Orchestrating Hair Cell Regeneration: A Supporting Player's Close-up

The older we get, the more likely we are to lose our hearing. This hearing loss is caused by death of or damage to our inner ear sensory hair cells, which, unlike their zebrafish counterparts, are irreplaceable. Researchers at the Stowers Institute, led by Associate Investigator Tatjana Piotrowski, PhD, studied the underlying mechanisms of this regeneration process in zebrafish sensory hair cells, in hopes to provide basic insights needed to develop therapies for hearing loss in humans.

Zebrafish use a lateral line organ system to discern water movement. The lateral line is composed of sensory organs called neuromasts that are made up of centrally-located sensory hair cells and surrounding support cells. "We've known for some time that fish hair cells regenerate from support cells," Piotrowski explains, "but it hasn't been clear if all support cells are capable of this feat, or if subpopulations exist, each with different fates."

By carefully tracking the location and behavior of each individual support cell following hair cell damage, first author of the study Andrés Romero-Carvajal, PhD, determined that the dividing support cells follow one of two trajectories: differentiation into hair cells or self-renewal to maintain a reserve. These lineage fate decisions are location-specific, as differentiation into hair cells occurs toward the center of neuromasts and self-renewal occurs at opposite poles of the structures, and depend on the interplay between Notch and Wnt signaling coming from the neuromast. The loss of hair cells in the center results in a transient suppression of Notch signaling, which triggers the differentiation of support cells into hair cells. "We found that Notch directly suppresses differentiation (of support cells into hair cells), and indirectly inhibits proliferation by down-regulating Wnt signaling," Piotrowski explains. Eventual restoration of neuromast hair cells restores this balance between Notch and Wnt signaling, ensuring that not all support cells answer the call to regenerate through proliferation and differentiation.

These findings were reported in the August 10, 2015, issue of Developmental Cell.