An Essential Signaling Cascade for Auditory Hair Cell Regeneration

Abstract

Hearing loss is a chronic disease affecting millions of people worldwide, yet no restorative treatment options are available. While non-mammalian species regenerate their auditory sensory hair cells, mammals cannot. Birds maintain facultative stem cells known as supporting cells that engage in proliferative regeneration when surrounding hair cells die. Here, we investigated gene expression changes in chicken supporting cells during auditory hair cell death. This revealed a pathway involving the receptor F2RL1, HBEGF, EGFR, and ERK signaling. We unraveled a cascade starting with the proteolytic activation of F2RL1, followed by matrix-metalloprotease-mediated HBEGF shedding and EGFR-mediated ERK signaling. Each component of this cascade is essential for supporting cell S-phase entry in vivo. STAT3-phosphorylation converges with this signaling towards upregulation of transcription factors ATF3, FOSL2, and CREM. Our findings could have a significant long-term impact on improving the quality of life for millions of people with hearing impairment.

Note:
Funding Information: N.B was supported by the School of Medicine Dean's Postdoctoral Fellowship, the American Hearing Research Foundation, and the Katharine McCormick advanced postdoctoral scholar fellowship, which supports women in academic medicine. We also acknowledge the generous support of the Hearing Restoration Project Consortium of the Hearing Health Foundation, the Stanford Initiative to Cure Hearing Loss, and the National Institutes of Health grant R01- DC019619 (S.H) and K08-DC019683 (T.A.J).

Declaration of Interests: S.H. is a paid consultant of Pipeline Therapeutics. I hereby confirm that there are no competing financial interests for the authors not mentioned in the statement on the PDF. All other authors have nothing to declare.

Ethical Approval Statement: Chicken hatching, housing, and animal procedures were approved by the Stanford University Institutional Animal Care and Use Committee.

Keywords: cochlea, Inner ear, otic, MAPK, progenitor cell, hearing loss