Summary: Study identifies the mechanisms behind regenerating new cochlear hair cells. The findings could have positive implications for treating or reversing hearing loss associated with damage to cochlear hair cells.
Source: University of Rochester
Taking a bite of an apple is considered a healthy choice. But have you ever thought about putting in earplugs before your favorite band takes the stage?
Just like your future body will thank you for the apple, your future ears (specifically your cochlear hair cells) will thank you for protecting them. The most common cause of hearing loss is progressive because these hair cells—the primary cells to detect sound waves—cannot regenerate if damaged or lost.
People who have repeated exposure to loud noises, like military personnel, construction workers, and musicians, are most at risk for this type of hearing loss. But, it can happen to anyone over time (even concert goers).
On the other hand, birds and fish can regenerate these hair cells, and now researchers at the Del Monte Institute for Neuroscience are getting closer to identifying the mechanisms that may promote this type of regeneration in mammals, as explained in research recently published in Frontiers in Cellular Neuroscience.
“We know from our previous work that expression of an active growth gene, called ERBB2, was able to activate the growth of new hair cells (in mammals), but we didn’t fully understand why,” said Patricia White, PhD, professor of Neuroscience and Otolaryngology at the University of Rochester Medical Center.
The 2018 study led by Jingyuan Zhang, PhD, a postdoctoral fellow in the White lab at the time, found that activating the growth gene ERBB2 pathway triggered a cascading series of cellular events by which cochlear support cells began to multiply and activate other neighboring stem cells to become new sensory hair cells.
“This new study tells us how that activation is happening—a significant advance toward the ultimate goal of generating new cochlear hair cells in mammals,” said White.
Using single-cell RNA sequencing in mice, researchers compared cells with an overactive growth gene (ERBB2 signaling) with similar cells that lacked such signaling.
They found the growth gene—ERBB2—promoted stem cell-like development by initiating the expression of multiple proteins—including SPP1, a protein that signals through the CD44 receptor. The CD44 receptor is known to be present in cochlear-supporting cells. This increase in cellular response promoted mitosis in the supporting cells, a key event for regeneration.
“When we checked this process in adult mice, we were able to show that ERBB2 expression drove the protein expression of SPP1 that is necessary to activate CD44 and grow new hair cells,” said Dorota Piekna-Przybylska, PhD, a staff scientist in the White Lab and first author of the study.
“This discovery has made it clear that regeneration is not only restricted to the early stages of development. We believe we can use these findings to drive regeneration in adults.”
“We plan to further investigation of this phenomenon from a mechanistic perspective to determine whether it can improve auditory function after damage in mammals. That is the ultimate goal,” said White.
Additional authors include Daxiang Na, Cameron Baker, and John Ashton, PhD, at the University of Rochester and Medical Center.
Funding: The research was supported by the U.S. Army Medical Research Mechanism, the National Institute on Deafness and Other Communication Disorders, UR Ventures, and the Schmitt Program on Integrative Neuroscience.
About this hearing loss and auditory neuroscience research news
Author: Kelsie Smith Hayduk
Source: University of Rochester
Contact: Kelsie Smith Hayduk – University of Rochester
Image: The image is in the public domain
Original Research: Open access.
“Single cell RNA sequencing analysis of mouse cochlear supporting cell transcriptomes with activated ERBB2 receptor indicates a cell-specific response that promotes CD44 activation” by Patricia White et al. Frontiers in Cellular Neuroscience
Abstract
Single cell RNA sequencing analysis of mouse cochlear supporting cell transcriptomes with activated ERBB2 receptor indicates a cell-specific response that promotes CD44 activation
Hearing loss caused by the death of cochlear hair cells (HCs) might be restored through regeneration from supporting cells (SCs) via dedifferentiation and proliferation, as observed in birds. In a previous report, ERBB2 activation in a subset of cochlear SCs promoted widespread down-regulation of SOX2 in neighboring cells, proliferation, and the differentiation of HC-like cells.
Here we analyze single cell transcriptomes from neonatal mouse cochlear SCs with activated ERBB2, with the goal of identifying potential secreted effectors. ERBB2 induction in vivo generated a new population of cells with de novo expression of a gene network.
Called small integrin-binding ligand n-linked glycoproteins (SIBLINGs), these ligands and their regulators can alter NOTCH signaling and promote cell survival, proliferation, and differentiation in other systems.
We validated mRNA expression of network members, and then extended our analysis to older stages. ERBB2 signaling in young adult SCs also promoted protein expression of gene network members. Furthermore, we found proliferating cochlear cell aggregates in the organ of Corti.
Our results suggest that ectopic activation of ERBB2 signaling in cochlear SCs can alter the microenvironment, promoting proliferation and cell rearrangements.
Together these results suggest a novel mechanism for inducing stem cell-like activity in the adult mammalian cochlea.
