Age-related transcriptome changes in Sox2+ supporting cells in the mouse cochlea

Abstract

BackgroundInner ear supporting cells (SCs) in the neonatal mouse cochlea are a potential source for hair cell (HC) regeneration, but several studies have shown that the regeneration ability of SCs decreases dramatically as mice age and that lost HCs cannot be regenerated in adult mice. To better understand how SCs might be better used to regenerate HCs, it is important to understand how the gene expression profile changes in SCs at different ages.MethodsHere, we used Sox2GFP/+ mice to isolate the Sox2+ SCs at postnatal day (P)3, P7, P14, and P30 via flow cytometry. Next, we used RNA-seq to determine the transcriptome expression profiles of P3, P7, P14, and P30 SCs. To further analyze the relationships between these age-related and differentially expressed genes in Sox2+ SCs, we performed gene ontology (GO) analysis.ResultsConsistent with previous reports, we also found that the proliferation and HC regeneration ability of isolated Sox2+ SCs significantly decreased as mice aged. We identified numerous genes that are enriched and differentially expressed in Sox2+ SCs at four different postnatal ages, including cell cycle genes, signaling pathway genes, and transcription factors that might be involved in regulating the proliferation and HC differentiation ability of SCs. We thus present a set of genes that might regulate the proliferation and HC regeneration ability of SCs, and these might serve as potential new therapeutic targets for HC regeneration.ConclusionsIn our research, we found several genes that might play an important role in regulating the proliferation and HC regeneration ability of SCs. These datasets are expected to serve as a resource to provide potential new therapeutic targets for regulating the ability of SCs to regenerate HCs in postnatal mammals.

High Frequency of AIFM1 Variants and Phenotype Progression of Auditory Neuropathy in a Chinese Population

“…In the auditory system, HCs and SGNs are very important for hearing ability; HCs convert the sound waves into electrical signals, and SGN transmit the electrical signals into the auditory cortex for hearing ability [29]. In a mammal's cochlea, HCs and SGNs are vulnerable for multiple damages, including noise, gene mutation, ototoxic drugs, inflammation, and aging [30][31][32][33][34]; while the mammal's cochlea only have very limited HC and SGN regeneration ability, majority of the damaged HC and SGN cannot be spontaneously regenerated [35][36][37][38][39][40][41]. Thus, hearing loss is usually irreversible, and AN may come from the damage of IHC and SGNs.…”

Four Novel Variants in POU4F3 Cause Autosomal Dominant Nonsyndromic Hearing Loss

“…HCs are sensitive to multiple stresses and injuries and are easy to damage. While a mammal's cochlea only has very limited HC regeneration ability, most of the HC damage is permanent and irreversible [28][29][30][31][32][33][34]. Genetic factor accounts for 50% of sensorineural hearing…”

Perspectives on Human Hearing Loss, Cochlear Regeneration, and the Potential for Hearing Restoration Therapies

“…These cells express the WNT response gene Lgr5 at birth [ 88 , 89 ], and divide when stimulated by either WNT ligands or agonists [ 88 , 89 ] or by SHH (Sonic hedgehog) agonists [ 90 ]. The ability to be propagated as spheres or to generate HCs declines with age, and is largely lost by P30 [ 91 , 92 ]. This matches results from tissues obtained from adult human cochlea, where only a single sphere was cultured from ten individual samples [ 93 ].…”

“…Additional hurdles remain to the development of HC differentiation from supporting cells in adults. Adult supporting cells have significant transcriptional differences from neonatal supporting cells [ 91 , 106 ], suggesting the need for additional strategies besides ATOH1 expression. Indeed, multifactorial approaches are increasingly employed [ 112 , 127 ].…”