A doctor examines the inner ear of a heraing loss patient. (Photo by Bangkoker on Shutterstock)
In a Nutshell
- New zebrafish research shows that sensory hair cells can regrow without traditional cell division, using a direct transformation pathway instead.
- This unexpected regenerative flexibility could help scientists rethink how to restore damaged hair cells that are vital for hearing.
- Future therapies might one day use direct conversion of existing cells to replace lost hair cells — but ensuring they orient correctly will be key to regaining full hearing function.
- While the study opens exciting possibilities, much more work is needed to see if similar pathways can be safely harnessed in the human inner ear.
KANSAS CITY — For decades, scientists believed that when sensory hair cells die, they must be replaced through cell division, a fundamental process where one cell splits into two. But new research using zebrafish upends this assumption, revealing that hair cells can actually regenerate without any cell division at all. The discovery could lead to a novel approach for treating hearing loss in humans, potentially offering new hope for the millions of Americans dealing with hearing impairment.
Published in Nature Communications, the study reveals that the regenerative process is far more flexible than previously understood, opening new avenues for therapeutic approaches that don’t rely on traditional cell division pathways.
Hair Cells Can Heal Themselves in an Entirely New Way
Research teams have long observed that when hair cells died, nearby stem cells would divide to create new replacement cells. This process, called proliferation, seemed essential for regeneration. However, the new research from the Stowers Institute for Medical Research reveals a completely different pathway.
Using genetic techniques, the scientists created zebrafish mutants lacking a gene called ccndx, which is essential for cell division in hair cell progenitors, which are the cells that normally divide to create new hair cells. According to conventional wisdom, these mutant fish should have been unable to regenerate hair cells at all.
Instead, something remarkable happened. The mutant zebrafish could still regenerate hair cells, just in smaller numbers. Rather than one progenitor cell dividing to create two hair cells, each progenitor simply transformed directly into a single hair cell.
“We were surprised, as previous studies had concluded that proliferation was absolutely essential for hair cell regeneration in the lateral line,” study co-author Tatjana Piotrowski, Ph.D., a developmental biologist at Stowers, tells StudyFinds. You can read our full Q&A with her at the end of the article.
Two Cell Types Follow Completely Different Regeneration Rules
Beyond the division discovery, the study uncovered another surprising finding: different types of cells follow completely separate rules for regeneration. The researchers discovered that two distinct cell populations, stem cells and progenitor cells, are controlled by entirely separate genes from the same family.
Stem cells, which maintain the organ’s structure, rely on a gene called ccnd2a for their division. Meanwhile, progenitor cells, which directly create new hair cells, depend on the ccndx gene. Scientists had never before shown that different cyclin D genes independently regulate proliferation in distinct cell populations within the same regenerating organ.
When scientists removed the ccnd2a gene, stem cell division stopped during development, but hair cell progenitors continued functioning normally. Conversely, removing ccndx prevented progenitor division but left stem cells unaffected.
The Catch: Regenerated Cells Have Direction Problems
While hair cells could regenerate without division, the process wasn’t perfect. The research revealed an unexpected consequence: hair cells that regenerated without division had defective polarity — they couldn’t properly sense the direction of water movement.
Normal hair cells are polarized, meaning they have a specific orientation that allows them to detect movement in particular directions. About half should face forward and half should face backward to provide comprehensive sensory coverage. However, in the mutant fish, 70% of regenerated hair cells faced the same direction, creating sensory blind spots.
Beyond creating more cells, cell division is also crucial for proper cell orientation. During normal division, two daughter cells receive different molecular signals that determine their eventual orientation. Without division, this orientation process becomes disrupted.
Rethinking Hearing Loss Treatment
These discoveries could fundamentally change how scientists approach hearing loss treatment in humans. Currently, most regenerative therapies focus on stimulating cell division to create new hair cells. However, this research suggests that direct conversion approaches — transforming existing cells into hair cells without division — might be viable.
The study also reveals that regeneration is more robust and flexible than previously thought. Even when one pathway fails, alternative mechanisms can compensate, albeit with some limitations.
However, the polarity findings provide important cautions. Any future therapies must ensure that regenerated hair cells not only function but also orient correctly. Otherwise, patients might regain some hearing but lose directional sensitivity.
Perhaps most significantly, this research demonstrates how entrenched scientific assumptions can limit discovery. For years, researchers used cell cycle inhibitors to study hair cell regeneration, and when these drugs prevented regeneration, they concluded that cell division was essential.
But the new study shows that for the commonly used cell cycle inhibitor aphidicolin, the failure of regeneration happened because the drug killed new hair cells, not because it blocked their formation outright. By switching to genetic approaches instead of drugs, the researchers uncovered the true regenerative pathway.
The research opens doors to new treatment possibilities while demonstrating that biological systems often have backup plans scientists haven’t discovered yet. For people dealing with hearing loss, this unexpected pathway might eventually lead to therapies that work differently than anyone previously imagined.
“Impressive progress has been made in inducing regeneration of a limited number of new hair cells in the mouse ear, but these hair cells are not yet perfectly formed and lead to either no or limited recovery of hearing or the vestibular system,” notes Piotrowski. “Therefore, more research is needed to identify additional key genes that need to be turned on or off in the mouse ear to regenerate perfectly shaped and functional hair cells.”
Disclaimer: This report summarizes early-stage research in zebrafish, a species with much higher regenerative capacity than humans. Findings do not imply that humans can naturally regrow hair cells this way, and any potential therapies remain speculative.
StudyFinds’ Q&A With Author Tatjana Piotrowski
What inspired you to test whether hair cells could regenerate without cell division?
TP: When we studied regeneration of larvae with a defective ccndx gene, we did not anticipate finding hair cells that developed in the absence of cell division. We initially observed that the mutant larvae possessed fewer hair cells and expected that the reduction was caused by a decrease in progenitor proliferation. We were surprised to find that the regenerated hair cells did not show any markers of previous cell divisions, suggesting that they must have developed from a support cell that differentiated into a hair cell without dividing first.
How did you come up with the idea to target the ccndx gene specifically?
TP: Cell divisions are essential for maintaining tissues as cells die or for regeneration after injury. As differentiated cells, such as sensory hair cells, intestinal, blood or skin cells die, the surrounding cells will divide and regenerate the missing cells. In the absence of cell proliferation, the surrounding cells would be depleted at some point.
Understanding how cell division is regulated during both normal tissue turnover and regeneration is crucial for advancing our knowledge of organ maintenance and repair. In our previous work, we utilized single-cell RNA sequencing to comprehensively profile gene expression at the individual cell level within the organ. Dr. Mark Lush, the study’s first author, analyzed the resulting data and identified cells actively expressing genes involved in cell division. Remarkably, he found that the CyclinD family member ccndx was specifically upregulated in dividing cells destined to become hair cells, but not in other proliferating cell populations. This finding indicates that distinct mechanisms may control cell proliferation in different cell types, an unexpected result that highlights the complexity of tissue regeneration and cellular specialization.
What was your reaction when you saw hair cells regenerating without dividing?
TP: We were surprised as previous studies had concluded that proliferation was absolutely essential for hair cell regeneration in the lateral line.
Why do you think previous studies using cell cycle inhibitors missed this direct conversion pathway?
TP: In previous studies, researchers had used pharmacological inhibitors of cell division, which, as it turns out, killed support cells as they started to divide. Therefore, in these experiments, the inability of the support cells to regenerate was not caused by the lack of cell division but rather because the support cells that would have normally differentiated into hair cells disappeared.
What are the biggest challenges in translating this discovery to human hearing loss treatments?
TP: Because the ability to study human embryos is limited, we still understand little about how hair cells develop in the inner ear of humans and why they do not regenerate. The vast majority of mammalian hair cell regeneration research is being performed in mice and the first step of translating our findings to other species would be to determine if the developing mouse ear also possesses different proliferating populations of supporting cells that are possibly controlled by different cell division regulators. We also have not yet identified the factors that turn on the specific cell cycle regulators in the different dividing cell types in zebrafish, which will be very useful in manipulating the cell division genes in mammals.
Also, studies over the years have shown that manipulations of individual genes is not sufficient to induce regeneration. We therefore need to gain a much better understanding of the cascade of genes that are activated or turned off at different time points of regeneration and identify the key genes that need to be activated.
Therefore, we still have more work cut out for us before we can translate these findings to humans.
Could direct conversion approaches work for other types of sensory cells or organs?
TP: Direct conversion of support cells into a differentiated cell type in other sensory organs or tissues is a possibility to regenerate these cells but needs to be accompanied by proliferation of stem cells to that maintain the support cell pool. In the absence of stem cells, all support cells eventually would differentiate and long term tissue turnover or regeneration would cease. In the case of the lateral line organs, the support cells that give rise to hair cells divide and both daughter cells make hair cells. The second population of support cells also divides but both daughter cells give rise to two support cells ensuring that the support cell pool is not depleted.
How does this change your perspective on “rules” we assume are universal in regeneration biology?
TP: The regeneration field is still in the midst of trying to understand what mechanisms underly the ability to regenerate cells and organs in certain species and we are only beginning to take a more comparative approach. As with developmental mechanisms, that are much better understood, we expect that some “rules” will apply to most regenerating species, whereas some processes might be species-specific. With respect to our study, it is therefore important to determine which cell types are dividing in other regenerating species, such as the chicken, or in developing mouse ears and if their division is regulated by distinct genes.
What are the next big experiments you want to do following this study?
TP: To elucidate how regeneration is controlled, why it fails to occur in mammals and how it could be triggered in mammals, we need to understand not only the function of individual genes but how the activity of hundreds of genes is orchestrated. We are therefore currently characterizing which genes are turned off and on during the regeneration time course in all cell types of the sensory organs with the long term goal to identify the key genes that control many other genes at different time points. These key genes are the most promising candidates, and if manipulated, could induce regeneration of functional hair cells and hearing and vestibular restoration in mammals.
What would you tell patients who read about this and hope for new therapies — how close are we really?
TP: It is challenging to put a timeline on how quickly findings from model organisms can be translated into applications in the clinic. Impressive progress has been made in inducing regeneration of a limited number of new hair cells in the mouse ear, but these hair cells are not yet perfectly formed and lead to either no or limited recovery of hearing or the vestibular system. Therefore, more research is needed to identify additional key genes that need to be turned on or off in the mouse ear to regenerate perfectly shaped and functional hair cells. Great progress has been made to cure causes of genetic hearing loss using gene therapy. In many cases of genetic hearing loss, the hair cells are present but lack a particular gene. When a perfect copy of the gene was experimentally introduced into the defective ear hair cells, it led to an impressive improvement in hearing.
Paper Summary
Methodology
Researchers used zebrafish, a model organism that can regenerate sensory hair cells, to study regeneration mechanisms. They created genetic mutants lacking specific cyclin D genes (ccndx and ccnd2a) using CRISPR gene editing technology. The team killed hair cells using neomycin antibiotic, then tracked regeneration using fluorescent markers and time-lapse imaging. They also performed single-cell RNA sequencing to analyze gene expression patterns in different cell types during regeneration. Additional experiments used drug treatments and genetic rescue approaches to confirm their findings.
Results
The study found that hair cells can regenerate without cell division, contradicting decades of established science. Two different cyclin D genes independently control proliferation in distinct cell populations: ccnd2a regulates stem cell division while ccndx controls progenitor cell division. Mutant fish lacking ccndx could still regenerate hair cells through direct differentiation, producing one hair cell per progenitor instead of two. However, these regenerated hair cells showed polarity defects, with 70% oriented in the same direction rather than the normal 50-50 split. The polarity problems resulted from downregulation of genes like hes2.2 and Emx2.
Limitations
The study was conducted in zebrafish, which have greater regenerative capacity than mammals. The relevance to human hearing loss remains unclear since mammals cannot naturally regenerate hair cells. The research focused on lateral line organs rather than inner ear structures. Additionally, while regeneration occurred without division, it was less efficient and produced fewer hair cells overall. The polarity defects also represent a significant limitation for potential therapeutic applications.
Funding and Disclosures
This research was supported by NIH (NIDCD) award 1R01DC015488-01A1, funding from the Hearing Health Foundation (Award #991977), and institutional support from the Stowers Institute for Medical Research. The authors declared no competing interests.
Publication Information
Lush, M.E., Tsai, Y., Chen, S. et al. “Stem and progenitor cell proliferation are independently regulated by cell type-specific cyclinD genes,” was published in Nature Communication on July 14, 2025. DOI: https://doi.org/10.1038/s41467-025-60251-0
