Galectin and Myc enable cochlear progenitor expansion in vitro and in vivo

Hearing relies on a delicate, intricate structure inside the inner ear called the cochlea. Within this spiral-shaped organ, tiny hair cells act as the body's microphones, converting sound waves into electrical signals the brain can understand. In mammals, once these hair cells are damaged by loud noise, aging, or certain medications, they do not grow back. The surrounding support cells, which are usually quiet and inactive, lack the ability to divide and replace the lost parts. This permanent loss leads to hearing impairment that current medicine cannot reverse. However, nature offers a brief window of opportunity in newborn mammals. For a short time after birth, a specific group of cells adjacent to the hearing organ, known as the greater epithelial ridge, remains capable of dividing and turning into new hair cells. This transient population disappears within the first week of life, just as hearing begins, leaving the ear without a natural repair mechanism. Understanding how these newborn cells manage to regenerate, and why they stop doing so, could provide the key to unlocking similar repair abilities in adults.

Researchers at Stanford University and other institutions have now taken a close look at these newborn cells to uncover the molecular instructions that drive their growth. They focused on the greater epithelial ridge cells from newborn mice, which are known to be powerful stem cells capable of forming three-dimensional clusters called organoids in a laboratory dish. These organoids mimic the developing inner ear, growing into structures that contain new hair cells and support cells. To understand the switch that turns these cells from a resting state into a rapidly dividing one, the scientists isolated the cells and watched them grow over several days. They captured snapshots of the genetic activity inside individual cells at one, three, and seven days after they started growing. By reading the genetic code of hundreds of these cells, they created a detailed map of how the cells changed as they began to multiply.

The analysis revealed a clear pattern of change. As the cells started to divide, they began producing high levels of specific proteins that help cells stick to one another and to their surroundings. Two of these proteins, known as galectin-1 and galectin-3, stood out as being particularly active during the early stages of growth. Another key player identified was a protein called Myc, which is well-known for its role in telling cells to enter the cell cycle and start dividing. The researchers found that these factors were not just present; they were essential. When the scientists used drugs to block the activity of galectin-1, galectin-3, or Myc, the cells stopped growing. The organoids failed to form or remained small and weak. Conversely, when they artificially increased the amount of galectin-1 or Myc in the cells, the organoids grew larger and contained more cells. This confirmed that these specific molecules act as regulators, controlling whether the cochlear cells expand and multiply.

The study went a step further to see if these findings could apply to older cells that have already lost their ability to regenerate. In adult mice, the greater epithelial ridge has disappeared, and the remaining cells in the cochlea are generally unable to form new organoids. The researchers tested whether they could wake up this dormant potential in cells taken from mice that were two weeks old, an age when hearing has already started. They used a harmless virus to deliver extra copies of the galectin-1 or Myc genes directly into these older cells. The result was striking: while adding extra galectin-1 did not change much, adding extra Myc successfully coaxed the older cells into dividing and forming organoids. This demonstrated that the genetic machinery required for regeneration is not entirely lost in older cells; it can be reactivated by the right molecular trigger.

To ensure these laboratory findings reflected what happens in a living animal, the team also looked at the inner ear of mice that had suffered damage. They used a method to destroy specific support cells in the cochlea of newborn mice, which normally triggers the nearby greater epithelial ridge cells to divide and replace the lost tissue. In these injured ears, the researchers observed a sharp increase in the levels of galectin-1, particularly in the cells that were starting to divide. When they blocked the action of galectin-1 in these injured animals, the cells stopped dividing, and the repair process was halted. This confirmed that the same mechanism identified in the dish is actively at work in the living ear, driving the natural response to injury.

The work provides a clear picture of how a specific set of molecular signals guides the regenerative capacity of the inner ear. It shows that the transition from a quiet, non-dividing state to an active, growing state is driven by changes in how cells interact with their environment and with each other, mediated by proteins like galectin-1 and Myc. While the study does not offer an immediate cure for hearing loss, it identifies the precise levers that control cell growth in the cochlea. By showing that these levers can be pulled to restart growth in older cells, the research opens a path toward developing therapies that might one day restore hearing by reawakening the ear's own dormant repair systems. The findings suggest that the potential for regeneration exists within the cells themselves, waiting for the correct molecular key to unlock it.