Regeneration of Hair Cells from Endogenous Otic Progenitors in the Adult Mammalian Cochlea: Understanding Its Origins and Future Directions

Abstract

Sensorineural hearing loss is caused by damage to sensory hair cells and/or spiral ganglion neurons. In non-mammalian species, hair cell regeneration after damage is observed, even in adulthood. Although the neonatal mammalian cochlea carries regenerative potential, the adult cochlea cannot regenerate lost hair cells. The survival of supporting cells with regenerative potential after cochlear trauma in adults is promising for promoting hair cell regeneration through therapeutic approaches. Targeting these cells by manipulating key signaling pathways that control mammalian cochlear development and non-mammalian hair cell regeneration could lead to regeneration of hair cells in the mammalian cochlea. This review discusses the pathways involved in the development of the cochlea and the impact that trauma has on the regenerative capacity of the endogenous progenitor cells. Furthermore, it discusses the effects of manipulating key signaling pathways targeting supporting cells with progenitor potential to promote hair cell regeneration and translates these findings to the human situation. To improve hearing recovery after hearing loss in adults, we propose a combined approach targeting (1) the endogenous progenitor cells by manipulating signaling pathways (Wnt, Notch, Shh, FGF and BMP/TGFβ signaling pathways), (2) by manipulating epigenetic control, and (3) by applying neurotrophic treatments to promote reinnervation.

Long-term survival of LGR5 expressing supporting cells after severe ototoxic trauma in the adult mouse cochlea

“…It is known SCs in neonatal mice express progenitor cell markers such as Lgr5 and Sox2 ( Chai et al, 2011 ; Shi et al, 2012 ; Zak et al, 2016 ) and proliferate and transdifferentiate to HCs as part of the continued development of the inner ear. The expression of Lgr5 and Sox2 is maintained in the adult cochlea and has been recently reviewed by us ( Smith-Cortinez et al, 2023 ). LGR5+ SCs are present in the adult cochlea up to P100 in DC3 and IPCs ( Shi et al, 2012 ; Smith-Cortinez et al, 2021 ), and here we show for the first time that the mRNA expression of Lgr5 is maintained at least up to P200.…”

“…In contrast, mammalian species do not spontaneously regenerate lost HCs. However, it has been recently described that supporting cells (SCs) in the cochlea of neonatal and adult mice act as endogenous otic progenitor cells and express the stem cell markers leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) ( Groves, 2010 ; Shi et al, 2012 , 2013 ; Bramhall et al, 2014 ; Zak et al, 2016 ; Smith-Cortinez et al, 2023 ), LGR4 ( Zak et al, 2016 ), and SOX2 ( Hume et al, 2007 ; Dabdoub et al, 2008 ).…”

“…Leucine-rich repeat-containing G-protein coupled receptor 5, LGR4, and SOX2 positive SCs in the cochlea are known to give rise to HCs during embryonic development ( Jacques et al, 2012 ; Shi et al, 2012 ; Zak et al, 2015 , 2016 ). This process is controlled by the Wnt, Notch, Sonic hedgehog (Shh), fibroblast growth factor (FGF), and bone morphogenetic proteins (BMP)/transforming growth factor-β (TGF-β) signaling pathways by upregulating Atoh1 , a key transcription factor in HC differentiation ( Li et al, 2005 ; Pujades et al, 2006 ; Driver et al, 2008 ; Zak et al, 2015 ; Ebeid and Huh, 2017 ; Ellis et al, 2019 ; Smith-Cortinez et al, 2023 ). These signaling pathways have also been described to participate in non-mammalian inner ear spontaneous regeneration ( Brignull et al, 2009 ; Jacques et al, 2014 ; Jiang et al, 2014 ) and are the focus of interest for promoting cochlear regeneration in mammalian species ( Smith-Cortinez et al, 2023 ).…”

“…This process is controlled by the Wnt, Notch, Sonic hedgehog (Shh), fibroblast growth factor (FGF), and bone morphogenetic proteins (BMP)/transforming growth factor-β (TGF-β) signaling pathways by upregulating Atoh1 , a key transcription factor in HC differentiation ( Li et al, 2005 ; Pujades et al, 2006 ; Driver et al, 2008 ; Zak et al, 2015 ; Ebeid and Huh, 2017 ; Ellis et al, 2019 ; Smith-Cortinez et al, 2023 ). These signaling pathways have also been described to participate in non-mammalian inner ear spontaneous regeneration ( Brignull et al, 2009 ; Jacques et al, 2014 ; Jiang et al, 2014 ) and are the focus of interest for promoting cochlear regeneration in mammalian species ( Smith-Cortinez et al, 2023 ). In order to promote HC regeneration in mammals as a treatment for hearing impairment, it is important to establish whether target cells for future regenerative therapies (i.e., SCs with potential progenitor capacity) survive after trauma.…”

Advanced Omics Techniques for Understanding Cochlear Genome, Epigenome, and Transcriptome in Health and Disease

“…The latter process is often followed by the degeneration of the downstream spiral ganglion neurons (SGNs) [4], whose axons form the auditory nerve. Although cochlear implants and hearing aids exhibit some beneficial outcomes in deaf patients, they cannot entirely replace the cochlea's functionality [5]. Thus, management-based approaches must give way to disease-modifying interventions.…”