technology to identify new pathways involved in hair cell regeneration. In a study published in Stem Cell Reports, they study a new molecular player called HIC1 that hinders the regeneration of hair cells. Their approach promises to help identify and test new genes and pathways important in hair cell development and regeneration.
Targeting Regulators of Hair Cell Development
Similar to humans and other mammals, adult mice are unable to restore lost hair cells. However, it takes approximately two weeks for a newborn mouse's ear to fully mature, which affords researchers an opportunity to study a critical development window when regeneration is still possible.
A well-known key player in the development of hair cells is transcription factor ATOH1, which is critical for inducing native progenitor cells, or stem cells, in the ear so that they can grow into hair cells. While overexpressing ATOH1 in cochlear progenitor cells early in development results in an overabundance of hair cells, no effect is seen shortly after birth, which suggests there are epigenetic factors blocking access to the ATOH1 gene locus in the maturing progenitor cell. Understanding which factors are blocking the expression of ATOH1 holds significant promise for hair cell restoration.
Previous studies have indicated that the protein HIC1 represses the ATOH1 gene in the human brain and in the intestine. These studies encouraged Drs. Abdul-Aziz and Edge to hypothesize that HIC1 may contribute to the inhibition of the ATOH1 gene in the inner ear and to the epigenetic blockage limiting regeneration.
A New Molecular Pathway
Testing hair cell development in a mammalian inner ear requires an abundance of progenitor cells that are capable of being differentiated, or turned into, hair cells. Drs. Abdul-Aziz and Edge created a sufficient number of these cells by building inner organoids from the cochlea cells of newborn mice.
The researchers then used genetic tools to limit the expression of HIC1 in the organoids and observed changes in ATOH1 levels. They saw that ATOH1 expression increased, and moreover, that there were markedly more hair cells generated from progenitor cells. Conversely, when the researchers overexpressed HIC1 in the organoid model, they witnessed ATOH1 inhibition and a subsequent decrease in hair cells. They went on to study the mechanism of HIC1's repression, which is caused in part by modulating Wnt signaling, a key developmental pathway for hair cells.
The findings also established a framework with which other molecular pathways can be studied. The organoid model, and the genetic toolkit, can be adjusted to test countless other genes and regulators, all of which could help move researchers one step closer to hearing restoration.
Funding for the study performed by Drs. Abdul-Aziz and Edge was made possible by grants from the National Institute of Health, Hearing Health Foundation, American Academy of Otolaryngology, American Neurotology Society.
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