Lately, scientists have made impressive headway on elucidating exactly how particular genes control cell division in zebrafish. This breakthrough has the potential to help us explore new approaches to treat hearing loss in humans. Tatjana Piotrowski and Mark Lush from a Columbia University team that was among the most successful. They recently published their findings in the prestigious journal Nature Communications, showcasing how two separate cyclinD genes regulate the onion-like proliferation of sensory support cells. This work has the potential to provide clues for routes to regeneration in mammals, which are not capable of such regenerative prowess.
The analysis uncovers the presence of two different cyclinD genes that are only present in specific cell populations. This unexpected finding calls attention to their special regulatory roles. The research team utilized advanced sequencing techniques to pinpoint which genes were active in the different cell types, leading to remarkable discoveries about how these genes operate independently to regulate cell division.
Regulation of Cell Division
The findings indicate that cyclinD genes play a crucial role in the proliferation of two key types of sensory support cells in zebrafish. These supporting cells are necessary and sufficient in the mouse for the production of new hair cells, the mechanosensitive cells that mediate hearing and balance. In this case one of the cyclinD genes is specifically active in stem cells, while the other acts in progenitor cells.
In a novel experiment, the researchers modified the stem cell-specific cyclinD gene to work inside progenitor cells. This manipulation successfully restored progenitor cell division, highlighting the gene’s vital role in maintaining cellular growth. In marked opposition, progenitor cells which are deficient for the specific cyclinD gene fail to undergo cellular division. Yet they retain an impressive capacity to produce new hair cells.
“When we rendered one of these genes non-functional, only one population stopped dividing,” – Tatjana Piotrowski, Ph.D.
This important discovery underscores the essential importance of cyclinD genes. They provide constant supply of functional cell populations to maintain and regenerate the tissue. Piotrowski examined this further. He explained that in the course of homeostatic maintenance, normal cellular turnover, or re-epithelialization after injury, cells need to divide to replace cells undergoing apoptosis or desquamation. For this process to work, there first need to be intermediate cells able to differentiate to replace them.
Implications for Mammals
These findings have broader implications beyond the world of zebrafish. Regardless, Piotrowski noted the evolutionary bind mammals are in, preventing mammals from benefiting from hair cell regeneration. We mammals, humans included, don’t regenerate hair cells in the inner ear, she explained. This reality highlights an alarming threat, as an inability to hear is more prevalent amongst older individuals and with prolonged exposure to loud sounds.
Researchers are confident that understanding how zebrafish can regenerate hair cells will provide important clues. These discoveries might one day shape our understanding of other organs and tissues, even those that do not regenerate in nature. This connection suggests a promising frontier in regenerative medicine, potentially opening doors to innovative treatments for hearing loss in humans.
“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,” – Tatjana Piotrowski
Future Research Directions
The study brings to light the surprising mechanisms driving this highly coordinated process. More broadly, though, it raises exciting and important questions for future study of similar processes in mammals. David Raible, Ph.D., emphasized the relevance and significance of their findings. He added, “This study shines light on a beautiful mechanism of keeping neuromast [stem cells] alive while enhancing hair cell renewal.” His most recent work, he stressed, is paving the way to explore if similar processes are present or could be turned on in mammals.
Our research demonstrated that the cyclinD genes contribute more broadly to the regulation of cell proliferation, in both zebrafish and non-zebrafish species. In fact, they dictate growth in many human cells, especially in gut and blood cells. This wide importance further highlights the impact this work has on uncovering conserved cellular mechanisms in humans and other organisms.