Generating Sensory Hair Cells via Lineage Reprogramming
Age-related deafness is the consequence of some mix of (a) a loss of sensory hair cells of the inner ear, and (b) a loss of connections between these cells and the brain. One approach to treating this problem is to introduce new cells, either via transplantation or via inducing the generation of replacement cells in situ. Both approaches have their challenges, and both would benefit from a greater detail-level understanding of how exactly hair cells develop and become dysfunction. Thus researchers are working towards the production of hair cells on demand. While the initial application of this capability will involve running in vitro studies in research facilities, ultimately it may lead to cell therapies in which patient-matched hair cells are introduced into the inner ear to replace those that are damaged or lost.
Hearing loss affects hundreds of millions of people worldwide and often results from the loss of sensory hair cells in the inner ear - specialised cells that convert sound vibrations into electrical signals for the brain. These hair cells can be damaged by exposure to loud noise, certain medications or infections, and aging. In humans, once these hair cells die, they do not regenerate, meaning hearing loss is often irreversible. Research into how this could be countered has been limited by the inaccessibility of real human hair cells and the inefficiency of lab-based models.
In earlier work, the authors showed that mouse cells can be reprogrammed into those that are more like hair cells using four transcription factors: Six1, Atoh1, Pou4f3, and Gfi1, collectively referred to as SAPG. However, this method relies on viral delivery, which poses challenges for consistency and scalability. Instead, researchers engineered a stable human stem-cell line carrying a doxycycline-inducible version of the SAPG transcription factors. By adding the antibiotic doxycycline to the culture, this method allowed precise control of the reprogramming process. To track when the cells began to take on hair cell characteristics, they included a fluorescent reporter gene that switched on as reprogramming progressed.
When doxycycline was added, the team observed the first signs of reprogramming within three days. By day seven, around 35-40% of the cells expressed key hair cell gene markers such as MYO7A, MYO6, and POU4F3. This represented a more than 19-fold increase in efficiency compared to their previous virus-based approach, in half the time.