Hair Cell Susceptibility and Regenerative Capacity

Hearing loss caused by the loss or damage of hair cells in the inner ear is a prevalent condition that affects millions of individuals worldwide. Despite significant advances in medical science, there is currently no pharmacological therapy available for hearing loss. However, recent research conducted by Zheng-Yi Chen, from Mass Eye and Ear at Harvard Medical School, has shed light on the potential for hair cell regeneration in the inner ear, offering hope of future treatments for people with hearing loss-related symptoms.

Cochlear hair cells, responsible for converting sound stimuli into electrical signals, are terminally differentiated cells and are highly susceptible to damage from noise trauma, ageing, and ototoxicity. In contrast, their non-sensory supporting cell counterparts exhibit greater resistance to these factors. Understanding the regenerative capacity of hair cells is crucial for developing strategies to restore hearing function, which we will be discussing in this blog post.

Regenerative Potential

Unlike mammals, fish, amphibians, and birds possess an incredible ability to regenerate damaged hair cells through direct and indirect trans-differentiation of supporting cells. In these species, damaged auditory hair cells are spontaneously replaced, highlighting the innate regenerative capabilities of the inner ear.

In mammals, inner ear stem cells found in the organ of the Corti and vestibular utricle hold promise as ideal precursors for hair cell regeneration. While the regenerative capacity of mammalian hair cells is limited 2 weeks after birth, transplantation of inner ear stem cells into the otic vesicles has shown the potential to generate new hair cells. These multipotent stem cells can be isolated from the cochlear organ of corti and the vestibular sensory epithelia, demonstrating their ability to differentiate into ectodermal cells in vivo and generate derivatives of all three germ layers in vitro.

Differentiation Potential and Induction of Hair Cells and Their Pathways

Inner ear stem cells have been found to differentiate into both hair cells and supporting cells. Co-culturing these stem cells with mesenchymal cells has been shown to promote their differentiation into hair cells. Pro-sensory cells derived from inner ear stem cells can express multiple hair cell markers and functional ion channels specific to nascent hair cells. However, further examination is needed to determine whether the regenerated hair cells possess the characteristics and functions of inner and outer hair cells.

Researchers have conducted studies in transgenic mice, zebrafish, and chickens to identify the molecular signalling pathways involved in inducing cell division and promoting hair cell regeneration. Two crucial pathways, Myc and Notch, have been identified as key regulators of this process. While manipulating these pathways has shown promising results in animal models like mice, the challenge lies in translating these findings to humans.

Promising Drug-Like Approaches and Next Steps

Recent breakthroughs in research have revealed the potential of drug-like approaches to enhance hair cell regeneration. In transgenic mice, the activation of Myc and Notch pathways led to the development of hair cell characteristics in remaining inner ear cells. In humans, however, directly turning on these pathways has not been feasible, until now. Dr. Chen composed an analogy, “Think about a brake when driving a car. If the brake is always engaged, you can’t drive. We found an siRNA that could remove the brake in this genetic pathway.”

Manipulation of this siRNA and further clinical testing are needed to progress this idea. The researchers at Harvard University verified that the hair cells were functional through advanced imaging and other techniques, however, there are many other elements still to investigate. Gene therapy seems to be the proper route to pursue further testing and analysis. The Mass General Brigham World Medical Innovation Forum recognized Chen’s study as one of the Disruptive Dozen, a technological advancement that should prove medically significant in upcoming years. Trials are now being run on larger animals, and researchers are testing specific techniques, like surgery, to narrow down the best way to access the inner ear for therapy. There is hope for hearing regeneration in the future.