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Written by ︱ Chen Peng editor ︱ Wang Sizhen Sensorineural hearing loss (SNHL) is the most common type of hearing loss, mainly due to damage to the structure and function of the inner ear and auditory nerve, including cochlear hair cells (hair cells), blood vessels stria (stria vascularis), spiral ganglion neurons (spiral ganglion neurons) and auditory nerves (auditory nerves) and so on
.
SNHL accounts for about 90% of all hearing loss types [1]
.
Aging, noise exposure and ototoxic drugs are the three main causes of SNHL [2]
.
Worldwide, more than half of the elderly over the age of 60 suffer from age-related hearing loss (age-related hearing loss).
noise-induced hearing loss, which can reach 21% in developing countries [4]; ototoxicity is the additional cochlear-damaging property of certain therapeutic drugs that causes Different degrees of ototoxicity-induced hearing loss (ototoxicity-induced hearing loss), its incidence varies from 4% to 90% [5]
.
Among cancer patients receiving chemotherapy drug cisplatin (cisplatin) treatment, the proportion of ototoxic hearing loss can be as high as 70% [6]
.
The pathological features of the hair cells, stria vascularis and spiral ganglion neurons in the inner ear of the three SNHLs mentioned above are very similar, suggesting that the three SNHLs may have the same molecular mechanism
.
Although most studies have focused on one or both of these factors, some common biological processes have been implicated, including mitochondrial dysfunction, oxidative stress, apoptosis, inflammation, and immune responses [7, 8]
.
However, the molecular mechanisms shared by multiple factors in sensorineural hearing loss still lack systematic and effective validation
.
Recently, the collaborative team of Researcher Shi Peng and Researcher Liu Zhen from the Kunming Institute of Zoology, Chinese Academy of Sciences published a research work entitled "Integrative functional transcriptomic analyses implicate shared molecular circuits in sensorineural hearing loss" in Frontiers in Cellular Neuroscience.
Through transcriptome sequencing analysis and related functional verification of the cochleae of three mouse models of hearing loss induced by aging, noise exposure and the ototoxic drug cisplatin, the multi-factor sensorineural hearing loss was systematically revealed.
shared molecular mechanisms
.
The researchers first established three animal models of hearing loss using C57BL/6 mice (Figure 1A)
.
Aging model: 2-month-old mice, 8-month-old mice and 12-month-old mice; noise model: 2-month-old mice were exposed to strong noise (4-24 kHz, 120 dB SPL) for 2 hours, and the noise was selected respectively.
1 hour and 24 hours post-exposure as study time points; cisplatin ototoxicity model: single dose of cisplatin (10 mg/kg dose) and furosemide diuretic (200 mg/kg dose) in 2-month-old mice 1 day and 3 days after the injection were selected as the time points of the study
.
The stability of the three hearing loss models was determined by the detection of auditory brainstem responses (Fig.
1B) and cochlear hair cell staining (Fig.
1C-L) of the three hearing loss models
.
Figure 1 Representative phenotypes of three SNHL mouse models (source: Chen, P et al.
, Front Cell Neurosci, 2022) After establishing three mouse models of hearing loss, in order to explore the three types of hearing loss To share the molecular mechanism, the researchers sequenced the transcriptomes of the cochlea of three animal models
.
The results of PCA (principal components analysis) showed that the cochlear samples of the same animal model tended to cluster together with good sample repeatability (Fig.
2A)
.
Using the WGVNA (signed weighted gene coexpression network analysis) method, a total of 22 co-expression modules (modules) were output, involving the expression dynamics of 17,040 genes (Fig.
2B)
.
The researchers then determined 2 up-regulated co-expression modules and 1 down-regulated co-expression module by calculating the Pearson correlation coefficient (R) values of each module eigengene among the three hearing loss models.
Co-expression modules (R > 0.
85) (Fig.
2C)
.
The genes of this three modules are thought to have similar expression dynamics in the three hearing losses, ie molecular mechanisms shared by the three hearing losses
.
At the same time, the GO (Gene Ontology) enrichment analysis results showed that the GO terms of TOP5 enriched by up-regulated genes included immune system process, inflammatory response, and apoptosis process, while the GO terms of TOP5 enriched by down-regulated genes included transport.
and ion transport process (Fig.
2D)
.
These results show that the three sensorineural hearing loss have the same molecular mechanism, in which up-regulated genes are significantly involved in biological processes such as immunity, inflammation, and apoptosis, and down-regulated genes are significantly involved in biological processes such as ion transport
.
Figure 2 Co-expression network and GO enrichment analysis (Source: Chen, P et al.
, Front Cell Neurosci, 2022) Further enrichment analysis by KEGG (Kyoto Encyclopedia of Genes and Genomes) showed that up-regulated genes were significantly enriched in NF -kappa B signaling pathway, TNF signaling pathway, Jak-STAT signaling pathway and other signaling pathways related to immune, inflammation, apoptosis and other biological processes (Figure 3A), and analyzed by protein-protein interaction (PPI) The hub genes were mostly involved in these signaling pathways (Fig.
3B, C); the down-regulated genes were significantly enriched in the biological process of oxidative phosphorylation (Fig.
3D), and the hub genes with protein-protein interactions were also intensively involved (Fig.
3B, C).
Figure 3E,F)
.
These results indicate that the shared up- and down-regulated genes are significantly involved in signaling pathways consistent with the GO enrichment results, and suggest that some hub genes play important roles in the three types of hearing loss, such as the inflammatory factor gene IL1B and the chemokine gene CCL2 (Figure 3C)
.
Figure 3 Signaling pathway enrichment and protein interaction (PPI) network analysis (Source: Chen, P et al.
, Front Cell Neurosci, 2022) The researchers further selected IL1B and CCL2 in the up-regulated genes for functional verification experiments
.
Several previous studies have shown that the expression of IL1B and CCL2 is increased in the cochlea after noise exposure, suggesting that they play a key role in noise-induced SNHL production [9-11]
.
HEI-OC1 (House ear institute-organ of Corti 1) cell line is a cell line widely used to study the loss and survival of cochlear hair cells [12]
.
Therefore, we examined the potential contribution of IL1B and CCL2 in senescence and ototoxic SNHL by D-galactose (D-gal)-induced senescence and cisplatin-induced ototoxicity in HEI-OC1 cell line
.
The results showed that interfering with the expression of IL1B or CCL2 in the aging model (D-gal induction) could significantly enhance the cell viability of the aging model (Fig.
4A, B), while overexpression of IL1B or CCL2 could further reduce the cell viability in the aging model (Fig.
4C, D)
.
Similar results were also validated in a model of cisplatin-induced ototoxicity (Fig.
4E–H)
.
In addition, interfering with the expression of IL1B and CCL2 in both models significantly reduced cellular ROS levels, whereas overexpression of IL1B and CCL2 significantly promoted the accumulation of cellular ROS (Fig.
4I–L)
.
These results suggest that IL1B and CCL2 may affect the occurrence of the three SNHLs by promoting the accumulation of cellular ROS
.
Figure 4 Experimental validation of the potential contribution of IL1B and CCL2 to SNHL
.
(Source: Chen, P et al.
, Front Cell Neurosci, 2022) Conclusions and discussions, inspiration and prospects In summary, researchers have systematically identified the existence of different types of sensorineural hearing loss (SNHL) in The shared molecular mechanisms provide evidence and underscore the importance of future studies on the shared molecular mechanisms of SNHL across multiple factors
.
At the same time, the study suggests some common potential targets for therapeutic drugs that could prevent or ameliorate aging, noise, and ototoxic SNHL
.
At present, there is no drug that can treat any kind of SNHL in the world, so the mechanism of SNHL still needs to be further studied.
Comprehensive research on SNHL with multiple factors can help us to understand the pathogenesis of SNHL more deeply.
.
Link to the original text: https:// Corresponding authors Researcher Shi Peng (left) and Researcher Liu Zhen (right) (Photo courtesy of: Shi Peng, Kunming Institute of Zoology, Chinese Academy of Sciences /Liu Zhen's team) Selected previous articles [1] Cell Death Dis︱Li Xian's research group revealed the role of ferroptosis in oligodendrocyte precursor cells in white matter damage after cerebral hemorrhage [2] Front Mol Neurosci︱Gao Shangbang Project Group analysis of the composition and molecular mechanism of motor neuron oscillators【3】Nat Neurosci review︱Two-photon holographic optogenetics to detect neural coding【4】Mol Psychiatry︱biological clock gene Bmal1 in autism and cerebellar ataxia mice Effects in models【5】Science︱Rapid eye movement sleep in mice is regulated by basolateral amygdala dopamine signaling【6】Nat Neurosci︱Amygdala and anterior cingulate neuroimmunity and synapse-related pathways are downregulated in patients with bipolar disorder【 7] Nat Commun︱ Zhou Xiaoming/Sun Ziyi's team revealed the molecular mechanism of its ligand entry pathway based on the open conformation of Sigma-1 receptor [8] Glia︱ Yuan Qiang's team revealed a new mechanism for regulating the proliferation of oligodendrocyte precursor cells: c-Abl phosphorylates Olig2【9】HBM︱Yu Lianchun’s group reveals the relationship between brain avalanche critical phenomenon and fluid intelligence and working memory【10】J Neuroinflammation︱Gu Xiaoping’s group reveals that astrocyte network plays an important role in long-term isoflurane The important role of alkane anesthesia-mediated postoperative cognitive dysfunction Recommended high-quality scientific research training courses [1] Scientific research skills︱ The 4th near-infrared brain function data analysis class (online: 2022.
4.
18~4.
30) [2] Scientific research Skills︱Introduction to Magnetic Resonance Brain Network Analysis (Online: 2022.
4.
6~4.
16) [3] Training Course︱Scientific Research Mapping·Academic Image Training [4] Seminar on Single-Cell Sequencing and Spatial Transcriptomics Data Analysis (2022.
4.
2-3 Tencent Online) References (swipe up and down to view) [1] Li L, Chao T, Brant J, O'Malley B, Jr.
, Tsourkas A, Li D:Advances in nano-based inner ear delivery systems for the treatment of sensorineural hearing loss.
Advanced drug delivery reviews 2017, 108:2-12.
[2]Liberman MC, Kujawa SG: Cochlear synaptopathy in acquired sensorineural hearing loss: Manifestations and mechanisms.
Hear Res 2017, 349:138-147.
[3]Gates GA, Mills JH: Presbycusis.
The Lancet 2005, 366(9491):1111-1120.
[4]Nelson DI, Nelson RY, Concha-Barrientos M, Fingerhut M : The global burden of occupational noise-induced hearing loss.
Am J Ind Med 2005, 48(6):446-458.
[5]Landier W: Ototoxicity and cancer therapy.
Cancer 2016, 122(11):1647-1658.
[6]Tang Q, Wang X, Jin H, Mi Y, Liu L, Dong M, Chen Y, Zou Z: Cisplatin-induced ototoxicity: Updates on molecular mechanisms and otoprotective strategies.
European journal of pharmaceutics and biopharmaceutics :official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik eV 2021, 163:60-71.
[7]Wang J, Puel JL: Toward Cochlear Therapies.
Physiological Reviews 2018, 98(4):2477-2522.
[8]Zhang Y, Li Y , Fu X, Wang P, Wang Q, Meng W, Wang T, Yang J, Chai R: The Detrimental and Beneficial Functions of Macrophages After Cochlear Injury.
Frontiers in cell and developmental biology 2021, 9:631904.
[9]Vethanayam RR , Yang W, Dong Y, Hu BH: Toll-like receptor 4 modulates the cochlear immune response to acoustic injury.
Cell Death Dis 2016, 7(6):e2245.
[10] Zhang G, Zheng H, Pyykko I, Zou J : The TLR-4/NF-κB signaling pathway activation in cochlear inflammation of rats with noise-induced hearing loss.
Hear Res 2019, 379:59-68.
[11] Wang Q, Shen Y, Hu H, Fan C, Zhang A, Ding R, Ye B, Xiang M:Systematic Transcriptome Analysis of Noise-Induced Hearing Loss Pathogenesis Suggests Inflammatory Activities and Multiple Susceptible Molecules and Pathways.
Front Genet 2020, 11:968.
[12] Kalinec G, Thein P, Park C, Kalinec F: HEI-OC1 cells as a model for investigating drug cytotoxicity.
Hear Res 2016, 335:105-117.
Plate making︱Sizhen Wang End of this article
.
SNHL accounts for about 90% of all hearing loss types [1]
.
Aging, noise exposure and ototoxic drugs are the three main causes of SNHL [2]
.
Worldwide, more than half of the elderly over the age of 60 suffer from age-related hearing loss (age-related hearing loss).
noise-induced hearing loss, which can reach 21% in developing countries [4]; ototoxicity is the additional cochlear-damaging property of certain therapeutic drugs that causes Different degrees of ototoxicity-induced hearing loss (ototoxicity-induced hearing loss), its incidence varies from 4% to 90% [5]
.
Among cancer patients receiving chemotherapy drug cisplatin (cisplatin) treatment, the proportion of ototoxic hearing loss can be as high as 70% [6]
.
The pathological features of the hair cells, stria vascularis and spiral ganglion neurons in the inner ear of the three SNHLs mentioned above are very similar, suggesting that the three SNHLs may have the same molecular mechanism
.
Although most studies have focused on one or both of these factors, some common biological processes have been implicated, including mitochondrial dysfunction, oxidative stress, apoptosis, inflammation, and immune responses [7, 8]
.
However, the molecular mechanisms shared by multiple factors in sensorineural hearing loss still lack systematic and effective validation
.
Recently, the collaborative team of Researcher Shi Peng and Researcher Liu Zhen from the Kunming Institute of Zoology, Chinese Academy of Sciences published a research work entitled "Integrative functional transcriptomic analyses implicate shared molecular circuits in sensorineural hearing loss" in Frontiers in Cellular Neuroscience.
Through transcriptome sequencing analysis and related functional verification of the cochleae of three mouse models of hearing loss induced by aging, noise exposure and the ototoxic drug cisplatin, the multi-factor sensorineural hearing loss was systematically revealed.
shared molecular mechanisms
.
The researchers first established three animal models of hearing loss using C57BL/6 mice (Figure 1A)
.
Aging model: 2-month-old mice, 8-month-old mice and 12-month-old mice; noise model: 2-month-old mice were exposed to strong noise (4-24 kHz, 120 dB SPL) for 2 hours, and the noise was selected respectively.
1 hour and 24 hours post-exposure as study time points; cisplatin ototoxicity model: single dose of cisplatin (10 mg/kg dose) and furosemide diuretic (200 mg/kg dose) in 2-month-old mice 1 day and 3 days after the injection were selected as the time points of the study
.
The stability of the three hearing loss models was determined by the detection of auditory brainstem responses (Fig.
1B) and cochlear hair cell staining (Fig.
1C-L) of the three hearing loss models
.
Figure 1 Representative phenotypes of three SNHL mouse models (source: Chen, P et al.
, Front Cell Neurosci, 2022) After establishing three mouse models of hearing loss, in order to explore the three types of hearing loss To share the molecular mechanism, the researchers sequenced the transcriptomes of the cochlea of three animal models
.
The results of PCA (principal components analysis) showed that the cochlear samples of the same animal model tended to cluster together with good sample repeatability (Fig.
2A)
.
Using the WGVNA (signed weighted gene coexpression network analysis) method, a total of 22 co-expression modules (modules) were output, involving the expression dynamics of 17,040 genes (Fig.
2B)
.
The researchers then determined 2 up-regulated co-expression modules and 1 down-regulated co-expression module by calculating the Pearson correlation coefficient (R) values of each module eigengene among the three hearing loss models.
Co-expression modules (R > 0.
85) (Fig.
2C)
.
The genes of this three modules are thought to have similar expression dynamics in the three hearing losses, ie molecular mechanisms shared by the three hearing losses
.
At the same time, the GO (Gene Ontology) enrichment analysis results showed that the GO terms of TOP5 enriched by up-regulated genes included immune system process, inflammatory response, and apoptosis process, while the GO terms of TOP5 enriched by down-regulated genes included transport.
and ion transport process (Fig.
2D)
.
These results show that the three sensorineural hearing loss have the same molecular mechanism, in which up-regulated genes are significantly involved in biological processes such as immunity, inflammation, and apoptosis, and down-regulated genes are significantly involved in biological processes such as ion transport
.
Figure 2 Co-expression network and GO enrichment analysis (Source: Chen, P et al.
, Front Cell Neurosci, 2022) Further enrichment analysis by KEGG (Kyoto Encyclopedia of Genes and Genomes) showed that up-regulated genes were significantly enriched in NF -kappa B signaling pathway, TNF signaling pathway, Jak-STAT signaling pathway and other signaling pathways related to immune, inflammation, apoptosis and other biological processes (Figure 3A), and analyzed by protein-protein interaction (PPI) The hub genes were mostly involved in these signaling pathways (Fig.
3B, C); the down-regulated genes were significantly enriched in the biological process of oxidative phosphorylation (Fig.
3D), and the hub genes with protein-protein interactions were also intensively involved (Fig.
3B, C).
Figure 3E,F)
.
These results indicate that the shared up- and down-regulated genes are significantly involved in signaling pathways consistent with the GO enrichment results, and suggest that some hub genes play important roles in the three types of hearing loss, such as the inflammatory factor gene IL1B and the chemokine gene CCL2 (Figure 3C)
.
Figure 3 Signaling pathway enrichment and protein interaction (PPI) network analysis (Source: Chen, P et al.
, Front Cell Neurosci, 2022) The researchers further selected IL1B and CCL2 in the up-regulated genes for functional verification experiments
.
Several previous studies have shown that the expression of IL1B and CCL2 is increased in the cochlea after noise exposure, suggesting that they play a key role in noise-induced SNHL production [9-11]
.
HEI-OC1 (House ear institute-organ of Corti 1) cell line is a cell line widely used to study the loss and survival of cochlear hair cells [12]
.
Therefore, we examined the potential contribution of IL1B and CCL2 in senescence and ototoxic SNHL by D-galactose (D-gal)-induced senescence and cisplatin-induced ototoxicity in HEI-OC1 cell line
.
The results showed that interfering with the expression of IL1B or CCL2 in the aging model (D-gal induction) could significantly enhance the cell viability of the aging model (Fig.
4A, B), while overexpression of IL1B or CCL2 could further reduce the cell viability in the aging model (Fig.
4C, D)
.
Similar results were also validated in a model of cisplatin-induced ototoxicity (Fig.
4E–H)
.
In addition, interfering with the expression of IL1B and CCL2 in both models significantly reduced cellular ROS levels, whereas overexpression of IL1B and CCL2 significantly promoted the accumulation of cellular ROS (Fig.
4I–L)
.
These results suggest that IL1B and CCL2 may affect the occurrence of the three SNHLs by promoting the accumulation of cellular ROS
.
Figure 4 Experimental validation of the potential contribution of IL1B and CCL2 to SNHL
.
(Source: Chen, P et al.
, Front Cell Neurosci, 2022) Conclusions and discussions, inspiration and prospects In summary, researchers have systematically identified the existence of different types of sensorineural hearing loss (SNHL) in The shared molecular mechanisms provide evidence and underscore the importance of future studies on the shared molecular mechanisms of SNHL across multiple factors
.
At the same time, the study suggests some common potential targets for therapeutic drugs that could prevent or ameliorate aging, noise, and ototoxic SNHL
.
At present, there is no drug that can treat any kind of SNHL in the world, so the mechanism of SNHL still needs to be further studied.
Comprehensive research on SNHL with multiple factors can help us to understand the pathogenesis of SNHL more deeply.
.
Link to the original text: https:// Corresponding authors Researcher Shi Peng (left) and Researcher Liu Zhen (right) (Photo courtesy of: Shi Peng, Kunming Institute of Zoology, Chinese Academy of Sciences /Liu Zhen's team) Selected previous articles [1] Cell Death Dis︱Li Xian's research group revealed the role of ferroptosis in oligodendrocyte precursor cells in white matter damage after cerebral hemorrhage [2] Front Mol Neurosci︱Gao Shangbang Project Group analysis of the composition and molecular mechanism of motor neuron oscillators【3】Nat Neurosci review︱Two-photon holographic optogenetics to detect neural coding【4】Mol Psychiatry︱biological clock gene Bmal1 in autism and cerebellar ataxia mice Effects in models【5】Science︱Rapid eye movement sleep in mice is regulated by basolateral amygdala dopamine signaling【6】Nat Neurosci︱Amygdala and anterior cingulate neuroimmunity and synapse-related pathways are downregulated in patients with bipolar disorder【 7] Nat Commun︱ Zhou Xiaoming/Sun Ziyi's team revealed the molecular mechanism of its ligand entry pathway based on the open conformation of Sigma-1 receptor [8] Glia︱ Yuan Qiang's team revealed a new mechanism for regulating the proliferation of oligodendrocyte precursor cells: c-Abl phosphorylates Olig2【9】HBM︱Yu Lianchun’s group reveals the relationship between brain avalanche critical phenomenon and fluid intelligence and working memory【10】J Neuroinflammation︱Gu Xiaoping’s group reveals that astrocyte network plays an important role in long-term isoflurane The important role of alkane anesthesia-mediated postoperative cognitive dysfunction Recommended high-quality scientific research training courses [1] Scientific research skills︱ The 4th near-infrared brain function data analysis class (online: 2022.
4.
18~4.
30) [2] Scientific research Skills︱Introduction to Magnetic Resonance Brain Network Analysis (Online: 2022.
4.
6~4.
16) [3] Training Course︱Scientific Research Mapping·Academic Image Training [4] Seminar on Single-Cell Sequencing and Spatial Transcriptomics Data Analysis (2022.
4.
2-3 Tencent Online) References (swipe up and down to view) [1] Li L, Chao T, Brant J, O'Malley B, Jr.
, Tsourkas A, Li D:Advances in nano-based inner ear delivery systems for the treatment of sensorineural hearing loss.
Advanced drug delivery reviews 2017, 108:2-12.
[2]Liberman MC, Kujawa SG: Cochlear synaptopathy in acquired sensorineural hearing loss: Manifestations and mechanisms.
Hear Res 2017, 349:138-147.
[3]Gates GA, Mills JH: Presbycusis.
The Lancet 2005, 366(9491):1111-1120.
[4]Nelson DI, Nelson RY, Concha-Barrientos M, Fingerhut M : The global burden of occupational noise-induced hearing loss.
Am J Ind Med 2005, 48(6):446-458.
[5]Landier W: Ototoxicity and cancer therapy.
Cancer 2016, 122(11):1647-1658.
[6]Tang Q, Wang X, Jin H, Mi Y, Liu L, Dong M, Chen Y, Zou Z: Cisplatin-induced ototoxicity: Updates on molecular mechanisms and otoprotective strategies.
European journal of pharmaceutics and biopharmaceutics :official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik eV 2021, 163:60-71.
[7]Wang J, Puel JL: Toward Cochlear Therapies.
Physiological Reviews 2018, 98(4):2477-2522.
[8]Zhang Y, Li Y , Fu X, Wang P, Wang Q, Meng W, Wang T, Yang J, Chai R: The Detrimental and Beneficial Functions of Macrophages After Cochlear Injury.
Frontiers in cell and developmental biology 2021, 9:631904.
[9]Vethanayam RR , Yang W, Dong Y, Hu BH: Toll-like receptor 4 modulates the cochlear immune response to acoustic injury.
Cell Death Dis 2016, 7(6):e2245.
[10] Zhang G, Zheng H, Pyykko I, Zou J : The TLR-4/NF-κB signaling pathway activation in cochlear inflammation of rats with noise-induced hearing loss.
Hear Res 2019, 379:59-68.
[11] Wang Q, Shen Y, Hu H, Fan C, Zhang A, Ding R, Ye B, Xiang M:Systematic Transcriptome Analysis of Noise-Induced Hearing Loss Pathogenesis Suggests Inflammatory Activities and Multiple Susceptible Molecules and Pathways.
Front Genet 2020, 11:968.
[12] Kalinec G, Thein P, Park C, Kalinec F: HEI-OC1 cells as a model for investigating drug cytotoxicity.
Hear Res 2016, 335:105-117.
Plate making︱Sizhen Wang End of this article
