Fish genes offer clues to reversing human hearing loss

Humans have limited regenerative abilities compared to some animals. Once sensory hair cells in the inner ear are damaged, hearing and balance often decline for good. Meanwhile, animals like fish, frogs, and chicks use gene-driven repair to easily renew these cells.

Scientists at the Stowers Institute for Medical Research have discovered how two genes guide this regeneration in zebrafish. This research may shape future work on hearing loss in humans.

“Mammals such as ourselves cannot regenerate hair cells in the inner ear,” said study co-author Dr. Tatjana Piotrowski. “As we age or are subjected to prolonged noise exposure, we lose our hearing and balance.”

Fish genes and hearing cells

The study was designed to investigate how zebrafish control cell division during hair cell regeneration. The team, led by Dr. Mark Lush, found two genes that regulate how two support cell types divide.

The researchers used single-cell RNA sequencing and lineage tracing to uncover gene activity patterns. This helped them see which genes were responsible for maintaining stem cells and triggering regeneration.

“During normal tissue maintenance and regeneration, cells need to proliferate to replace the cells that are dying or being shed – however, this only works if there are existing cells that can divide to replace them,” said Piotrowski.

Why zebrafish offer rare insight

Zebrafish have sensory structures called neuromasts, which contain hair cells resembling those in the human inner ear. These neuromasts are distributed in a line from head to tail and help detect water motion.

Because zebrafish larvae are transparent, scientists can observe their cells directly. The team studied how hair cells regrow using imaging, gene editing, and molecular tracing.

“We can manipulate genes and test which ones are important for regeneration,” said Piotrowski. “By understanding how these cells regenerate in zebrafish, we hope to identify why similar regeneration does not occur in mammals and whether it might be possible to encourage this process in the future.”

Two genes control hearing cell repair

Within neuromasts, two groups of support cells drive regeneration. Stem cells lie at the edges, while progenitor cells are in the center. The research team discovered two cyclinD genes, each linked to only one cell group.

“When we rendered one of these genes non-functional, only one population stopped dividing,” said Piotrowski.

“This finding shows that different groups of cells within an organ can be controlled separately, which may help scientists understand cell growth in other tissues, such as the intestine or blood.”

Uncoupling division and differentiation

When the progenitor-specific gene was removed, those cells stopped dividing but still turned into hair cells. This meant cell division wasn’t always needed for differentiation. When the stem-cell gene was added to progenitors, their division restarted.

The ability to separate growth from differentiation could have broad biological implications.

The study illustrates this gene-switching in detail, using labeled cell populations and fluorescent markers to track regeneration.

“Our findings have important implications for the understanding of how proliferation of symmetrically dividing stem and progenitor cells is controlled during homeostasis and disease,” wrote the researchers.

Fish genes may help human hearing

Dr. David Raible, a professor at the University of Washington, highlighted the significance of the research.

“This work illuminates an elegant mechanism for maintaining neuromast stem cells while promoting hair cell regeneration. It may help us investigate whether similar processes exist or could be activated in mammals,” said Dr. Raible.

CyclinD genes also affect many human tissues, such as the gut, brain, skin, and blood. The findings in zebrafish may offer clues for regenerative therapies beyond hearing.

“Insights from zebrafish hair cell regeneration could eventually inform research on other organs and tissues, both those that naturally regenerate and those that do not,” said Piotrowski.

The study received funding from the NIH, the Hearing Health Foundation, and the Stowers Institute. The findings reflect the authors’ views and not necessarily those of the NIH.

The study is published in the journal Nature Communications.

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