Transcriptomic and epigenomic analyses explore the potential role of H3K4me3 in neomycin-induced cochlear Lgr5+ progenitor cell regeneration of hair cells

Ma, Xiangyu; Zhang, Shasha; Qin, Si; Guo, Juanjuan; Yuan, Jia; Qiang, Ruiying; Zhou, Shan; Cao, Wei; Yang, Jianming; Ma, Fei; Chai, Renjie

doi:10.1007/s13577-022-00727-z

Cited by 6 publications

(7 citation statements)

References 82 publications

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“…Cochlear SCs have the potential to be reprogrammed to reenter the cell cycle and convert into HCs, especially after injury. 42 The MEK/ERK pathway was uniquely activated in the SCs and not in HCs after neomycin treatment, which suggested that activation of the MEK/ERK pathway might participate in the fate determination of cochlear cells. Our results are consistent with the observation that upregulation of MEK/ERK reprograms SCs into an activated state because the pro-proliferative factor IGF induced upregulated p-ERK expression in Hensen’s cells and Claudius cells.…”

Section: Discussionmentioning

confidence: 91%

MEK/ERK signaling drives the transdifferentiation of supporting cells into functional hair cells by modulating the Notch pathway

Ma,

Xia,

Guo

et al. 2024

Stem Cells Translational Medicine

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Loss of cochlear hair cells (HCs) leads to permanent hearing loss in mammals, and regenerative medicine is regarded as an ideal strategy for hearing recovery. Limited genetic and pharmaceutical approaches for HC regeneration have been established, and the existing strategies cannot achieve recovery of auditory function. A promising target to promote HC regeneration is MEK/ERK signaling because dynamic shifts in its activity during the critical stages of inner ear development have been observed. Here, we first showed that MEK/ERK signaling is activated specifically in supporting cells (SCs) after aminoglycoside-induced HC injury. We then selected 4 MEK/ERK signaling inhibitors, and PD0325901 (PD03) was found to induce the transdifferentiation of functional supernumerary HCs from SCs in the neonatal mammalian cochlear epithelium. We next found that PD03 facilitated the generation of HCs in inner ear organoids. Through genome-wide high-throughput RNA sequencing and verification, we found that the Notch pathway is the downstream target of MEK/ERK signaling. Importantly, delivery of PD03 into the inner ear induced mild HC regeneration in vivo. Our study thus reveals the importance of MEK/ERK signaling in cell fate determination and suggests that PD03 might serve as a new approach for HC regeneration.

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Section: Discussionmentioning

confidence: 91%

MEK/ERK signaling drives the transdifferentiation of supporting cells into functional hair cells by modulating the Notch pathway

Ma,

Xia,

Guo

et al. 2024

Stem Cells Translational Medicine

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“…A study employed ChIP-seq to investigate H3K4me3 modifications in Lgr5+ progenitor cells, a subgroup of supporting cells. The authors showed that these supporting cells can be activated and proliferated to produce new hair cells after treatment with neomycin that caused injury (Ma et al, 2022). They identified 12 key shared genes, such as Hey1 driven by H3K4me3 modification, and provided insights into their potential roles in transdifferentiation and regeneration, emphasizing the involvement of H3K4me3 histone modifications in the process.…”

Section: Unveiling Epigenetic Dynamics In Inner Ear Development and R...mentioning

confidence: 99%

Insights into the regulation of hearing regeneration

Khalaily,

Avraham

2024

Front. Audiol. Otol.

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Our perception of sound is mediated by sound-sensitive hair cells in the inner ear, located in a specialized neuro-epithelium that transmits information to the auditory cortex via the auditory pathway. A major cause of hearing loss is damage to and the death of these sensory hair cells. In humans, hair cells are only generated during embryonic development and cannot be replaced if damaged due to aging, excessive noise, ototoxic drugs, or illness. Much research is currently being invested worldwide in identifying methods to improve the ability to regenerate hair cells and circumvent their age-dependent limitations. Compared to numerous studies focused on gene therapy to restore deafness caused by a specific mutation before the onset of hair cell damage, research on auditory epigenetics is relatively recent. Although research indicates that epigenetic alterations play a crucial role in the differentiation, development, and regeneration of auditory hair cells, a dearth of comprehensive knowledge still exists regarding the specific role played by epigenetic modifications in the auditory system, with a particular emphasis on their potential correlation with the function and development of the auditory system. In addition, these modifications have been linked to the regeneration of hair cells caused by using pharmaceutical inhibitors (e.g., inhibition of the Notch pathway) and genetic (e.g., induced Atoh1 expression) treatments, which can lead to regenerating hair cells and restoring hearing. Recent developments in targetable epigenome-editing tools, such as CRISPR, and direct reprogramming enable targeted genome editing. In addition, the emergence of organoids and epigenetic drugs presents novel prospects for hearing restoration by manipulating regeneration pathways, making them promising methods for future regenerative treatments for hair cells. The potential of epigenetic modifiers as viable targets for pharmacological manipulation is becoming evident. Future therapies aimed at hair cell regeneration are particularly beneficial because of their advantage of restricting drug exposure within the inner ear.

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“…Histone modifications and DNA methylations are the main epigenetic modifications controlling the access of transcription factors to chromatin. In Lgr5+ inner ear stem cells, modifications in histone H3K4me regulate proliferation and hair cell regeneration after neomycin treatment [165]. Interestingly, inhibition of histone deacetylases (HDAC) with valproic acid (VPA) has been shown to promote hair cell differentiation in vitro [109].…”

Section: Epigenetic Barrier To Hair Cell Regeneration In Adult Cochleamentioning

confidence: 99%

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

Smith-Cortinez

Tan

Stokroos

et al. 2023

IJMS

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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.

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Transcriptomic and epigenomic analyses explore the potential role of H3K4me3 in neomycin-induced cochlear Lgr5+ progenitor cell regeneration of hair cells

Cited by 6 publications

References 82 publications

MEK/ERK signaling drives the transdifferentiation of supporting cells into functional hair cells by modulating the Notch pathway

MEK/ERK signaling drives the transdifferentiation of supporting cells into functional hair cells by modulating the Notch pathway

Insights into the regulation of hearing regeneration

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

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