While humans can regularly replace certain cells, like those in our blood and gut, we cannot naturally regrow most other parts of the body. For example, when the tiny sensory hair cells in our inner ears are damaged, the result is often permanent hearing loss, deafness, or balance problems. In contrast, animals like fish, frogs, and chicks regenerate sensory hair cells effortlessly.
Now, scientists at the Stowers Institute for Medical Research have identified how two distinct genes guide the regeneration of sensory cells in zebrafish. The discovery improves our understanding of how regeneration works in zebrafish and may guide future studies on hearing loss and regenerative medicine in mammals, including humans.
“Mammals such as ourselves cannot regenerate hair cells in the inner ear,” said Stowers Investigator Tatjana Piotrowski, Ph.D., the study’s co-author. “As we age or are subjected to prolonged noise exposure, we lose our hearing and balance.”
New research from the Piotrowski Lab, published in Nature Communications on July 14, 2025, seeks to understand how cell division is regulated to both promote regeneration of hair cells and to also maintain a steady supply of stem cells. Led by former Stowers Researcher Mark Lush, Ph.D., the team discovered that two different genes regulating cell division each control the growth of two key types of sensory support cells in zebrafish. The finding may help scientists study whether similar processes could be triggered in human cells in the future.
“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. “To understand how proliferation is regulated, we need to understand how stem cells and their offspring know when to divide and at what point to differentiate.”
Zebrafish are an excellent system for studying regeneration. Dotted in a straight line from their head to tailfin are sensory organs called neuromasts. Each neuromast resembles a garlic bulb with “hair cells” sprouting from its top. A variety of supporting cells encompass the neuromast to give rise to new hair cells. These sensory cells, which help zebrafish detect water motion, closely resemble those in the human inner ear.
Because zebrafish are transparent during development and have accessible sensory organ systems, scientists can visualize, as well as genetically sequence and modify, each neuromast cell. This allows them to investigate the mechanisms of stem cell renewal, the proliferation of progenitor cells — direct precursors to hair cells — and hair cell regeneration.
“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 key populations of support cells contribute to regeneration within neuromasts: active stem cells at the neuromast’s edge and progenitor cells near the center. These cells divide symmetrically, which allows the neuromast to continuously make new hair cells while not depleting its stem cells. The team used a sequencing technique to determine which genes were active in each type and found two distinct cyclinD genes present in only one or the other population.
The researchers then genetically altered each gene in the stem and progenitor populations. They discovered that the different cyclinD genes were independently regulating cell division of the two types of cells.
“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.”
Progenitor cells lacking their cell type-specific cyclinD gene did not proliferate; however, they did form a hair cell, uncoupling cell division with differentiation. Notably, when the stem cell-specific cyclinD gene was engineered to work in progenitor cells, progenitor cell division was restored.
David Raible, Ph.D., a professor at the University of Washington who studies the zebrafish lateral line sensory system, commented on the significance of the new study. “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.”
Because cyclinD genes also regulate proliferation in many human cells, like those in the gut and blood, the team’s findings may have implications beyond hair cell regeneration.
“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.
Additional authors include Ya-Yin Tsai, Shiyuan Chen, Daniela Münch, Julia Peloggia, Ph.D., and Jeremy Sandler, Ph.D.
This work was funded by the National Institute on Deafness and Other Communication Disorders of the National Institutes of Health (NIH) (award: 1R01DC015488-01A1), the Hearing Health Foundation, and with institutional support from the Stowers Institute for Medical Research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
