Stem Cell Treatment Hearing Loss

Stem Cell Treatment Hearing Loss at SIRM

Two Types:

1. Conductive hearing loss

A conductive hearing impairment is present when the sound is not reaching the inner ear, the cochlea. This can be due to external ear canal malformation, dysfunction of the eardrum or malfunction of the bones of the middle ear. The ear drum may show defects from small to total resulting in hearing loss of different degree. Scar tissue after ear infections may also make the ear drum dysfunction as well as when it is retracted and adherent to the medial part of the middle ear.

Dysfunction of the three small bones of the middle ear; hammer, anvil and stapes may result in conductive hearing loss. The mobility of the ossicles may be impaired of different reasons and disruption of the ossicular chain due to trauma, infection or anchylosis may also result in hearing loss.

2. Sensorineural hearing loss

A sensorineural hearing loss is one resulting from dysfunction of the inner ear, the cochlea, the nerve that transmits the impulses from the cochlea to the hearing centre in the brain or damage in the brain. The most common reason for sensorineural hearing impairment is damage to the hair cells in the cochlea. As we grow older the hair cells degenerate and lose their function, and our hearing deteriorates. Depending on the definition it could be estimated that more than 50% of the population over the age of 70 has an impaired hearing. Impaired hearing is the most common physical handicap in the industrialized world.

Another common reason for hearing loss due to hair cell damage is noise-induced hearing loss. These types of hearing loss are often most pronounced in the high frequency range. This will often interfere with speech understanding, as it is in the high frequency range that we find the consonant sounds that are most important especially in noisy surroundings. Head trauma, ear infections, tumours and ototoxic drugs such as gentamyacin are other reasons for sensorineural hearing loss.

Mixed hearing loss

Mixed hearing loss is a combination of the two types discussed above. Chronic ear infection that is a fairly common diagnosis could result in a defect ear drum and/or middle ear ossicle damages.

Stem Cell Treatment for Hearing Loss

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Related Articles GeneReviews® Book. 1993 Authors: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A Abstract CLINICAL CHARACTERISTICS: Mucopolysaccharidosis type II (MPS II; also known as Hunter syndrome) is an X-linked multisystem disorder characterized by glycosaminoglycan (GAG) accumulation. The vast majority of affected individuals are male; on rare occasion heterozygous females manifest findings. Age of onset, disease severity, and rate of progression vary significantly among affected males. In those with early progressive disease, CNS involvement (manifest primarily by progressive cognitive deterioration), progressive airway disease, and cardiac disease usually result in death in the first or second decade of life. In those with slowly progressive disease, the CNS is not (or is minimally) affected, although the effect of GAG accumulation on other organ systems may be early progressive to the same degree as in those who have progressive cognitive decline. Survival into the early adult years with normal intelligence is common in the slowly progressing form of the disease. Additional findings in both forms of MPS II include: short stature; macrocephaly with or without communicating hydrocephalus; macroglossia; hoarse voice; conductive and sensorineural hearing loss; hepatosplenomegaly; dysostosis multiplex; spinal stenosis; and carpal tunnel syndrome. DIAGNOSIS/TESTING: The diagnosis of MPS II is established in a male proband by identification of deficient iduronate 2-sulfatase (I2S) enzyme activity in white cells, fibroblasts, or plasma in the presence of normal activity of at least one other sulfatase. Detection of a hemizygous pathogenic variant in IDS confirms the diagnosis in a male proband with an unusual phenotype or a phenotype that does not match the results of GAG testing. The diagnosis of MPS II is usually established in a female proband with suggestive clinical features by identification of a heterozygous IDS pathogenic variant on molecular genetic testing. MANAGEMENT: Treatment of manifestations: Interventions commonly include: developmental, occupational, and physical therapy; shunting for hydrocephalus; tonsillectomy and adenoidectomy; positive pressure ventilation (CPAP or tracheostomy); carpal tunnel release; cardiac valve replacement; inguinal hernia repair; hip replacement. Prevention of primary manifestations: Weekly enzyme replacement therapy (ERT) with infusions of idursulfase (Elaprase®), a recombinant form of human iduronate 2-sulfatase, is approved to treat somatic manifestations and prolong survival. Pretreatment with anti-inflammatory drugs or antihistamines may be needed for mild or moderate infusion reactions. Hematopoietic stem cell transplantation (HSCT) (using umbilical cord blood or bone marrow) could provide sufficient enzyme activity to slow or stop the progression of the disease; however, no controlled clinical studies have been conducted in MPS II. Prevention of secondary complications: Anesthesia is best administered in centers familiar with the potential complications in persons with MPS II. Surveillance: Depends on organ system and disease severity and usually includes annual: cardiology evaluation and echocardiogram; pulmonary evaluation including pulmonary function testing; audiogram; ophthalmology examination; developmental assessment; neurologic examination. Additional studies may include: sleep study for obstructive apnea; nerve conduction velocity to assess for carpal tunnel syndrome; head/neck MRI to document ventricular size and cervicomedullary narrowing; opening pressure on lumbar puncture; and orthopedic evaluation to monitor hip disease. Evaluation of relatives at risk: While clinical experience suggests that early diagnosis of at-risk males allows initiation of ERT before the onset of irreversible changes and often before significant disease progression, it is unclear at present whether the potential benefits of early initiation of ERT justify early diagnosis by either newborn screening or testing of at-risk male relatives. GENETIC COUNSELING: MPS II is inherited in an X-linked manner. The risk to sibs depends on the genetic status of the mother. If the mother of the proband has the pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers. Germline mosaicism has been observed. Affected males pass the pathogenic variant to all of their daughters and none of their sons. Carrier testing for at-risk female relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variant in the family is known. PMID: 20301451
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Related Articles Cochlear gene therapy with ancestral AAV in adult mice: complete transduction of inner hair cells without cochlear dysfunction. Sci Rep. 2017 04 03;7:45524 Authors: Suzuki J, Hashimoto K, Xiao R, Vandenberghe LH, Liberman MC Abstract The use of viral vectors for inner ear gene therapy is receiving increased attention for treatment of genetic hearing disorders. Most animal studies to date have injected viral suspensions into neonatal ears, via the round window membrane. Achieving transduction of hair cells, or sensory neurons, throughout the cochlea has proven difficult, and no studies have been able to efficiently transduce sensory cells in adult ears while maintaining normal cochlear function. Here, we show, for the first time, successful transduction of all inner hair cells and the majority of outer hair cells in an adult cochlea via virus injection into the posterior semicircular canal. We used a "designer" AAV, AAV2/Anc80L65, in which the main capsid proteins approximate the ancestral sequence state of AAV1, 2, 8, and 9. Our injections also transduced ~10% of spiral ganglion cells and a much larger fraction of their satellite cells. In the vestibular sensory epithelia, the virus transduced large numbers of hair cells and virtually all the supporting cells, along with close to half of the vestibular ganglion cells. We conclude that this viral vector and this delivery route hold great promise for gene therapy applications in both cochlear and vestibular sense organs. PMID: 28367981 [PubMed - indexed for MEDLINE]
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Related Articles Genome-wide RNA-seq of iPSC-derived motor neurons indicates selective cytoskeletal perturbation in Brown-Vialetto disease that is partially rescued by riboflavin. Sci Rep. 2017 04 06;7:46271 Authors: Rizzo F, Ramirez A, Compagnucci C, Salani S, Melzi V, Bordoni A, Fortunato F, Niceforo A, Bresolin N, Comi GP, Bertini E, Nizzardo M, Corti S Abstract Riboflavin is essential in numerous cellular oxidation/reduction reactions but is not synthesized by mammalian cells. Riboflavin absorption occurs through the human riboflavin transporters RFVT1 and RFVT3 in the intestine and RFVT2 in the brain. Mutations in these genes are causative for the Brown-Vialetto-Van Laere (BVVL), childhood-onset syndrome characterized by a variety of cranial nerve palsies as well as by spinal cord motor neuron (MN) degeneration. Why mutations in RFVTs result in a neural cell-selective disorder is unclear. As a novel tool to gain insights into the pathomechanisms underlying the disease, we generated MNs from induced pluripotent stem cells (iPSCs) derived from BVVL patients as an in vitro disease model. BVVL-MNs explained a reduction in axon elongation, partially improved by riboflavin supplementation. RNA sequencing profiles and protein studies of the cytoskeletal structures showed a perturbation in the neurofilament composition in BVVL-MNs. Furthermore, exploring the autophagy-lysosome pathway, we observed a reduced autophagic/mitophagic flux in patient MNs. These features represent emerging pathogenetic mechanisms in BVVL-associated neurodegeneration, partially rescued by riboflavin supplementation. Our data showed that this therapeutic strategy could have some limits in rescuing all of the disease features, suggesting the need to develop complementary novel therapeutic strategies. PMID: 28382968 [PubMed - indexed for MEDLINE]
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Related Articles Survival of human embryonic stem cells implanted in the guinea pig auditory epithelium. Sci Rep. 2017 04 07;7:46058 Authors: Lee MY, Hackelberg S, Green KL, Lunghamer KG, Kurioka T, Loomis BR, Swiderski DL, Duncan RK, Raphael Y Abstract Hair cells in the mature cochlea cannot spontaneously regenerate. One potential approach for restoring hair cells is stem cell therapy. However, when cells are transplanted into scala media (SM) of the cochlea, they promptly die due to the high potassium concentration. We previously described a method for conditioning the SM to make it more hospitable to implanted cells and showed that HeLa cells could survive for up to a week using this method. Here, we evaluated the survival of human embryonic stem cells (hESC) constitutively expressing GFP (H9 Cre-LoxP) in deaf guinea pig cochleae that were pre-conditioned to reduce potassium levels. GFP-positive cells could be detected in the cochlea for at least 7 days after the injection. The cells appeared spherical or irregularly shaped, and some were aggregated. Flushing SM with sodium caprate prior to transplantation resulted in a lower proportion of stem cells expressing the pluripotency marker Oct3/4 and increased cell survival. The data demonstrate that conditioning procedures aimed at transiently reducing the concentration of potassium in the SM facilitate survival of hESCs for at least one week. During this time window, additional procedures can be applied to initiate the differentiation of the implanted hESCs into new hair cells. PMID: 28387239 [PubMed - indexed for MEDLINE]
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Related Articles Prevention of ischemia-induced hearing loss by intravenous administration of hydrogen-rich saline in gerbil. Neurosci Lett. 2018 02 05;665:195-199 Authors: Ogawa H, Okada M, Shudou M, Gyo K, Hato N Abstract OBJECTIVE: Hydrogen-rich water, which is a potent antioxidant agent, was investigated for its protective effects against ischemic damage of the cochlea in gerbils. METHODS: The animals were subjected to transient cochlear ischemia by occluding the bilateral vertebral arteries for l5min. Five milliliters of hydrogen-rich saline was then intravenously administered immediately after the insult. Saline without hydrogen was used as a control. Effects of hydrogen were evaluated using the auditory brainstem response (ABR) and histological studies of the inner ear. RESULTS: In non-ischemia animals, ABR thresholds and histological findings of the cochlea did not change by administration of saline or hydrogen-rich saline. In contrast, transient cochlear ischemia caused a 24.2±3.8dB increase in the ABR threshold at 8kHz, and a decrease of 14.1%±1.8% in the number of inner hair cells (IHCs) at the basal turn on day 7. Ischemic damage was more severe at 16 and 32kHz. When the animals were treated with hydrogen-rich saline, cochlear damage was significantly reduced: the increase in ABR threshold was 11.7±2.6dB at 8kHz and the IHC loss was 7.5%±2.1% at the basal turn on day 7. The effects of hydrogen-rich saline were more prominent at higher frequencies. CONCLUSIONS: Intravenous administration of hydrogen-rich saline was effective in preventing acute hearing loss due to transient cochlear ischemia. PMID: 29223865 [PubMed - indexed for MEDLINE]
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Related Articles Auditory Neural Activity in Congenitally Deaf Mice Induced by Infrared Neural Stimulation. Sci Rep. 2018 01 10;8(1):388 Authors: Tan X, Jahan I, Xu Y, Stock S, Kwan CC, Soriano C, Xiao X, García-Añoveros J, Fritzsch B, Richter CP Abstract To determine whether responses during infrared neural stimulation (INS) result from the direct interaction with spiral ganglion neurons (SGNs), we tested three genetically modified deaf mouse models: Atoh1-cre; Atoh1 f/f (Atoh1 conditional knockout, CKO), Atoh1-cre; Atoh1 f/kiNeurog1 (Neurog1 knockin, KI), and the Vglut3 knockout (Vglut3 -/-) mice. All animals were exposed to tone bursts and clicks up to 107 dB (re 20 µPa) and to INS, delivered with a 200 µm optical fiber. The wavelength (λ) was 1860 nm, the radiant energy (Q) 0-800 µJ/pulse, and the pulse width (PW) 100-500 µs. No auditory responses to acoustic stimuli could be evoked in any of these animals. INS could not evoke auditory brainstem responses in Atoh1 CKO mice but could in Neurog1 KI and Vglut3 -/- mice. X-ray micro-computed tomography of the cochleae showed that responses correlated with the presence of SGNs and hair cells. Results in Neurog1 KI mice do not support a mechanical stimulation through the vibration of the basilar membrane, but cannot rule out the direct activation of the inner hair cells. Results in Vglut3 -/- mice, which have no synaptic transmission between inner hair cells and SGNs, suggested that hair cells are not required. PMID: 29321651 [PubMed - indexed for MEDLINE]
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Related Articles Differentiation of stem cells from human deciduous and permanent teeth into spiral ganglion neuron-like cells. Arch Oral Biol. 2018 Apr;88:34-41 Authors: Gonmanee T, Thonabulsombat C, Vongsavan K, Sritanaudomchai H Abstract OBJECTIVE: Stem cells from pulp tissue are a promising cell-based therapy for neurodegenerative patients based on their origin in the neural crest. The aim of this study was to differentiate and evaluate the ability of human dental pulp stem cells from permanent teeth (DPSC) and stem cells from human exfoliated deciduous teeth (SHED) to differentiate into spiral ganglion neurons. DESIGN: After isolation and characterization of mesenchymal stem cell properties, DPSC and SHED were treated with the neurotrophins brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and glial cell-derived neurotrophic factor (GDNF). The differentiation was identified by immunostaining and qRT-PCR analysis of neuronal markers and measuring intracellular calcium activity. RESULTS: After 2 weeks of induction, morphological changes were observed in both DPSC and SHED. The differentiated cells expressed neuron-specific class III beta-tubulin, GATA binding protein 3 (GATA3) and tropomyosin receptor kinase B, protein markers of spiral ganglion neurons. These cells also showed upregulation of the genes encoding these proteins, namely GATA3 and neurotrophic receptor tyrosine kinase 2. Intracellular calcium dynamics that reflect neurotransmitter release were observed in differentiated DPSC and SHED. CONCLUSION: These results demonstrate that dental pulp stem cells from permanent and deciduous teeth can differentiate into spiral ganglion neuron-like cells. PMID: 29407749 [PubMed - indexed for MEDLINE]
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Related Articles Transient Abnormalities in Masking Tuning Curve in Early Progressive Hearing Loss Mouse Model. Biomed Res Int. 2018;2018:6280969 Authors: Souchal M, Labanca L, Alves da Silva Carvalho S, Macedo de Resende L, Blavignac C, Avan P, Giraudet F Abstract Damage to cochlear outer hair cells (OHCs) usually affects frequency selectivity in proportion to hearing threshold increase. However, the current clinical heuristics that attributes poor hearing performance despite near-normal auditory sensitivity to auditory neuropathy or "hidden" synaptopathy overlooks possible underlying OHC impairment. Here, we document the part played by OHCs in influencing suprathreshold auditory performance in the presence of noise in a mouse model of progressive hair cell degeneration, the CD1 strain, at postnatal day 18-30 stages when high-frequency auditory thresholds remained near-normal. Nonetheless, total loss of high-frequency distortion product otoacoustic emissions pointed to nonfunctioning basal OHCs. This "discordant profile" came with a huge low-frequency shift of masking tuning curves that plot the level of interfering sound necessary to mask the response to a probe tone, against interfering frequency. Histology revealed intense OHC hair bundle abnormalities in the basal cochlea uncharacteristically associated with OHC survival and preserved coupling with the tectorial membrane. This pattern dismisses the superficial diagnosis of "hidden" neuropathy while underpinning a disorganization of cochlear frequency mapping with optimistic high-frequency auditory thresholds perhaps because responses to high frequencies are apically shifted. The audiometric advantage of frequency transposition is offset by enhanced masking by low-frequency sounds, a finding essential for guiding rehabilitation. PMID: 29662891 [PubMed - indexed for MEDLINE]
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Related Articles Cochlear hair cell regeneration: an emerging opportunity to cure noise-induced sensorineural hearing loss. Drug Discov Today. 2018 Aug;23(8):1564-1569 Authors: Youm I, Li W Abstract In mammals, cochlear hair cells have a pivotal role in transducing mechanical energy into electrical signals. Cochlear hair cells are sensitive to acoustic trauma, drug insults, aging, and environmental or genetic influences that can cause permanent hearing loss. Currently, many researchers have focused on noise-induced sensorineural hearing loss (SNHL). Noise-induced SNHL is primarily caused by damage to hair cells of the cochlear sensory epithelium. Here, we summarize recent progress in restoring the sensory epithelium after SNHL resulting from noise exposure. The prevalent strategy to regenerate cochlear hair cells is through transdifferentiation of the supporting cells via the inhibition of the NOTCH 1 pathway. PMID: 29733894 [PubMed - indexed for MEDLINE]
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Related Articles Association between age‑related hearing loss and cognitive decline in C57BL/6J mice. Mol Med Rep. 2018 Aug;18(2):1726-1732 Authors: Dong Y, Guo CR, Chen D, Chen SM, Peng Y, Song H, Shi JR Abstract Accumulating evidence has revealed the link between age‑related hearing loss (presbycusis) and cognitive decline; however, their exact association remains unclear. The present study aimed to investigate the association between age‑related hearing loss and cognitive decline, and to explore the underlying mechanisms. Briefly, three groups of C57BL/6J mice were evaluated, based on their age, as follows: Young group, 3 months; adult group, 6 months; and middle‑aged group, 15 months. The results of an auditory brainstem response (ABR) test demonstrated that the hearing threshold levels of the mice were increased in those aged 6 and 15 months compared with those aged 3 months, thus suggesting that significant hearing loss occurred at 6 months, and worsened at 15 months. The results of a Morris water maze test demonstrated that spatial learning and memory function was significantly decreased in 15‑month‑old mice, but not in 6‑month‑old mice. Pearson analysis indicated that the escape latency was positively correlated with hearing threshold at 16 kHz and percentage of time in the target quadrant was negatively correlated with hearing threshold at 16 kHz, thus suggesting a correlation between age‑related hearing loss and cognitive decline. The auditory cortex and hippocampal CA1 region in 15‑month‑old mice exhibited significantly decreased cell numbers, abnormal arrangement and morphological alterations. Transmission electron microscopy revealed reduced synapse numbers and synaptic vesicle density in mice aged 15 months. Furthermore, the protein expression levels of matrix metalloproteinase (MMP)‑9 in the auditory cortex and hippocampus in the 15‑month‑old mice were significantly higher than in the 3‑month‑old mice. In conclusion, these findings support the correlation between age‑related hearing loss and cognitive decline in C57BL/6J mice, and indicated that MMP‑9 expression in the auditory cortex and hippocampus may be associated with the underlying mechanisms. PMID: 29901198 [PubMed - indexed for MEDLINE]
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Related Articles The first successful application of preimplantation genetic diagnosis for hearing loss in Iran. Cell Mol Biol (Noisy-le-grand). 2018 Jun 30;64(9):1718 Authors: Karimi Yazdi A, Davoudi-Dehaghani E, Rabbani Anari M, Fouladi P, Ebrahimi E, Sabeghi S, Eftekharian A, Fatemi KS, Emami H, Sharifi Z, Ramezanzadeh F, Tajdini A, Zeinali S, Amanpour S Abstract Hearing impairment (HI) caused by mutations in the connexin-26 gene (GJB2) accounts for the majority of cases with inherited, nonsyndromic sensorineural hearing loss. Due to the illegality of the abortion of deaf fetuses in Islamic countries, preimplantation genetic diagnosis (PGD) is a possible solution for afflicted families to have a healthy offspring. This study describes the first use of PGD for GJB2 associated non-syndromic deafness in Iran. GJB2 donor splicing site IVS1+1G>A mutation analysis was performed using Sanger sequencing for a total of 71 Iranian families with at least 1 deaf child diagnosed with non-syndromic deafness. In Vitro Fertilization (IVF) was performed, followed by PGD for a cousin couple with a 50% chance of having an affected child. Bi-allelic pathogenic mutations were found in a total of 12 families (~17 %); of which a couple was a PGD volunteer. The deaf woman in this family was homozygous and her husband was a carrier of the IVS1+1G>A gene mutation. Among 8 biopsied embryos, two healthy embryos were implanted which resulted in a single pregnancy and subsequent birth of a healthy baby boy. This is the first report of a successful application of PGD for hearing loss in Iran. Having a baby with a severe hearing impairment often imposes families with long-term disease burden and heavy therapy costs. Today PGD has provided an opportunity for high-risk individuals to avoid the birth of a deaf child. PMID: 30030956 [PubMed - indexed for MEDLINE]
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Related Articles Mimic Cochlear Implant Surgery-Induced Cochlear Infection Fails to Further Damage Auditory Pathway in Deafened Guinea Pigs. Med Sci Monit. 2018 Aug 06;24:5448-5456 Authors: Han Z, Wang C, Gu Y, Cong N, Ma R, Chi F Abstract BACKGROUND Kanamycin and subsequent furosemide administration was applied to the healthy guinea pigs to induce deafness. MATERIAL AND METHODS Of the deafened guinea pigs, 10 were further infused with anti-infection procedures (Group B) and the other 10 animals did not undergo anti-infection procedures (Group C). In Group B, the deafened animals were able to restore cochlear and middle ear functions following the anti-infection procedure. In Group C, all animals developed cochlear and middle ear infections. RESULTS Compared to the healthy guinea pigs, hair cells and spiral ganglion neurons (SGN) of deafened animals (in Group B and Group C) were severely damaged. SGN density of deafened animals was significantly lower than that of healthy control animals in all ear turns except the basal turn. There was no significant difference between Group B and Group C in SGN density. The average optical density value of neurofilaments of deafened animals was also significantly decreased after the ototoxic drug administration. Notably, the density of the neurons in the cochlear nucleus region (CNR) of the brainstem were not significantly different between the healthy control guinea pigs and deafened animals. CONCLUSIONS Mimic cochlear implant surgery-induced cochlear infection caused no significant damage to the auditory pathway in ototoxic drug-induced deafened guinea pigs. PMID: 30078839 [PubMed - indexed for MEDLINE]
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Related Articles The olfactory mucosa: a potential source of stem cells for hearing regeneration. Regen Med. 2018 07 01;13(5):581-593 Authors: Young E, Westerberg B, Yanai A, Gregory-Evans K Abstract The olfactory mucosa contains cells that enable it to generate new neurons and other supporting cells throughout life, allowing it to replace cells of the mucosa that have been damaged by exposure to various insults. In this article, we discuss the different types of stem cell found within the olfactory mucosa and their properties. In particular, the mesenchymal-like cells found within the lamina propria will be reviewed in detail. In addition, we discuss potential applications of olfactory-derived stem cells toward hearing regeneration secondary to either inner hair cell loss or primary or secondary auditory nerve degeneration. PMID: 30113240 [PubMed - indexed for MEDLINE]
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Related Articles Valproic acid promotes the neuronal differentiation of spiral ganglion neural stem cells with robust axonal growth. Biochem Biophys Res Commun. 2018 Sep 18;503(4):2728-2735 Authors: Moon BS, Lu W, Park HJ Abstract Hearing loss occurs with the loss of hair cells of the cochlea and subsequent degeneration of spiral ganglion neurons (SGNs). Regeneration of SGNs is a potentially promising therapeutic approach to hearing loss in addition to the use of a cochlear implant (CI), because this device stimulates SGNs directly to restore hearing bypassing the missing hair cells. The presence of SGN-neural stem cells (NSCs) has been reported in adult human and mice. These cells have the potential to become SGNs and thus represent a cellular foundation for regeneration therapies for hearing loss. Valproic acid (VPA) has been shown to influence the neural differentiation of NSCs through multiple signaling pathways involving glycogen synthase kinase3β (GSK3β). Our present study therefore aimed to modulate the neural differentiation potential of SGN-NSCs by treatment with VPA. We here report that a clinically relevant concentration of 1 mM VPA induced the differentiation of basic fibroblast growth factor (bFGF)-treated P1- and P14-SGN-NSCs into neuronal and glial cells, confirmed by neuronal marker (Tuj1 and MAP2) and glial cell marker (GFAP and S100β) detection. VPA-treated cells also promoted much longer neurite outgrowth compared to differentiated cells cultured without bFGF. The effects of VPA on the regulation of differentiation may be related to the activation of the Wnt/β-catenin signaling pathway, but not the inhibition of histone deacetylases (HDACs). We propose that VPA has the potential to convert SGN-NSCs into SGNs and thereby restore hearing when combined with a CI. PMID: 30119886 [PubMed - in process]
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Related Articles N-Methyl-D-Aspartate Receptors Involvement in the Gentamicin-Induced Hearing Loss and Pathological Changes of Ribbon Synapse in the Mouse Cochlear Inner Hair Cells. Neural Plast. 2018;2018:3989201 Authors: Hong J, Chen Y, Zhang Y, Li J, Ren L, Yang L, Shi L, Li A, Zhang T, Li H, Dai P Abstract Cochlear inner hair cell (IHC) ribbon synapses play an important role in sound encoding and neurotransmitter release. Previous reports show that both noise and aminoglycoside exposures lead to reduced numbers and morphologic changes of synaptic ribbons. In this work, we determined the distribution of N-methyl-D-aspartate receptors (NMDARs) and their role in the gentamicin-induced pathological changes of cochlear IHC ribbon synaptic elements. In normal mature mouse cochleae, the majority of NMDARs were distributed on the modiolar side of IHCs and close to the IHC nuclei region, while most of synaptic ribbons and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) were located on neural terminals closer to the IHC basal poles. After gentamicin exposure, the NMDARs increased and moved towards the IHC basal poles. At the same time, synaptic ribbons and AMPARs moved toward the IHC bundle poles on the afferent dendrites. The number of ribbon synapse decreased, and this was accompanied by increased auditory brainstem response thresholds and reduced wave I amplitudes. NMDAR antagonist MK801 treatment reduced the gentamicin-induced hearing loss and the pathological changes of IHC ribbon synapse, suggesting that NMDARs were involved in gentamicin-induced ototoxicity by regulating the number and distribution of IHC ribbon synapses. PMID: 30123246 [PubMed - indexed for MEDLINE]
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Related Articles Knock-In Mice with Myo3a Y137C Mutation Displayed Progressive Hearing Loss and Hair Cell Degeneration in the Inner Ear. Neural Plast. 2018;2018:4372913 Authors: Li P, Wen Z, Zhang G, Zhang A, Fu X, Gao J Abstract Myo3a is expressed in cochlear hair cells and retinal cells and is responsible for human recessive hereditary nonsyndromic deafness (DFNB30). To investigate the mechanism of DFNB30-type deafness, we established a mouse model of Myo3a kinase domain Y137C mutation by using CRISPR/Cas9 system. No difference in hearing between 2-month-old Myo3a mutant mice and wild-type mice was observed. The hearing threshold of the ≥6-month-old mutant mice was significantly elevated compared with that of the wild-type mice. We observed degeneration in the inner ear hair cells of 6-month-old Myo3a mutant mice, and the degeneration became more severe at the age of 12 months. We also found structural abnormality in the cochlear hair cell stereocilia. Our results showed that Myo3a is essential for normal hearing by maintaining the intact structure of hair cell stereocilia, and the kinase domain plays a critical role in the normal functions of Myo3a. This mouse line is an excellent model for studying DFNB30-type deafness in humans. PMID: 30123247 [PubMed - indexed for MEDLINE]
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Related Articles Safety of Autologous Umbilical Cord Blood Therapy for Acquired Sensorineural Hearing Loss in Children. J Audiol Otol. 2018 Oct;22(4):209-222 Authors: Baumgartner LS, Moore E, Shook D, Messina S, Day MC, Green J, Nandy R, Seidman M, Baumgartner JE Abstract BACKGROUND AND OBJECTIVES: Sensorineural hearing loss (SNHL) in children is associated with neurocognitive morbidity. The cause of SNHL is a loss of hair cells in the organ of Corti. There are currently no reparative treatments for SNHL. Numerous studies suggest that cord blood mononuclear cells (human umbilical cord blood, hUCB) allow at least partial restoration of SNHL by enabling repair of a damaged organ of Corti. Our objective is to determine if hUCB is a safe treatment for moderate to severe acquired SNHL in children. Subjects and. METHODS: Eleven children aged 6 months to 6 years with moderate to severe acquired SNHL were treated with intravenous autologous hUCB. The cell dose ranged from 8 to 30 million cells/kg body weight. Safety was assessed by measuring systemic hemodynamics during hUCB infusion. Infusion-related toxicity was evaluated by measuring neurologic, hepatic, renal and pulmonary function before and after infusion. Auditory function, auditory verbal language assessments and MRI with diffusion tensor imaging (DTI) were obtained before and after treatment. RESULTS: All patients survived, and there were no adverse events. No infusionrelated changes in hemodynamics occurred. No infusion-related toxicity was recorded. Five subjects experienced a reduction in auditory brainstem response (ABR) thresholds. Four of those 5 subjects also experienced an improvement in cochlear nerve latencies. Comparison of MRI with DTI sequences obtained before and after treatment revealed increased fractional anisotropy in the primary auditory cortex in three of five subjects with reduced ABR thresholds. Statistically significant (p<0.05) reductions in ABR thresholds were identified. CONCLUSIONS: TIntravenous hUCB is feasible and safe in children with SNHL. PMID: 30126263 [PubMed]
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Related Articles Late effects in high-risk neuroblastoma survivors treated with high-dose chemotherapy and stem cell rescue. Pediatr Blood Cancer. 2019 Jan;66(1):e27421 Authors: Elzembely MM, Dahlberg AE, Pinto N, Leger KJ, Chow EJ, Park JR, Carpenter PA, Baker KS Abstract BACKGROUND: Current treatment strategies have improved the outcome of high-risk neuroblastoma (HRNB) at the cost of increasing acute and late effects of treatment. Although high-dose chemotherapy with stem cell rescue (HDC-SCR) has replaced total body irradiation (TBI) based HRNB therapy, late effects of therapy remain a significant concern. OBJECTIVES: To describe late effects prevalence, severity, and risks after HDC-SCR. METHODS: Retrospective chart review of relapse-free HRNB survivors ≥1 year after single HDC-SCR between 2000 and 2015 at Fred Hutchinson Cancer Research Center. RESULTS: Sixty-one survivors (30 males) were eligible. Median age (years) at SCR was 3.5 years (range 0.7-27 years) and median posttransplant follow-up was 5.4 years (1.2-16.3 years) . Fifty-three (86.9%) survivors developed late effects that increased over time (P < 0.001) and varied in severity from grade 1 (35) to grade 5 (1). These were unrelated to gender or age. High-frequency hearing loss seen in 82% of survivors was the most common abnormality present and 43% of those required hearing aids. Seventeen (27.9%) survivors developed dental late effects and these were most common in children <2 years of age at transplant (P = 0.008). Other toxicities included endocrine (18%), orthopedic (14.8 %), renal (3.9%), melanotic nevi (8.2%), neuropsychological impairments (8.2%), subsequent malignancies (4.9%), pulmonary (4.9%), cardiac (4.9%), and focal nodular liver hyperplasia (3.3%). At 9 years posttransplant, the median height and weight Z-scores were significantly lower than Z-scores at the time of HDC-SCR (-0.01/-1.08, P < 0.001; -0.14/-0.78, P = 0.005). CONCLUSION: Avoidance of TBI does not mitigate the need to provide diligent, ongoing surveillance for late effects. PMID: 30151986 [PubMed - in process]
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Related Articles Differentiation and transplantation of human induced pluripotent stem cell-derived otic epithelial progenitors in mouse cochlea. Stem Cell Res Ther. 2018 Aug 29;9(1):230 Authors: Chen J, Hong F, Zhang C, Li L, Wang C, Shi H, Fu Y, Wang J Abstract BACKGROUND: Inner ear hair cells as mechanoreceptors are extremely important for hearing. Defects in hair cells are a major cause of deafness. Induced pluripotent stem cells (iPSCs) are promising for regenerating inner ear hair cells and treating hearing loss. Here, we investigated migration, differentiation, and synaptic connections of transplanted otic epithelial progenitors (OEPs) derived from human iPSCs in mouse cochlea. METHODS: Human urinary cells isolated from a healthy donor were reprogramed to form iPSCs that were induced to differentiate into OEPs and hair cell-like cells. Immunocytochemistry, electrophysiological examination, and scanning electron microscopy were used to examine characteristics of induced hair cell-like cells. OEP-derived hair cell-like cells were cocultured with spiral ganglion neurons (SGNs), and the markers of synaptic connections were detected using immunocytochemistry and transmission electron microscope. In vivo, OEPs derived from iPSCs were transplanted into the cochlea of mice by injection through the round window. Migration, differentiation, and synaptic connections of transplanted cells were also examined by thin cochlear sectioning and immunohistochemistry. RESULTS: The induced hair cell-like cells displayed typical morphological characteristics and electrophysiological properties specific to inner hair cells. In vitro, OEP-derived hair cell-like cells formed synaptic connections with SGNs in coculture. In vivo, some of the transplanted cells migrated to the site of the resident hair cells in the organ of Corti, differentiated into hair cell-like cells, and formed synaptic connections with native SGNs. CONCLUSIONS: We conclude that the transplantation of OEPs is feasible for the regeneration of hair cells. These results present a substantial reference for a cell-based therapy for the loss of hair cells. PMID: 30157937 [PubMed - in process]
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Related Articles A young patient with a lytic skull lesion. J Clin Pathol. 2018 Sep 26;: Authors: Chong VC, Tan CL, Chee YL, De Mel S Abstract CLINICAL QUESTION: A man in his mid-20s presented with a 2-month history of an enlarging left-sided skull swelling associated with focal pain. His medical history and systems enquiry were otherwise unremarkable. Specifically, he had no neurological deficits and respiratory, skin or constitutional symptoms. MRI brain scan revealed a lytic focus in the left parietal bone. Within this lytic lesion was an enhancing soft-tissue mass with central necrosis. The mass extended over the inner and outer surface of the skull vault and had both an extradural and a deep scalp component. There was no cerebral oedema, hydrocephalus or midline shift. The patient underwent a left parietal craniotomy and excision of the lytic parietal skull and extradural lesion. The histopathology of the skull lesion is shown in the scanned slide.Review the high-quality, interactive digital Aperio slides at http://virtualacp.com/JCPCases/jclinpath-2018-205016/ and consider your diagnosis WHAT IS YOUR DIAGNOSIS?: Erdheim-Chester disease (ECD)Follicular dendritic cell sarcoma (FDCS)Histiocytic sarcoma (HS)Langerhans cell histiocytosis (LCH)Rosai Dorfman disease (RDD)-The correct answer is after the discussion. DISCUSSION: Histological sections of our patient revealed an infiltrative tumour composed of sheets of cells with oval nuclei, prominent nuclear grooves and minimal nuclear atypia, admixed with numerous eosinophils and some multinucleate giant cells. Necrosis was present. The cells were positive on immunohistochemistry for CD68, CD1a and S-100, supporting the diagnosis of LCH.LCH can be distinguished from the other differentials morphologically and immunohistochemically, and the distinguishing features are summarised in table 1. LCH is a rare disorder affecting one to two adults per million each year. It is a clonal myeloid neoplasm associated with BRAF V600E mutation, which results in constitutive activation of the mitogen-activated protein kinase signalling pathway which regulates critical cellular functions. The clinical presentation of LCH is variable depending on the site and number of organs involved. Bone, in particular the skull, is a commonly affected site. Extension of skull lesions may result in diabetes insipidus, proptosis, hearing loss, cranial nerve palsies and neurodegenerative symptoms such as cognitive decline and ataxia. Central nervous system disease is more common in lesions affecting the craniofacial bones excluding the skull vault.1 Bony lesions tend to be lytic compared with ECD, another rare multisystem histiocytic disorder, which tends to present with long bone pain and symmetrical osteosclerotic lesions. Skin is the second most common site of involvement and can be confused with eczema, Candida infection, vasculitis or cutaneous ECD. Haematopoietic system, liver and spleen involvement are less common and portend a worse prognosis.jclinpath;jclinpath-2018-205016v2/T1T1T1Table 1Histopathological and molecular characteristics of histiocytic neoplasmsMorphologyImmunohistochemistryMolecular diagnosticsLCHLangerhans cells have a convoluted nucleus and linear condensation of the chromatin, resulting in a coffee bean appearance. This combined with prominent accompanying eosinophils distinguishes LCH from the other differentials. Examining for Birbeck granules, a cytoplasmic organelle associated with CD207, under electron microscopy, has fallen out of favour due to time and cost concerns.Positive for CD68, CD1a, S-100 and CD207 (langerin).BRAF V600E mutation in up to 60% of cases.ECDFoamy histiocytes associated with inflammatory cells and giant multinuclear cells. Surrounding fibrosis present. There is only sparse lymphoplasmacytic infiltrate and eosinophils.Positive for CD68, CD163 and Factor XIIIa. Negative for CD1a and S100.BRAF V600E mutation is present in about 50% of ECD cases. Mutations involving PIK3CA, NRAS, KRAS, MAP2K1 and ARAF have been reported.RDDMixed infiltrate composed of numerous plasma cells and scattered large pale histiocytes. Emperipolesis, engulfment of intact lymphocytes or plasma cells within the cytoplasm of the histiocytes, is a helpful feature.Positive for S100, CD68 and CD163. Negative for CD1a.Not associated with BRAF mutations. Case reports of NRAS, KRAS and SMAD4 mutations.FDCSA rare dendritic cell sarcoma that is composed of syncytial sheets of dendritic cells with vesicular nuclei and accompanying lymphoplasmacytic cellular infiltrates.Positive for CD21, CD23, CD35, vimentin, fascin, human leucocyte antigen-DR and desmoplakin. May also express S100 and CD68.Associated with BRAF mutations, overexpression of epidermal growth factor receptor and programmed death ligand-1 and ligand-2 (PD-L1 and PD-L2).HSTumour cells are typically large with copious eosinophilic cytoplasm and prominent nucleoli. There is also notable cytologic atypia, necrosis and high proliferative activity.Positive for CD68, lysozyme, CD4 and CD163. Negative for CD1a and S100 protein.BRAF mutations have been seen in some case reports but is not uniformly present in all HS cases.ECD, Erdheim-Chester disease; FDCS, follicular dendritic cell sarcoma; HS, histiocytic sarcoma; LCH, Langerhans cell histiocytosis; RDD, Rosai Dorfman disease.Patients should be stratified into single system LCH (SS-LCH) with unifocal or multifocal organ involvement or multisystem LCH (MS-LCH), which entails two or more organs/systems involved, with or without 'risk organs' involvement. SS-LCH with unifocal bone involvement of 'non CNS Risk facial bones' requires only local therapy such as curettage and careful observation. Patients with MS-LCH should undergo a 6-week course of vinblastine and prednisone. Those who achieve complete remission should have maintenance therapy with 3 weekly vinblastine and prednisone and daily 6-mercaptopurine for a total treatment duration of 12 months. There is no consensus on the second line therapy for patients with relapse/refractory LCH. However, those with 'risk organs' involvement have shown response to 2-chlorodeoxyadenosine and cytarabine as well as reduced intensity conditioning stem cell transplantation.2 Further studies are required to evaluate targeted therapies such as tyrosine kinase inhibitors in patients with LCH with platelet-derived growth factor receptor alpha mutation3 as well as the use of BRAF V600E inhibitors dabrafenib and vemurafenib.4 Our patient's full blood count, renal and liver function, along with serum calcium were normal. A skeletal survey and whole-body PET/CT scan were both unyielding. He therefore had single-system LCH with unifocal bone involvement. There was no other indication for systemic therapy and he is currently well on outpatient follow-up. PMID: 30257852 [PubMed - as supplied by publisher]
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Related Articles Gene Delivery into the Inner Ear and Its Clinical Implications for Hearing and Balance. Molecules. 2018 Sep 30;23(10): Authors: Kanzaki S Abstract The inner ear contains many types of cell, including sensory hair cells and neurons. If these cells are damaged, they do not regenerate. Inner ear disorders have various etiologies. Some are related to aging or are idiopathic, as in sudden deafness. Others occur due to acoustic trauma, exposure to ototoxic drugs, viral infections, immune responses, or endolymphatic hydrops (Meniere's disease). For these disorders, inner ear regeneration therapy is expected to be a feasible alternative to cochlear implants for hearing recovery. Recently, the mechanisms underlying inner ear regeneration have been gradually clarified. Inner ear cell progenitors or stem cells have been identified. Factors necessary for regeneration have also been elucidated from the mechanism of hair cell generation. Inducing differentiation of endogenous stem cells or inner ear stem cell transplantation is expected. In this paper, we discuss recent approaches to hair cell proliferation and differentiation for inner ear regeneration. We discuss the future road map for clinical application. The therapies mentioned above require topical administration of transgenes or drug onto progenitors of sensory cells. Developing efficient and safe modes of administration is clinically important. In this regard, we also discuss our development of an inner ear endoscope to facilitate topical administration. PMID: 30274337 [PubMed - in process]
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Related Articles Vestibulotoxicity Associated With Platinum-Based Chemotherapy in Survivors of Cancer: A Scoping Review. Front Oncol. 2018;8:363 Authors: Prayuenyong P, Taylor JA, Pearson SE, Gomez R, Patel PM, Hall DA, Kasbekar AV, Baguley DM Abstract Background: Cochleotoxicity following the treatment with platinum-based chemotherapy is well documented. The potential for vestibulotoxicity is still unclear. This scoping review examined the extent of current research literature, summarized research findings and identified research gaps regarding vestibular-related adverse effects associated with platinum-based chemotherapy in survivors of cancer. Methods: Inclusion criteria followed the PICO principles: Participants, adult, and pediatric cancer patients of any cancer type; Intervention, platinum-based chemotherapy (such as cisplatin, carboplatin, and oxaliplatin); Control, none or any; Outcomes, vestibular-related adverse effects. English language articles published since 1978 were retrieved. Seventy-five eligible studies were identified from a systematic literature search, and relevant data were charted, collated, and summarized. Results: Testing for vestibulotoxicity predominately featured functional evaluation of the horizontal semicircular canal using the caloric and rotational tests. The rate of abnormal vestibular function test results after chemotherapy administration varied from 0 to 50%. The results of objective testing did not always correspond to patient symptoms. There is tentative support for patients with pre-existing loss of vestibular function to be more likely to experience vestibular toxicity after dosing with cisplatin. Conclusions: A number of studies reported significant evidence of vestibular toxicities associated with platinum-based chemotherapy, especially cisplatin. This scoping review emphasizes that vestibular toxicity needs more attention and comprehensive evaluation. Specifically, studies that analyse cumulative dose of platinum-based chemotherapy, affected sites of lesion in vestibular end organs, and the correlation and temporal patterns of cochlear and vestibular toxicity are needed. PMID: 30319960 [PubMed]
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Related Articles Pluripotent stem cell-derived cochlear cells: a challenge in constant progress. Cell Mol Life Sci. 2018 Oct 19;: Authors: Czajkowski A, Mounier A, Delacroix L, Malgrange B Abstract Hearing loss is a common affection mainly resulting from irreversible loss of the sensory hair cells of the cochlea; therefore, developing therapies to replace missing hair cells is essential. Understanding the mechanisms that drive their formation will not only help to unravel the molecular basis of deafness, but also give a roadmap for recapitulating hair cells development from cultured pluripotent stem cells. In this review, we provide an overview of the molecular mechanisms involved in hair cell production from both human and mouse embryonic stem cells. We then provide insights how this knowledge has been applied to differentiate induced pluripotent stem cells into otic progenitors and hair cells. Finally, we discuss the current limitations for properly obtaining functional hair cell in a Petri dish, as well as the difficulties that have to be overcome prior to consider stem cell therapy as a potential treatment for hearing loss. PMID: 30341460 [PubMed - as supplied by publisher]
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Related Articles Combined Growth Factor and Gene Therapy: An Approach for Hair Cell Regeneration and Hearing Recovery. ORL J Otorhinolaryngol Relat Spec. 2018 Oct 25;:1-12 Authors: Mahmoudian-Sani MR, Jamshidi M, Asgharzade S Abstract INTRODUCTION: Fibroblast growth factor, nerve growth factor neurotrophins, and insulin-like growth factor 1 are considered 3 families of growth factors that can be involved in the process of otic neurogenesis. In this respect, otic neurons can also be connected with mechanoreceptors in the ear, the hair cells (HCs), as well as the central nervous system. As a growth factor is combined with gene transfer technology, it can be used for hair cell regeneration. Gene therapy can be similarly employed to introduce genes into a system in order to induce the expression of genes for therapeutic agents, to replace defective genes, or to re-program supporting or surrounding cells to acquire the phenotype of lost or damaged cells in order to repair or regenerate the damaged tissue. OBJECTIVE: The purpose of this review article was to investigate the epigenetic and growth factors involved in the differentiation pathway of embryonic stem cells (ESCs) into HCs and auditory neurons (ANs). METHODS: To this end, the databases of Directory of Open Access Journals, Google Scholar, PubMed (NLM), LISTA (EBSCO), as well as Web of Science were searched. RESULTS: Given the results available in the related literature, the differentiation efficacy of ESCs toward the ANs and the HCs, the important role of growth factors, and 3 different strategies of application of miRNA, epigenetic regulation, and preparation of three-dimensional (3D) environments were suggested to be taken into consideration in order to improve these studies in the future. Furthermore, the role of epige-netic mechanisms and miRNA in this differentiation process became quite obvious; hence, the utilization of such procedures in the near future would be significant. CONCLUSION: Combining several techniques with a synergic effect (such as growth factor gene therapy and 3D environments) seemed to lead to obtaining the best results as a therapeutic strategy. PMID: 30359973 [PubMed - as supplied by publisher]
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Related Articles The Effect of the MicroRNA-183 Family on Hair Cell-Specific Markers of Human Bone Marrow-Derived Mesenchymal Stem Cells. Audiol Neurootol. 2018 Oct 31;23(4):208-215 Authors: Mahmoudian-Sani MR, Jami MS, Mahdavinezhad A, Amini R, Farnoosh G, Saidijam M Abstract Hearing loss is considered the most common sensory disorder across the world. Nowadays, a cochlear implant can be an effective treatment for patients. Moreover, it is often believed that sensorineural hearing loss in humans is caused by loss or disruption of the function of hair cells in the cochlea. In this respect, mesenchymal cells can be a good candidate for cell-based therapeutic approaches. To this end, the potential of human bone marrow-derived mesenchymal stem cells to differentiate into hair cells with the help of transfection of microRNA in vitro was investigated. MicroRNA mimics (miRNA-96, 182, and 183) were transfected to human bone marrow-derived mesenchymal stem cells using Lipofec-tamine as a common transfection reagent following the manufacturer's instructions at 50 nM for microRNA mimics and 50 nM for the scramble. The changes in cell morphology were also observed under an inverted microscope. Then, the relative expression levels of SOX2, POU4F3, MYO7A, and calretinin were assayed using real-time polymerase chain reaction according to the ΔΔCt method. The ATOH1 level was similarly measured via real-time polymerase chain reaction and Western blotting. The results showed that increased expression of miRNA-182, but neither miRNA-96 nor miRNA-183, could lead to higher expression levels in some hair cell markers. The morphology of the cells also did not change in this respect, but the evaluation of gene expression at the levels of mRNA could promote the expression of the ATOH1, SOX2, and POU4F3 markers. Furthermore, miRNA-182 could enhance the expression of ATOH1 at the protein level. According to the results of this study, it was concluded that miRNA-182 could serve as a crucial function in hair cell differentiation by the upregulation of SOX2, POU4F3, and ATOH1 to promote a hair cell's fate. PMID: 30380528 [PubMed - as supplied by publisher]
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Related Articles Otologic, audiometric and speech findings in patients undergoing surgery for cleft palate. BMC Pediatr. 2018 Nov 08;18(1):350 Authors: Garcia-Vaquero C, Mir C, Graterol D, Ortiz N, Rochera-Villach MI, LLeonart ME, Lorente J Abstract BACKGROUND: Although considerable progress has been made in the last 30 years in the treatment of cleft palate (CP), a multidisciplinary approach combining examinations by a paediatrician, maxillofacial surgeon, otolaryngologist and speech and language pathologist followed by surgical operation is still required. In this work, we performed an observational cross-sectional study to determine whether the CP grade or number of ventilation tubes received was associated with tympanic membrane abnormalities, hearing loss or speech outcomes. METHODS: Otologic, audiometric, tympanometric and speech evaluations were performed in a cohort of 121 patients (children > 6 years) who underwent an operation for CP at the Vall d'Hebron Hospital, Barcelona from 2000 to 2014. RESULTS: The most and least frequent CP types evaluated according to the Veau grade were type III (55.37%) and I (8.26%), respectively. A normal appearance of the membrane was observed in 58% individuals, of whom 55% never underwent ventilation ear tube insertion. No statistically significant associations were identified between the CP type and number of surgeries for insertion of tubes (p = 0.820). The degree of hearing loss (p = 0.616), maximum impedance (p = 0.800) and tympanic membrane abnormalities indicative of chronic otitis media (COM) (p = 0.505) among examined patients revealed no statistically significant association with the grade of CP. However, an association was identified between hypernasality and the grade of CP (p = 0.053), COM (p = 0.000), hearing loss (p = 0.000) and number of inserted ventilation tubes. CONCLUSION: Although the placement of tympanic ventilation tubes has been accompanied by an increased rate of COM, it is still important to assess whether this is a result of the number of ventilation tubes inserted or it is intrinsic to the natural history of middle ear inflammatory disease of such patients. Our results do not support improvements in speech, hearing, or tympanic membrane abnormalities with more aggressive management of COM with tympanostomy tubes. PMID: 30409226 [PubMed - in process]
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Related Articles DNA methylation dynamics during embryonic development and postnatal maturation of the mouse auditory sensory epithelium. Sci Rep. 2018 Nov 26;8(1):17348 Authors: Yizhar-Barnea O, Valensisi C, Jayavelu ND, Kishore K, Andrus C, Koffler-Brill T, Ushakov K, Perl K, Noy Y, Bhonker Y, Pelizzola M, Hawkins RD, Avraham KB Abstract The inner ear is a complex structure responsible for hearing and balance, and organ pathology is associated with deafness and balance disorders. To evaluate the role of epigenomic dynamics, we performed whole genome bisulfite sequencing at key time points during the development and maturation of the mouse inner ear sensory epithelium (SE). Our single-nucleotide resolution maps revealed variations in both general characteristics and dynamics of DNA methylation over time. This allowed us to predict the location of non-coding regulatory regions and to identify several novel candidate regulatory factors, such as Bach2, that connect stage-specific regulatory elements to molecular features that drive the development and maturation of the SE. Constructing in silico regulatory networks around sites of differential methylation enabled us to link key inner ear regulators, such as Atoh1 and Stat3, to pathways responsible for cell lineage determination and maturation, such as the Notch pathway. We also discovered that a putative enhancer, defined as a low methylated region (LMR), can upregulate the GJB6 gene and a neighboring non-coding RNA. The study of inner ear SE methylomes revealed novel regulatory regions in the hearing organ, which may improve diagnostic capabilities, and has the potential to guide the development of therapeutics for hearing loss by providing multiple intervention points for manipulation of the auditory system. PMID: 30478432 [PubMed - in process]
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