Researchers at the Stowers Institute for Medical Research have identified two cell division genes that are essential for the regeneration of sensory hair cells in fish. Their findings, published in Nature Communications, offer a new avenue of research for regenerative therapies targeting hearing loss conditions.
While fish, birds, and amphibians can naturally regenerate sensory hair cells, mammals have lost that ability over the course of evolution. “Mammals such as ourselves cannot regenerate hair cells in the inner ear,” said Tatjana Piotrowski, PhD, principal investigator at the Stowers Institute and senior author of the study. “As we age or are subjected to prolonged noise exposure, we lose our hearing and balance.”
Studying the molecular mechanisms that allow other animals to regenerate these cells could provide important clues for the development of hearing loss therapies. Following this premise, the researchers used single-cell RNA sequencing to identify genes that drive hair cell regeneration in two distinct types of support cells found in zebrafish.
“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…. 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.”
The study identified two key genes involved in hair cell regeneration in zebrafish. The ccnd2a gene was found to be responsible for establishing and maintaining a pool of stem cells during development, while the ccndx gene enabled progenitor cells to divide and differentiate into hair 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.”
Both of these genes encode proteins in the Cyclin D protein family, which play a key role in cell division across many species. In humans, overexpression of proteins in this family has been linked to several forms of cancer, including colorectal cancer and melanomas.
Furthermore, the researchers found that while each gene was expressed in a specific cell type, both played a similar function. Experiments showed that expressing ccnd2a in progenitor cells missing ccndx could restore cell division and normal cell differentiation. This could have important implications in future research in human models, given the fact that while the ccnd2a gene is conserved in humans, ccndx has been lost to evolution.
Since other CyclinD genes are known to regulate stem cell proliferation and differentiation in other organs, such as the lining of the digestive tract and the skin, the researchers stated that their findings could have important implications for medical research beyond hearing loss. “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.
