Hepatocyte growth factor protects auditory hair cells from aminoglycosides

Kikkawa, Yuichiro; Nakagawa, Takayuki; Tsubouchi, Hirohito; Ido, Akio; Inaoka, Takatoshi; Ono, Kazuya; Ito, Juichi

doi:10.1002/lary.20602

Cited by 16 publications

(19 citation statements)

References 15 publications

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“…However, these insults cannot be applied to the explant culture system. Therefore, we used aminoglycoside (neomycin), which is commonly used in this type of study (Kikkawa et al, 2009;Yoshida et al, 2011) to injure hair cells of cochlear explants. The administration of 100 ng/ml of IGF-1 markedly protected both the inner and outer hair cells (IHCs and OHCs) from neomycin injury ( Figure 1A and B).…”

Section: Igf-1 Protects Cochlear Hair Cells Against Neomycinmentioning

confidence: 99%

Insulin-like growth factor 1 inhibits hair cell apoptosis and promotes the cell cycle of supporting cells by activating different downstream cascades after pharmacological hair cell injury in neonatal mice

Hayashi

Yamamoto

Nakagawa

et al. 2013

Molecular and Cellular Neuroscience

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Sensorineural hearing loss, which is mainly caused by cochlear hair cell damage, is an intractable disease, as cochlear hair cells and supporting cells are unable to proliferate in postnatal mammals. As a novel and potent treatment for sensorineural hearing loss, we have studied IGF-1 and found that it protects cochlear hair cells from the damage caused by noise and ischemic trauma. Through a clinical trial, we have also confirmed that IGF-1 is an effective treatment for idiopathic sudden sensorineural hearing loss. In the current study, we attempted to identify the downstream pathways of the IGF-1 signal and the mechanisms by which IGF-1 protects the neonatal mouse cochlear hair cells that have been damaged by neomycin. IGF-1 activated both the PI3K/Akt and MEK/ERK pathways to maintain the hair cell numbers in the injured cochlea. The PI3K/Akt pathway specifically protected the cochlear inner hair cells through the inhibition of apoptosis. In contrast, the MEK/ERK pathway induced the cell cycle promotion of Hensen's and Claudius' cells, the supporting cells that are located lateral to the outer hair cells of the cochlea. This cell cycle promotion of the supporting cells resulted in the maintenance of the outer hair cell numbers. These results indicate that IGF-1 is a growth factor that efficiently regulates different mechanisms through different downstream cascades, thereby protecting cochlear hair cells.

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Section: Igf-1 Protects Cochlear Hair Cells Against Neomycinmentioning

confidence: 99%

Insulin-like growth factor 1 inhibits hair cell apoptosis and promotes the cell cycle of supporting cells by activating different downstream cascades after pharmacological hair cell injury in neonatal mice

Hayashi

Yamamoto

Nakagawa

et al. 2013

Molecular and Cellular Neuroscience

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“…S4F). Several studies of inner ear disease have reported that HGF protects hair cells and improves hearing (25)(26)(27). However, HGF levels appear to be tightly regulated, as too much or too little HGF is associated with hearing loss (28).…”

Section: Resultsmentioning

confidence: 99%

Targeting the cMET pathway augments radiation response without adverse effect on hearing in NF2 schwannoma models

Zhao

Liu

Zhang

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Neurofibromatosis type II (NF2) is a disease that needs new solutions. Vestibular schwannoma (VS) growth causes progressive hearing loss, and the standard treatment, including surgery and radiotherapy, can further damage the nerve. There is an urgent need to identify an adjunct therapy that, by enhancing the efficacy of radiation, can help lower the radiation dose and preserve hearing. The mechanisms underlying deafness in NF2 are still unclear. One of the major limitations in studying tumor-induced hearing loss is the lack of mouse models that allow hearing testing. Here, we developed a cerebellopontine angle (CPA) schwannoma model that faithfully recapitulates the tumor-induced hearing loss. Using this model, we discovered that cMET blockade by crizotinib (CRZ) enhanced schwannoma radiosensitivity by enhancing DNA damage, and CRZ treatment combined with low-dose radiation was as effective as high-dose radiation. CRZ treatment had no adverse effect on hearing; however, it did not affect tumor-induced hearing loss, presumably because cMET blockade did not change tumor hepatocyte growth factor (HGF) levels. This cMET gene knockdown study independently confirmed the role of the cMET pathway in mediating the effect of CRZ. Furthermore, we evaluated the translational potential of cMET blockade in human schwannomas. We found that human NF2-associated and sporadic VSs showed significantly elevated HGF expression and cMET activation compared with normal nerves, which correlated with tumor growth and cyst formation. Using organoid brain slice culture, cMET blockade inhibited the growth of patient-derived schwannomas. Our findings provide the rationale and necessary data for the clinical translation of combined cMET blockade with radiation therapy in patients with NF2.

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“…Genetic studies of hundreds of genes necessary for audition have uncovered several pathways important for normal hearing. Based initially upon studies of animal model, growth factors are now being explored for treatment of noise and ototoxic induced deafness and age-related hearing loss, [100][101][102][103][104][105][106][107][108][109] and some of these are currently in clinical trials. 110,111 For example, topical application of IGF1 to the middle ear was used to treat sudden sensorineural hearing loss in humans, and some treated individuals showed improvements of 10 to 30 dB for tested frequencies as compared to controls.…”

Section: Discussionmentioning

confidence: 99%

Growth factor and receptor malfunctions associated with human genetic deafness

Naz

Friedman

2019

Clinical Genetics

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A variety of different signaling pathways are necessary for development and maintenance of the human auditory system. Normal hearing allows for the detection of soft sounds within the frequency range of 20 to 20 000 Hz, but more importantly to perceive the human voice frequency band of 250 to 6000 Hz. Loss of hearing is common, and is a clinically heterogeneous disorder that can be caused by environmental factors such as exposure to loud noise, infections and ototoxic drugs. In addition, variants of hundreds of genes have been reported to disrupt processes required for hearing. Noncoding regulatory variants and variants of additional genes necessary for hearing remain to be discovered as many individuals with inherited deafness are without a genetic diagnosis, despite the advent of whole exome sequencing. Here, we discuss in detail some of these deafnesscausing variants of genes encoding a ligand or its receptor. Spotlighted in this review are three growth factor-receptor-pairs EDN3/EDNRB, HGF/MET and JAG/NOTCH, which individually are necessary for normal hearing. We also offer our perspective on unanswered questions, future challenges and potential opportunities for treatments emerging from molecular genetic and mechanistic studies of deafness due to these causes. K E Y W O R D SEDN3, EDNRB, hearing, HGF, inner ear defects, JAG, MET, NOTCH

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Hepatocyte growth factor protects auditory hair cells from aminoglycosides

Abstract: These findings demonstrate that a functional HGF/c-Met coupling is present in the cochlea, and HGF application exerts protective effects on hair cells, indicating the potential of HGF as a therapeutic agent for sensorineural hearing loss.

Cited by 16 publications

References 15 publications

Insulin-like growth factor 1 inhibits hair cell apoptosis and promotes the cell cycle of supporting cells by activating different downstream cascades after pharmacological hair cell injury in neonatal mice

Insulin-like growth factor 1 inhibits hair cell apoptosis and promotes the cell cycle of supporting cells by activating different downstream cascades after pharmacological hair cell injury in neonatal mice

Targeting the cMET pathway augments radiation response without adverse effect on hearing in NF2 schwannoma models

Growth factor and receptor malfunctions associated with human genetic deafness

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